Marihuana and health

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Title:
Marihuana and health
Physical Description:
: ; 24 cm.
Language:
English
Creator:
United States -- Dept. of Health, Education, and Welfare
United States -- Congress. -- Senate. -- Committee on Labor and Public Welfare. -- Subcommittee on Alcoholism and Narcotics
Publisher:
U.S. Govt. Print. Off.
Place of Publication:
Washington
Frequency:
annual
regular
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Doc. ed.

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Subjects / Keywords:
Marijuana -- Physiological effect -- Periodicals   ( lcsh )
Drugs -- Physiological effect -- Periodicals   ( lcsh )
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federal government publication   ( marcgt )

Notes

Bibliography:
Includes bibliograpical references.
Dates or Sequential Designation:
1st- 1971-
General Note:
"Annual report to the U.S. Congress from the Secretary of Health, Education, and Welfare, prepared for the Subcommittee on Alcoholism and Narcotics of the Committee on Labor and Public Welfare, United States Senate"
General Note:
At head of title: 94th Congress, 2d session. Committee print.
General Note:
1975.

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University of Florida
Rights Management:
All applicable rights reserved by the source institution and holding location.
Resource Identifier:
aleph - 026112951
oclc - 01124763
System ID:
AA00024883:00001

Related Items

Related Items:
Departmental edition

Full Text
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94th eongress COMMITTEE PRINT
2d4Sessonge } L OF UNI.V OIELU


DOCUMENTS DEPT.


MARIHUANA AND HEALTH


FIFTH ANNUAL REPORT
TO THE

U.S. CONGRESS
FROM THE

SECRETARY OF HEALTH, EDUCATION,

AND WELFARE, 1975

PREPARED FOR THE

SUBCOMMITTEE ON ALCOHOLISM AND NARCOTICS

OF THE

COMMITTEE ON LABOR AND

PUBLIC WELFARE

UNITED STATES SENATE


AUGUST 1976


Printed for the use of the Committee on Labor and
Public Welfare


U.S. GOVERNMENT PRINTING OFFICE
WASHINGTON : 1976


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COMMITTEE ON LABOR AND PUBLIC WELFARE
HARRISON A. WILLIAMS, JR., New Jersey, Chairman


JENNINGS RANDOLPH, West Virginia
CLAIBORNE PELL, Rhode Island
EDWARD M. KENNEDY, Massachusetts
GAYLORD NELSON, Wisconsin
WALTER P. MONDALE, Minnesota
THOMAS F. EAGLETON, Missouri
ALAN CRANSTON, California
WILLIAM D. HATHAWAY, Maine
JOHN A. DURKIN, New Hampshire


JACOB K. JAVITS, New York
RICHARD S. SCHWEIKER, Pennsylvania
ROBERT TAFT, JR., Ohio
J. GLENN BEALL. JR., Maryland
ROBERT T. STAFFORD, Vermont
PAUL LAXALT, Nevada


DONALD ELISBURG, General Counsel
MARJORIID M. WHITTAKER, Chief Clerk
JAY B. CUTLER, Minority Counsel



SUBCOMMITTEE ON ALCOHOLISM AND NARCOTICS
WILLIAM D. HATHAWAY, Maine, Chairman


JENNINGS RANDOLPH, West Virginia
HARRISON A. WILLIAMS, Jn., New Jersey
EDWARD M. KENNEDY, Massachusetts
WALTER F. MONDALE, Minnesota
ALAN CRANSTON, California
JOHN A. DURKIN, New Hampshire


RICHARD S. SCHWEIKER, Pennsylvania
JACOB K. JAVITS, New York
J. GLENN BEALL, JR., Maryland
PAUL LAXALT, Nevada


LARRY GAGE, Counsel
JAY B. CUTLER, Minority Counsel
(n)













FOREWORD


The ongoing debate over marihuana has always been among the
most schizophrenic of our national drug abuse policy issues.
On the one hand. we are struggling toward an understanding of the
complex dysfunctional effects of heroin on our society, and attempting
vigorously to develop programs to reduce both the supply and demand
of this, as well as other dangerous illicit drucs.
In addition. we are taking a cold, hard look at many of our pre-
scription and over-the-counter drugs, asking whether there needs to
be further restrictions or more rigorous controls over many of them,
due to the adverse health consequences they may well entail.
We are looking with disfavor, for example, upon our increasing
reliance on tranquilizers and other anti-depressant drugs. We are
viewing with alarm the hawking of over-the-counter remedies during
popular, child-oriented television programs, commercials which teach
our children that one drug is better than another for a headache-
but not (as psychiatrist Gerald Shulman pointed out in recent hear-
ings) that a headache is a perfectly natural way for the human body
to express its own momentary need for relaxation and quiet, and that
dulling the pain could sometimes be the worst possible solution to that
type of medical problem.
We are worried, in short, about becoming a chemical culture. a na-
tion of people whose solution to every little problem is a drink or a
pill.
Only with regard to mariihuana. on the other land, do liberall "
minds appear to be moving in the opposite direction.
Many States are coiidering the decriminalization of the possession
of marihuana. and some have already enacted such laws.
For the first time, national survey data indicate that a majority of
persons in the 18 to 25 age bracket have tried marihuana. Thus, even
if the drug is to become completely legal. as is alcohol or tobacco. it
would be even more important for us to understand as many of its
potential health consequences as is possible. For it is important to
bear in mind that. while heavy penalties for possession or use do not
themselves create (or even necessarily reflect) sinister medical dangers
from a substance, neither does legalization or decriminalization magi-
cally remove any such dangers, if they actually exist.
It is imperative, then, regardless of our opinion about decriminali-
zation, that we continue our inquiry into the health consequences of
marihuana use and abuse. This Fifth Annual Report makes many
valuable contributions to that inquiry.
HARRISON A. IWILLIAMS, Jr.,
Chairman.
(iii)



















Digitized by the Internet Archive
in 2013













http://archive.org/details/marihuanahunit










LETTER OF TRANSMITTAL


U.S. SENATE,
COxMMEE ON LABOR AND PUBLIC WELFARE,
Washington, D.C., July 21,1976.
Hon. HARRISOx A. WILLTAMS. Jr.,
Chairman, Committee on Labor and Public Welfare, DIr~ksen Senate
Office Building, Washington, D.C.
DEAR MR. CIIAIIRMiiAN: I am pleased to transmit to you the fifth an-
nual report by the Secretary of Health, Education, and Welfare on
Marihuana and Health. The annual publication of this report is re-
quired by Title V of Public Law 91-296. It contains the latest scientific
findings on the health consequences of marihuana use. This report has
proven to be a valuable educational tool and policy guide to inform
the public on the issues surrounding the effects of using (and abusing)
marihuana.
I am pleased, therefore, to transmit MJarihuana and Health, Fifth
Annual Report to the U.S. Congress from the Secretary of Health,
Education, and Welfare to you and to recommend its distribution by
the Committee.
Sincerely,
WILLIA.M D. HATHAWAY,
Chairman, Subcomm ittee on
Alcohol .m?, & Narcotics.









ACKNOWLEDGMENTS


As has been true in the past, preparation of the fifth annual Mari-
huana and Health Report was made easier by the generous cooperation
of the many members of the scientific community who supplied useful
information on their current inarihuana research. Their contribution
is gratefully acknowledged.
The technical chapters were written by knowledgeable members of
the research community who generously gave of their time on short
notice to maintain a tight production schedule. They are:
Dr. Sidney Cohen, University of California at Los Angeles, Chap-
ter 9, Therapeutic Aspects;
Dr. Douglas Ferraro, University of New Mexico, Albuquerque,
Chapters 4, 5 and 6, dealing with preclinical unlearned and learned be-
havior and with chronic effects on both;
Drs. Lissy Jarvik and Steven Matsuyama, University of Califor-
nia at Los Angeles, Chapter 8, Effects on the Genetic and Immune
Systems;
Dr. Reese Jones, Langley-Porter Neuropsychiatric Institute, San'
Francisco, Chapter 7, Human Effects;
Dr. Ralph Karler, University of Utah, Chapters 2 and 3, dealing
with Chemistry and Metabolism and with Toxicological and Pharma-
cological Effects; and
Dr. William McGlothlin, University of California at Los Angeles,
Chapter 1, Epidemiology of Marihuana Use.
Scientists on the staff of the National Institute on Drug Abuse who
contributed to the report in a variety of ways include: Drs. Monique
Braude, Norman Krasnegor, Daniel Lettieri, William Pollin, Joan
Rittenhouse, Louise Richards, Stephen Szara, Robert Willette and
Ms. Eleanor Carroll.
Thanks are also due to Ms. Georgette Semick, Carol Tuckerman and
Dr. Michael Rumsey for their editorial and production skills.
Dr. Robert C. Petersen wrote the summary of the Report and as
senior editor had primary responsibility for its overall preparation.


(VI)













CONTENTS

Page
Foreword--------------------------------------------------------- iii
Letter of Transmittal----------------------------------------------- v
Acknowledgements------------------------------------------------- vi
Introduction------------------------------------------------------- 1
Marihuana and health, 1975: Summary and overview----------------- 3
Technical chapters:
1. Epidemiology of marihuana use-------------------------------- 17
Present patterns and changes in use----------------------- 17
Social and psychological correlates------------------------ 22
References---------------------------------------------- 25
2. Chem i.try and metabolism -------------------------------------- 27
Drug sources-------------------------------------------- 28
Analytical techniques: Detection-------------------------- 28
Metabolism--------------------------------------------- 30
References----------------------------------------------- 32
3. Toxicological and pharmacological effects------------------------ 35
Toxicological effect.--------------------------------------- 36
Pharmacological effects ---------------------------------- 39
References --------------------------------------------- 46
4. Preclinical effects: Unlearned behavior-------------------------- 51
Gross behavior------------------------------------------ 51
Activity and expli-ration--------------------------------- 52
Consumimatory behavior---------------------------------- 53
Aggressive behavior- ------------------------------------ 54
References--------------------------------------------- 57
5. Preclinical effects: Learned behavior---------------------------- 61
Avoidance learning and aversive control ------------------- 61
Reinforcement schedules and maze learning---------------- 62
Discrimination learning- --------------------------------- 64
References---------------------------------------------- 66
6. Preclinical chronic effects: Unlearned and learned behavior --------- 69
References---------------------------------------------- 72
7. Human effects----------------------------------------------- 75
Acute effects---------------------------------------- 75
Cannabis and psychopathology--------------------------- 84
Chronic effects------------------------------------------- 88
References --------------------------------------------- 91
8. Effects of marihuana on the genetic and imnmnun-e systems ----------- 99
Animal studies------------------------------------------- 99
Human studies------------------------------------------ 100
Summary and conclusion--------------------------------- 104
References--------------------------------------------- 106
9. Therapeutic a.,pects, ------------------------------------------ 109
The Ancient Lore--------------------------------------- 110
The Middle Period-------------------------------------- ill
The Current Period-------------------------------------- 112
Summary---------------------------------------------- 119
References--------------------------------------------- 120
Indexes:
Author index-------------------------------------------------- 123
Subject index------------------------------------------------- 121
(vI)














INTRODUCTION


Marihuana, an issue once marked by emotionalism, is increasingly
being examined thoughtfully. Much has been learned about mari-
huana use and its personal and social consequences. Yet, much remains
to be understood. It is clear that marihuana is not a subject for sim-
plistic analysis.
This present edition of "Marihuana and Health" represents the fifth
in a series of annual reports from the Secretary of Health, Education,
and Welfare to the Congress as required by Title V of Public Law
91-296. Last year, the fourth report in this series raised fundamental
questions about the role of cannabis in altering the body's immune
response, endocrine functioning and basic cell metabolism. Although
more data are now available, the direct health implications of these
earlier laboratory findings are still not certain.
There is little question that marihuana intoxication, like alcohol
intoxication, poses significant hazards. For example, psychomotor per-
formance is impaired by cannabis intoxication. This can have dan-
gerous consequences in such areas as traffic safety and industrial per-
formance. Intellectual performance and in particular, immediate mem-
ory, are also impaired while under the influence of the drug. Since
marihuana is the third most widely used -recreational drug-exceeded
only by alcohol and tobacco-any adverse implications of its use are
likely to be far-reaching.
It has become increasingly clear that marihuana use is inextricably
bound up with the use of many other drugs. Those who use other licit
and illicit drugs are far more likely to use marihuana than those who
do not. Conversely, heavy marihuana users are more likely than those
who are not, to use other drugs as well. While it was once thought, for
example, that marihuana users were less likely to use alcohol than non-
users, it is now evident that they are, in fact, more likely to do so.
Frequently the two drugs are used simultaneously-a combination that
may be more hazardous than either used alone.
The increasing availability of higher potency materials makes it
more likely that adverse consequences will ensue if the use of these
stronger cannabis preparations becomes widespread.
This report does not give marihuana a "clean bill of health," as some
would hope. Nor does it support the fear and irrationality that still
characterize some of the public debate about marihuana. Instead, it is a
progress report on our effort to understand a challenging health prob-
lem with immense social, political, and economic implications.
This year, in order to provide a somewhat broader perspective, the
report is being issued as a general overview accompanied by a series of
technical chapters which discuss the research findings in greater detail.
In this manner we hope to better serve the needs of both the general
reader and the research specialists.
ROBERT L. DUPONT, M.D.,
Director, National Institute on Drug Abuse.
(1)















SUMMARY


MARIHUANA AND HEALTH- 1975: SUMMARY AND OVERVIEW

EXTENT AND NATURE OF USE
Present evidence indicates that cannabis use has significantly in-
ercased among Americans during the last two years.
Throughout most of its history American marihuana use has con-
sistently involved a minority of any national age group; however, the
most recent national survey data indicate that in the 18-25 age group
a majority (53%) have now tried the drug, up from 48% in 1972.
Among those surveyed under 18, nearly one in four (23%) has ever
tried marihuana-an increase from the one in seven (14%) who re-
ported in the 1972 survey ever having done so.
Current use-defined as use within the past month preceding the
survey-has also significantly increased among those under 18. Seven
perce11t reported such use in 1972, 12% did so in the most recent survey.
There does not appear to have been a similar increase in such use
among those over 18-among whom current use has remained the same
or has slightly diminished depending on age. since 1972.
When questioned regarding their plans for future use, one third of
those who have used marihuana indicate they definitely intend to do
so again. Another third of this group indicate they might do so.
Slightly smaller numbers of adults than of youths indicated their in-
tention to continue use (1-1).
While there has been an increase in use by high school and junior
high school age groups (attested to by both local and national survey
results), future trends of marihuana use in America continue to be
uncertain. Despite the other increases noted, use among adults has not
increased. In part, this may be explained by research reported in the
fourth Marihuana, and Health report: changes such as marriage,
parenthood and the assumption of other adult roles are inimical to
continued marihuana use.
Support for the above interpretations is also found in data garnered
from research conducted on a. national sample of 20-30 year old men.
This nationwide survey found that even within this restricted age
group, larger proportions of the men in the younger subgroups used
marihuana than did those who were older. Men pursuing more conven-
tional life, styles in that they were married and employed full time,
were considerably less likely to be using marihuana than were either
the unmarried or the unemployed (1-23).
Although there is good evidence of a continuing increase in mari-
huana use among younger people, there is little indication that such
NOTE.-Numbers in parentheses refer to the several technical chapters and their lists
of references. Thus. 1-1 refers to reference one in Chapter 1. This is the specific study from
which the data are abstracted.
(3)






Tuse has come to involve a significant proportion of the older popula-
tion. For example, if we examine the behavior of those ages 26-34,
in contrast to the 18-25 age group less than one third (29%) have ever
used marihuana compared to over half (53%) of the younger group.
One in four of the 18-25 group had, in fact, used in the month pre-
ceding the survey but less than one in twelve (8%) of those 26-34 had
done so. In still older age groups use is even less common. Only 7% of
those between 35-49 have ever used and only 2% of those over 50 have
ever done so. Less than one in one hundred of the over 35 group had
used during the month prior to the interview (1-1).
Despite the indications that marihuana has not become popular with
older groups and the evidence that its use may be diminished as adult
roles are adopted, any prediction regarding the future of cannabis in
American society must be hedged with caution. A Gallup poll con-
ducted in 1967 among college students indicated that only one in twenty
had ever used the substance, but by 1974 over half (55%) reported use
in the Gallup survey (1-9). In seven years, what was once clearly
statistically deviant behavior has become the norm for this age group.
While in previous years use was correlated with level of education, the
percentage now reporting marihuana use is virtually identical for high
school drop-outs, high school graduates and college graduates in simi-
lar age ranges.
National trends and use patterns mask distinctly different patterns
in particular communities or geographical areas. In one Northern
California county in which a survey of junior and senior high school
students has been conducted each year since 1968, even the earliest
findings indicated over one quarter of the ninth grade males (27%'c)
had had some experience with marihuana during the previous year.
Among male seniors nearly half (45%) reported use in the year pre-
ceding. Current (1975) comparable figures are now 49% for ninth
graders and 64% for senior boys. However, the percentage reporting
use on 50 or more occasions in the previous year has not markedly in-
creased for the past five consecutive years (1971-1975) (1-4).
During the past five years since the first Marihuana and Health re-
port, cannabis use in the United States has changed in character. Origi-
nally marihuana's popularity was concentrated among young people
associated with a "counter culture." It was regarded as symbolic of
their opposition to traditional values and to the prevailing political
climate (Cf. the first Report. 1971).
As use has spread to involve larger numbers and to more conserva-
tive segments-it has now been experienced by a majority in many
groups-it has lost some of its nontraditional, antiestablishment sym-
bolism. Early use often involved opposition to more traditional alcohol
use. Now those who use marihunna are also very likely to use alcohol-
frequently simultaneously. Marijuana use seems unlikely to displace
more traditional alcohol use even among the young. Continuing re-
search on patterns of multiple drug use and drug using contingencies
may better enable us to predict both individual and group drug use.
Use patterns in other countries, even those in which cannabis use
has been endemic for many years., provide few clues to future use in
the United States. In other countries use is typically class related with
the lower classes. the traditional users. While in some of these coun-






5

fries of traditional use thire are now middle or upper class users, such
users seem to have adopted marihuana as part of an international
youth culture rather than by diffusion from native users. Expectations
with respect. to drug effects also differ in that traditional users do
not share the recreational orientation that characterizes American
users.
CHEMISTRY AND CHARACTERISTICS OF CANNABIS
Although a detailed discussion of developments in cannabinoid
chemistry is of primary interest to the specialist, there is a range of
developments of more general interest. The plant, cannabis sativa, far
from being a simple substance is, in fact, chemically quite complex.
The last several years of research have resulted in an increasingly
sophisticated knowledge about this complex substance. There is a grow-
ing awareness of the need to much more adequately describe several
major cannabis constituents if we are to adequately specify the nature
of the material. The United Nations has now recommended that all
research reports on cannabis describe not only the amount of delta-9-
tetrahydrocannabinol (the major psychoactive ingredient) but that of
cannabidiol and cannabinol as well.
The ability to synthesize various chemical components of mari-
huana as well as the drug's metabolites (i.e., compounds resulting from
the biological transformation of the originally ingested material) is a
significant advance. Availability of such pure substances provides re-
searchers with necessary materials for careful study of the physio-
logical role of marihuana's various components.
While primary interest has tended to center on delta-9-THC because
of its role as the principal psychoactive ingredient in cannabis, the
part played by several other ingredients may be important in produc-
ing other cannabis effects. These other ingredients alone or in combina-
tion, may account for possible adverse health consequences or con-
tribute to the possible therapeutic usefulness of the drug.
The detection and analysis of marihuana in body contents such as
blood, saliva, urine and breath is a problem important both to basic
research and to forensic medical applications. For research, it is im-
portant to develop methods that accurately determine how much
smoked or otherwise ingested marihuana actually becomes physio-
logically available. These amounts may be substantially different than
the amount ingested because of losses that occur in consuming mari-
huana, delayed bodily absorption, and individual differences in ability
to metabolize the drug.
In the clinical setting, appropriate treatment of the unconscious
patient brought to the Emergency Room following an accident may be
dependent on knowing whether he or she is marihuana intoxicated. In
other medical situations being able to determine with certainty the
level or fact of being intoxicated may make the diagnosis of the
patient much easier.
The general increase in marihuana use has undoubtedly brought
with it an increase in the numbers who drive while cannabis intoxi-
cated. Recent evidence (Cf. Driving Effects) further confirms cannabis
adversely affects driving. Thus, there is a real need for the develop-
ment of one or more roadside methods that can be rapidly employed
in much the same way as current tests for alcohol intoxication.






Although simple, rapid detection methods are badly needed, detect-
ing marihuana use is inherently much more difficult than detecting
alcohol use. The quantities of drug involved are much smaller and
they are very rapidly transformed into metabolites which differ chemi-
cally from the originally consumed material. As with alcohol, it is
important to quantify the level of use for all of the purposes outlined.
During the past year considerable progress has been made in improv-
ing detection techniques.
In addition to newer, thin played chromatography and high pressure
liquid chromatography methods, two other techniques have shown un-
usual promise. Radioimmunoassay (RIA) is a technique. in which an
antibody specific to a drug or its metabolites is developed and then
"tagged" by means of a radioactive molecule. in its structure. When
a solution of the tagged antibodies and of the body fluid in which the
drug to be detected is made, the radioactive markers are displaced
proportionately to the drug quantity present.. The accuracy of RIA
is now being compared with that. of more cumbersome procedures.
A second technique under development is called the enzyme multi-
plied immunoassay test, or EMIT. The antibody reaction which is its
basis is similar to that used in the radioimmunoassay technique.
EMIT has the added advantages of involving less work, less sophisti-
cated equipment and is more rapid thus making it more suitable for
rapid screening. Field trials on EMIT are ongoing.
A third method which also shows promise of shortly becoming
available is likely to be most useful for traffic safety purposes. It
utilizes breath samples in a manner roughly analogous to present road-
side alcohol intoxication detection.
As lias been repeatedly emphasized, marihuana and hashish vary
widely in THC content and thus in their ability to intoxicate. This
variability results from differences in plant genetic origin, conditions
of cultivation and preparation of the material including the degree
of concentration of leaves and flowering tops. A relatively recent addi-
tion to the illicit market is hashish oil, a substance having a THC con-
centration of 40-50% as compared to the 1-2% THC content of most
ma rihuana ordinarily available in the United States. Increasing avail-
ability of such more potent cannabis preparations may have quite
different implications from the more commonly used, weaker prepara-
tions that have been available in the past. Use of stronger material,
particularly by relatively naive users unaccustomed to its effects, is
considerably more likely to result in acute panic and other adverse
reactions. Stronger cannabis and cannabis derivatives used under con-
ditions in which the dose is more difficult to control, may also result
in marked impairment. in driving or other complex psychomotor skills.
Such unexpected effects could have serious implications.
ANIMAL RESEARCH
A wide. range of research on the effects of marihuana has been con-
ducted with animals because their genetic and learning histories, un-
like those of humans, can be accurately specified. Animal models also
permit the use of high doses and other procedures not possible in
human research. Apart from studies of various physiological effects






of the drug which have been discussed primarily in relation to human
findings, there are some behavioral observations in animals that are
of interest.
Because there has been some question about the role of marihuana
as a possible release of azoression, studies of animal aggression fol-
lowing marihuana or THC administration have beeii done. Generally,
these drugs have been consistently found to suppress aggression when
the animals are not under 4 re-s. When animals are stressed by a
variety of means (e.g., food deprivation, sleep deprivation, morphine
withdrawal, etc.) THC or marihuana tends to increase aggression.
The results of behavioral studies in animals sugge-t that the effects
of cannabis on aggres-ion may be complexly related to the degree to
which the animal is subject to stress and the length of time over which
it has received the drug. The degree to which these observations are
relevant to liumim behavior is unknown although they do provide a
basis for devising related human studies.
In an experiment which studied monkeys in three to six member
social groups several changer- of interest were found. Given oral doso--
equivalent to very heavy hunian cannal is use. the monkeys respond--1
much like. humans. They slept and rested more f IeqIuentlyv active social
interaction such as groominig of others was reduced. Over more ex-
tended periods of administration, the monkeys gradiially show2'd ms.-
and less of the.e etfects. While a !s-io was initially reduced. after
receiving THC for weeks or months during the vear-longz study the
monkeys became irritable and ag^'re--ive (hitting biting., cliasino be-
havior increased). There was no evidence of tlie reduction in te.-tos-
terone levels that has been reported in hiiniais nor were inei-triial
cycles of females apparently disturbed (4-67).
More detailed discivi-;ion of the extensive re-earch that has been
done with animals is to be found in the technical chapters of this report.

HUMAN EFFECTS AND HEALTH IMPLICATIONS
Effects of marihuana can conveniently be divided into: (1) the acute
effects of caflnalis intoxication and (2) the longer range consequences
of regular or chronic use. It is considerably easier to study acute effects
and so after eight years of intensive investigations many, if not most,
of these effects have been elucidated.
Human acute physiological effects
An increase in heart rate and a reddening of the eyes have been the
most consistently reported physiological effects of ia iarihu ana. Heart
rate increa-es are closely dose related. Early awareness of this ma, -
huana-induced tachycardia created concern over po-.-ible adverse car-
diovascular effects of the drug especially in those with coronary disease.
Several reports issued in the past year have confirmed a preliminary
finding from last year. Marijuana use decreases exercise tolerance
prior to the onset of chest pain (angina) in those with heart di-ease
(7-137, 3, 4). Use of those with already existing cardiovascular defi-
ciencies, therefore. appears to be unwise. The contrasting finding that
marihuana produces minimal changes in heart function (aside from a
rate increase) in young, healthy men illustrates that the drug's effects








may significantly differ in persons with pre-existing medical problems
from those in normals.
A number of reports have confirmed and extended initial evidence
that smoked marihuana when acutely administered, results in improved
pulmonary function as measured by bronchodilation (7-156,157,158).
Optimism created by this finding has since been tempered by evidence.
that under conditions of more chronic use pulmonary function is im-
paired, rather than enhanced (7-62).
Evidence that marihuana and especially its principal psychoactive
ingredient, delta-9-THC, are effective in reducing intraocular pres-
sure in both normals and in glaucoma patients has been further con-
firmed. While some question exists whether this effect is due to a non-
specific drug-induced relaxation shared with other sedative drugs or-
to a more specific marihuana reaction, more recent evidence suggests
it is THC-specific (Cf. Therapeutic Aspects).
Understanding of the metabolism and the mechanisms of action re-
sponsible for various marihuana effects has increased although many
questions remain open.
More sophisticated attempts to measure various aspects of psycho-
logical and psychomotor performance have been generally consonant
with subjective reports. Impaired memory, altered time sense and per-
formance decrements on a variety of tasks have been experimentally
confirmed. Generally, the more complex the task, the greater the de-
gree of disruption produced by acute intoxication. Tasks which are
relatively simple and with which the person is familiar are minimally
affected. As the task becomes more demanding and novel and/or the
dose of drug increases, performance decrements become larger. At
lower doses, evidence confirms users' assertions that they are often
able to "suppress the marihuana high" when the situations so demand.
Although users have reported enhanced auditory, visual and tactual'
awareness and sensitivity, experimental research has not confirmed'
these reports.
Driver performance and traffic safety
Because of the prominent role the automobile plays in our society,
the possible implications of marihuana intoxication for traffic safety
hav'- been emphasized. Early reports were more optimistic about driver
performance than recent evidence. Those consuming alcohol to the-
level of legal intoxication were originally found to make significantly
more driving errors in a driving simulator situation than those who
had consumed at "social dose" of marihuana. While the marihuana-
intoxicated subjects indicated that their driving performance was af-
fected, they felt they could compensate. by driving more slowly and
cantioucsly.
Present evidence, whether derived from driver test course perform-
ance, from actual traffic conditions or from the experimental study
of components of the driving task, all indicate that driving under the
influence of marihuana is hazardous (7-90). The increasing simultane-
ous use of both alcohol and marihuana by drivers poses a threat that
may well exceed that of either substance alone. While the parameters
of risk connected with the use. of marihuana alone or in combination
with alcohol prior to driving are not yet known, discouragement of








such use appears justified. A more accurate determination of the ex-
tent of risk involved in the various levels of intoxification would be
desirable. Such studies are complicated by individual differences but
are by no means impossible to execute.
Although there has been little systematic study of the relationship
of inarihuana smoking to possible pilot error, evidence related to
driving is at least partially germane. Such skills as detection of pe-
ripheral stimuli and complex psychomotor coordination involved in
driving are probably equally important in flying. In fact, the inher-
ently greater complexity of flying suggests that performance is even
more likely to be impaired under conditions of marihuana intoxica-
tion than is driving. Only one preliminary report of pilot performance
has appeared in the research literature. This report indicates that
under flight simulator test conditions experienced pilots show marked
deterioration in their performance while marihuana intoxicated
(7-108). More detailed studies are planned to better understand the
nature of the performance deficits produced and their duration. A
danger common to both driving and flying is that some perceptual
or other deficits may persist for some time beyond the period of sub-
jective intoxication. Under such circumstances an individual may
attempt to fly or drive without realizing that his functioning is still
impaired although he no longer feels "high."
Chroliic use-special problem areas
Last year's report singled out several special problem areas involv-
ing potentially serious adverse consequences of chronic cannabis use.
Subsequent research has not definitively resolved the questions rai.-ed
but has expanded our knowledge base.
Some apparent inconsistencies in research findings regarding re-
duced plasma levels of the male hormone, testosterone, may be ex-
plained by the differing length of time users had been smoking before
such levels were assessed. For example, the findings of one study that
did not show a decrease during a several week period were matched
by those in another study in which there were early negative findings.
However, after four weeks elapsed a definite drop occurred (7-100).
The decreases that have been found have still been within what are
generally conceded to be normal limits. Their biological significance
remains in considerable doubt. A preliminary finding that a marked
reduction of sperm count (58%) occurred in five cannabis smokers fol-
lowing controlled conditions of smoking has been reported (7-171).
While this poses the possibility of diminished fertility in chronic
users, the small size of the sample and the study's preliminary nature
make the work inconclusive.
With regard to hormonal aspects, two other adverse effects remain
possibilities: (1) Interference with normal growth and sexual develop-
ment of adolescent heavy users and, (2) Abnormal sexual differentia-
tion of the male fetus developing in a mother who heavily uses mari-
huana during early pregnancy. No actual evidence for either of tliu
speculative. possibilities has yet appeared in the scientific literature.

The question of a cannabis induced impairment of the body's im-
mune response remains important because of its potentially far reach-


67-062-76-2






ing clinical implications. While a number of investigators have
published findings that suggest that marihuana may interfere with
r''ll-in'~l iat~'d im jh', ntber investilrntors have not found such
evidence. Some of these differences may reflect procedural variations;
nevertheless, the clinical significance of the positive findings remains
in considerable doubt. At least one study of experienced marihuana
smokers under well-controlled, closed experimental ward conditions
found initial evidence of impaired immunity upon their admission to
the study. However, by the C03rd day of controlled cannabis adminis-
tration, their immune response had -apparently returned to normal
(8-39). This finding suggests that. the impairment of immunity ini-
tially detected in these and oiher marihuana smokers may be related
to factors other than mnarihuana use.
The implications of laboratory findings of inhibition of DNA, R'NA
and protein synthesis. all basically related to cellular reproduction and
metabolism, are at present unknown. These findings based on in vitro
(outside the body) study of animal and human tissue cultures are also
bei ng followed up and extended.
Similarly, no conclusion evidence exists regarding damage to human
genetic functioninng (i.e., chromosomal damage produced by mari-
huinaa). While the most carefully controlled studies have failed to
demonstrate such damage, the research to date must be regarded as
insufficient to permit definitive conclusions.
Plre.ently, preliminary evidence of a range of potentially serious
consequences of marihuana use exists. As indicated. these. include:
Disruption of basic cell metabolism through interference with DNA
and R NA synthesis, possible interference with pituitary function, in
turn, affecting testosterone production and possibly having other en-
docrine effects and interference with the body's disease defenses by
aiffecting the immune response. Despite this laboratory evidence, the
clinical implications remain in doubt. While no evidence has appeared
indicating that marihuana users here or abroad suffer from unusually
high rates of infectious disease. or cancer which might result. from
defects in the immune response, carefully controlled large scale clini-
cal studies have not yet been conducted. Similarly, there is no evi-
dence-hut neither have there been adequate systematic studies-to
epthlish whether users have significantly lower fertility rates or more
serious problems with impotence than non-users.
The failure to detect gross clinical findings that might. be expected
does not, of course. mean that. these issues have been resolved. To date
S vsteiimtic studies of matched samples have been modest. in size. Detec-
tion of rarer consequences of use. is less likely in studies of limited
size and extent. As the numilber of chronically using Americans in-
creases,. larger scale epidemiological studies are become ing feasible.
Plans for such studies are. underway.
OTrHiER CHRONIC 1HTUMAN EFFECTS
Toho'ranve and depended nre
Tolraince to cannabis-diminished response to a given repeated
drug (dose-hits been substantiated by research evidence. Development
of tolerance to marihuana's effects was originally suspected because






of the obvious ability of cannabis users overseas to ingest larger quan-
tities of the drug without disruptive effects than was possible for less
experienced American users. Systematic, controlled studies in which
known doses of marihuana or TIlC were administered over extended
periods have now confirmed this (8-53,80, 109. 1).
The meaning of cannabis dependence is often somewhat vague. If
we define it as a, physical depeindency manifested by physica I symptoms
following drug withdrawal, there is now evidence that it caiI occur.
The symptoms that have been reported following discontinuance of
high dose chronic administration of delta-9-TIIC include: Irritability,
restlessness, decreaseil appetite, sleep disturbance, sweating, tremor,
nausea., vomiting and diarrhea (8-80). It should be noted, however,
that the after effects reported followed unusually high doses of orally
administered THC under re'-a rch ward conldilions. Such changes have
not commonly been observed in other studies nor lias a, "withdrawal
syndrome" typically been found among users here or abroad.
Psych opatho log ical i/( ne.rol0og;cal aspects
The question of possible prolonged behavioral effects of chronic*
cannabis usa re has been an area of fundamental concern throughout
the Americ;: i cannabis rese:irch program. As indicated in earlier re-
ports. foreign rJb.rvers have argued that a rann'e of such effects occurs,
including a specifc v-,?,inabis psychosis, dim finished intellectual per-
forimance and an "amivotivationiv syndromiie" (ch1,ar'icterlzed by a lo-s of
interest in work and other conveiitional activity Interpretatiooif
such reports has unfortunately been complicated by the lack of ade-
quate control groups, poor re-search design use of opium and other
drin s, poor diagnostic criteria, nutritional deficiencies and other differ-
ing actors of life style.
Even when a particular consequence is correlated with marihuana
uso, it is often erroneously attributed to the drug use. A recent study
of 38 first admissions to a psychiatric hospital illustrates the problem
of interpretation involved: While there was a correlation between
marihuana and subsequent p-ychiatric illness, it was less than with
such cawialHy unrelated variables as having danced and having drunk
beer (7-2).
The acute panic anxiety reaction. previously mentioned in the dis-
cussion of acute effects, is probably the most common adverse reaction.
However, a more prolonged cannabis psychosis has been reported in
Eastern literature. It appears to occur under conditions of unusually
heavy use or as a result of ingesting a larger amount than usual. De-
scriptions do not always distinguish between an acute brain syndrome
or toxic deliriumni marked by clouded mental proc(-sses. disorientation,
confusion and i marked memory impa irment and a more prolonged
p1:'Nchotic reaction precipitated by cannabis use. Often it is difficult to
isolate the causative role of marihuana from that of pre-existing psy-
chopat-I1ology or other drug use (7-64,112).
Three NIDA-supported research studies of heavy chronic users
conducted in Jamaica, Greece and Costa Rica have failed to detect
evidence for a cannabis psychosis. However, given the comparative
rarity of this syndrome and the small sample sizes used, it is possible
that such a consequence was missed.








Studies of college student performance have generally failed to
prove evidence of impaired intellectual performance related to mari-
huana use.
While there was no evidence of differences in grade point average
or in educational achievement, marihuana users in one major study
had greater difficulties than non-users in deciding career goals and
were more likely to have dropped out of college to reassess their goals
(7-11). Some of these studies suffer from several shortcomings, how-
ever; the samples studied may not have adequately emphasized college
drop-outs thus excluding the very group that might have been most
adversely affected by heavy use. A second consideration is that students
typically have higher levels of ability than the general population.
Particularly in more competitive academic environment, they may
have above average motivation allowing them to better compensate
for cannabis effects. Finally, even moderately heavy American student
users use the drug less frequently, in less potent forms and in lesser
quantity than more heavily using overseas populations.
Assessing the psychosocial effects of marihuana use in chronically
using populations can be complicated. Changes in values and behavior
attributed to marihuana use may, in fact, have preceded use rather
than the use affecting the change in values. Especially in earlier years,
users were much more likely to hold counterculture, antiest-a'blishmient
views. For these users marihuana had symbolic value as a means of
indicating their disdain for the prevailing value system. This disdain
was frequently accompanied by a rejection of the traditional work
ethic with its emphasis on competitive achievement. The group dy-
namics of marihuana use may, however, reinforce these counterculture
views of more conventional motivation rather than result from any
pharmacological action of the drug itself.
Similarly, attempts to create experimental models for testing the
existence of such an "amotivational syndrome" have had serious limi-
tations. Tasks chosen as tests may significantly depart from more re~al-
istic work tasks; the artificial environment if the research setting
may not provide more typical motivational conditions. Two studies
involving marihuana administration coupled with monetary reward
for work performance did find a decline. in productivity with heavier
marihuana consumption. In one. the task was simple. and relatively
undemanding, involving repetitive button pushing that could be car-
ried on sinmultaneoiisdy with other activity (7-111). In the other, a
more typical work task-the making of wooden stools-was carried
on (7-13). The distinction between a direct. effect on performance. as
a result of marihuana and on performance as a result of it decline. in
motivation is not easily made, however. In a third, quite limited
study of agriciltiiral performance undertaken in connection with the.
Jal n(ic in study of chronic users, researchers found some. decline in
work performance although the decline Nvas not dramatic (7-141).
When one turns to the, neurological evidence there is little question
tlihat there are acute effects of marihuana. intoxication although these
are not easily distinguished from those. of other psychoactivep drius as
mne~asured by con voentional electroencephalograms. The EEG changes
resullting from electrodes implanted deeply in the brain are dissimilar
to otlier pl-ychoiitive drugs (7-67). The behavioral significance of the








EEG changes that have been found in chronically using monkeys and
in very limited human studies is not presently known.
Work in Greece has not supported previously cited evidence sug-
gesting that brain damage marked by enlarged ventricles may result
from marihuana use. The Grecian study, using noninvasive echo-
encephalographic techniques for measurement of ventricle enlarge-
ment, found no evidence of such brain damage in heavily hashish
using men matched with non-using controls (7-49).
Field Oiidies of chronic users
Although other portions of this and previous reports touch on one
or another of the three Federally sponsored studies of chronic mari-
huana use in Jamaica, Greece and Costa Rica, it may be useful to
summarize their findings, strengths and weaknesses here. The Ja-
maican study has been extensively reported in previous Marihuana
and Health reports, a recently published book and in the research
literature. (7-141). A report on the Greek study was delayed in order
to make the data base as complete as possible. The third study in Costa
Rica was just completed: its detailed findings will be released by
Spring, 1976. In each of these research efforts, an attempt was made
to match drug-using subjects with appropriate nonusing counterparts.
In the Jamaican and Costa Rican projects rather careful matching
was done; in the Greek study such matching was less possible. All sub-
jects were males because male use predominates in the cultures studied.
Numbers of subjects were necessarily limited by the detailed pro-
cedures followed (Jamaica: 30 experimental, 30 control; Greece: 47
experimental, 40 control; Costa Rica: 40 experimental, 40 control,
although 80 and 140 users and non-users respectively were actually
examined).
The Jamiaican study found few physiological or psychological differ-
ences bet ween the matched smoker nonsmoker populations. A rather
extensive battery of tests of physical and psychological functioning
found no differences that could be directly attributed to marihuana
use as such. While an attempt was also made to assess chromosomal
abnormalities, that portion of the study must be regarded as incon-
clusive because of technical deficiencies in the methodology for that
phase of the project.
The Greek study arose from a clinical impression by Greek observers
that Greek hashish users, because, of their heavy use patterns and
already established researcher-subject rapport, would make a good
study population for examining the effects of unusually heavy cannabis
use.
A variety of neurological, psychological and physical measures
found few changes attributable to cannabis use. Heavy emphasis was
placed on possible brain damage as measured by electroencephalo-
graphic, echo-encephalographic (Cf. preceding section) and psycho-
logical test procedures. None of these measures showed evidence of
brain damage (7-49).
The most recent. Costa Rican study also examined matched samples
ot users and non-users especially carefully matched on such variables
as age, marital status, education, tabocca smoking and alcohol use.
Emphasis was placed on extensive medical examinations with special
attention to pulmonary and neuropsychological functioning. Although






14


detailed results have not yet been published, no evidence for a greater
incidence of disease or of psychological deterioration has been found
in the cannabis-using group (7-23).
None of the three studies found evidence of increased psychopathol-
ogy or of an motivational syndrome stemming from tdie use of
cannabis.
While results of these studies must be regarded as somewhat reas-
suring of the lack of grossly adverse consequences of marihuania use,
they can not, of course, be regarded as conclusive for several reasons.
All three studies involve relatively small numbers of subjects. Equally
limited studies of cigarette smoking, for example, which is known to
have serious adverse health consequences, would not have been likely
to detect those. consequences. Psychological testing techniques are less
apt to be satisfactory when used with subjects markedly different from
the original standardization samples. To the extent that they are not
culture free. performance for both experimental and control groups in
cultures unlike those on which they were standardized may both show
a culturally derived deficit. This deficit may mask a drug-related defi-
cit in performance. Thus, the tests used may not be sufficiently sensitive
to detect a difference that may in fact exist. Finally, it may be argued
that. the demands of a less technologically oriented society are less com-
plex than those of the industrialized United States. Thus, the failure
to find a drug-related decrement in social or work performance may
reflect an unimpaired ability to meet the demands of a simpler situa-
tion that would not be true under more demanding circumstances.

ThERAPEUTIC ASPECTS
Although cannabis has been used for over 3,000 years as a medicinal
herb in native and scientific medicine, its use in Western medicine
sharply declined in modern times. By the 1930s. American medicine
had largely supplanted cannabis with more convenient and more. stable
pharmaceutical preparations. Our relatively recent concern with mari-
huana as a drug of abuse has led to scientific investigation into its
properties by means of modern pharmacological techniques. Synthe-
sized constituents of the natural material have been produced enabling
researchers to study the properties and effects of each of the compo-
nents of this complex material. This recent, study has reawakened scien-
tific interest in possible therapeutic uses for the natural material or its
synthesized ingredients.
Although some of marihuana's properties-notably its psychoactiv-
ity and its tendency to accelerate heart rate-are undesirable for most
medicinal purposes, cannabis has one highly desirable property. Com-
pared to most pharmaceuticals it is very low in biological toxicity. In-
deed, it is questionable whether any deaths can be directly attributed
to an overdose of marihuana or hashish.
Whether or not cannabis or perhaps some modified constituent again
becomes useful in medical practice will depend on whether some of
the drug's promising therapeutic properties prove to be sufficiently
persistent and its side effects controllable. Marihuana 's usefulness as a
medication for chronic disorders may also prove to be limited by the
development of tolerance to its therapeutic effects.








The most promising therapeutic applications of the drug are in the
treatment of glaucoma, as an anti-emetic for cancer patients receiving
chemotherapy and possibly in the treatment of asthmatics. Other ap-
plications as a sedative-hypnotic, an ant iconvulsant, an antidepressant,
an analgesic and in connection with the treatment of alcoholics have
been attempted, but the results have either been inconsistent or highly
preliminary.
The use of cannabis and THC in treating the elevated intraocular
pressures in glaucoma patients arose from the observation in normals
that internal eye pressures were reduced by the drug. Subsequent re-
search with patients has confirmed that the effect is also produced
in the diseased eye and is as great as that produced by more traditional
medications. Topical preparations applied to the eyes of rabbits have
successfully reduced pres1smre raising the possibility of using such a
preparation with humans. Human experimentation is not, however,
expected in the immediate future because of the formidable problems
in making certain that such a preparation is safe and can meet regula-
tory requirements (9-12, 25, 26).
The use of THC as an anti-emetic with ciciier patients receiving
chemotherapy shows unusual proinise. One of the undesirable side
effects of chemotherapeutic agents administered to cancer patients is
that they produce marked nausea and vomiting. This side effect is very
difficult for patients to tolerate and is also debilitating. Standard anti-
emetic drugs have not. unfortunately, been notably successful in re-
ducing this side effect. THC, by contrast, was found in a recent double-
blind study (neither patient nor physician knew whether the drug
received was active or inert) to be effective in virtually all of the
patients receiving it. While 13 of the 16 patients receiving the drug
became "high" and one third developed drowsiness, these effects were
viewed as minor compared to the therapeutic benefit achieved (9-58).
Use of THC in the treatment of asthmatics is predicated on the
observation that it dilates pulmonary air passages and decreases air-
way resistance (9-64). Based on observations in normal research with
asthmatics has demonstrated that marihuana relieves bronchospasm
and has a more persistent action than traditional medication (9-65).
Since smoked marihuana has obvious lung irritant properties, more
recent research has employed aerosolized THC, also with promising
results (9-46).
There has been a growing awareness that constituents other than
delta-9-THC may have valuable therapeutic properties if freed of some
of the undesirable side effects noted with THC. It is also possible for
the organic chemist to produce a very wide range of chemical com-
pounds which are broadly based on the chemical structure of the
cannabinoids, but with changes in that structure which can markedly
alter their action. Such chemically more remote compounds may ulti-
mately prove more useful therapeutically than either the natural mate-
rial itself or its synthesized ingredients. Because they are not the
parent compounds they must, of course, be carefully tested for toxicity
and therapeutic properties like any other new compound.















CHAPTER 1


EPIDEMIOLOGY OF MARIHUANA USE
PRESENT PATTERNS AND CHANGES IN USE
National household surveys (adult)
The National Commission on Marihuana and Drug Abuse sponsored
national household surveys of marihuana and other drug use in 1971
and 1972 (2, 3). A third national survey conducted in late 1974-early
1975 provides a comparison with the earlier periods (1). (See Table
A-i)
Another national survey conducted for the Drug Abuse Council in
1974 found very similar results. The percentages of adults (18 and
over) reporting ever having used and currently using were 1S and
8% respectively (24). As can be seen in Table A-i, the number of
adults currently using marihuana has not changed appreciably in tho
past two years. Usage continues to be concentrated in the 18-25 age
bracket and is about twice as frequent for males as females.
Current usage is about equal for white and non-white groups. It is
positively associated with education, and is highest for those now in
college (33%). Current usage continues to be highest in the West
(11%) and lowest in the South (4%), and higher in large metro-
politan areas (9%) than in non-metropolitan regions (3%). However.
all of these differences have become less pronounced in the past three
years.
Because of the relatively small numbers involved, national general
population surveys do not provide very accurate estimates of changes
in heavy marihuana use; nevertheless, some information is available.
The 1971 Marihuana Commission survey reported daily or more fre-
quent use among adults at 0.5%, while the comparable value for 1972
was 1.4%. The follow-on survey in 1974 did not report the rate of daily
use, but noted that adult usage of nine or more days in the past month
was 2.7%. The 1974 Drug Abuse Council national survey reported
1.5% of the adult sample used marihuana daily or more frequently.
These limited data do not appear to indicate a change in adult daily
usage in the past two years.
National household surveys (youth)
The results of the Marihuana Commission surveys of youth ages
12-17 and the results of the 1974 follow-on study are found in Table
A-2.
(17)









TABLE A-1.-MARIHUANA USE AMONG ADULTS, 1971-74 (1, 2, 3)

Percent ever used Percent current use t
1971 1972 1974 1971 1972 1974

All adults-------------------------- 15 16 19 5 8 7
Age:
18 to 25------------------------ 39 48 53 17 28 2i
26to30------------------------ 19 20 29 5 ---------------
35to 49 ------------------------ 9 6 7 1 1 1
50 plus------------------------- 6 2 2 ------------------------------------
Sex:
Male -------------------------- 21 22 24 7 11 9
Female------------------------ 10 10 14 3 5 5

I Used during last month.

TABLE A-2.-MARIHUANA USE AMONG YOUTH, 1971-74 (1, 2, 3)

Percent ever used Percent current use I
1971 1972 1974 1971 1972 1974

All youth-------------------------- 14 14 23 6 7 12
Age:
12 to 13------------------------ 6 4 6 2 1 2
14 to 15---------------------- - 10 10 22 7 6 12
16 to 17------------------------ 27 29 39 10 16 20
Sex:
Male-------------------------- 14 15 24 7 9 12
female ----------------------- 14 13 21 5 6 11

i Used during last month.

Another set of national household data collected in a Columbia
University study reported quite similar results (8, 16):
Percent
Age 12 to 17: ever used
1971-------- -------------------------------------------------- 15
1972-------------------------------------------------------------- 15
1973--------------------------------------------------------- 17
1974 to 1975---------------------------------------------------- 22
Age 16 to 17:
1971---------------------------------------------------------- 28
1972-------------------------------------------------------------- 31
1973---------------------------------------------------------- 32
1974 to 1975---------------------------------------------------- 40
However, the 1974 national survey conducted for the Drug Abuse
Council reported considerably lower marihuana usage for 12-17 age
group, 14% in the "ever used" category and 5% as "currently using"
(24). This discrepancy may have been related to the relatively small
sample size of 505. This survey also utilized "rider questions" attached
to a larger unrelated survey.
The Marihuana Commission surveys in 1971 and 1972 reported daily
marihuana usage for the 12-17 age group at 0.6% and 1.3% respec-
tively. The follow-on 1974 survey found 4.4% indicated usage of nine
or more times in the past month. The 1974-75 national survey for the
Columbia University study found 2% of youth ages 12-17 and 4%
of those either 16 or 17 years of age reported using marihuana 60 or
more times within the two-month period. While the percentage of
daily use was not reported for the earlier years, the 1974 Drug Abuse
Council survey reported daily or more frequent usage by 1% of 12-17
age group and 3% of those 16-17.







19

Student surveys
A longitudinal study of high school males followed from their senior
year to five years after graduation provides an indication of changes
in marihuana usage over time in the same group (14,15). The sample
,of over 2,000 was selected from 87 public high schools so as to be
representative of American males entering high school in 1966. (Data
arrayed in Table A-3.)
Another study surveyed drug usage in 22 selected high schools
throughout the United States in 1971 and 1973 (16). These data are
not necessarily representative of the student population, but do pro-
vide an indication of changes in marihuana use over the two-year pe-
riod. (Table A-4)
A survey of 16,000 male and female high school seniors in 130
schools, selected to be representative of public and private high schools
throughout the country, was conducted in 1975 (15) and is to be re-
peated on an annual ba-,is. The percentage of high school seniors re-
porting marihuana usage in the 1975 survey were:

TABLE A-3.-PERCENTAGE OF MARIHUANA USE AMONG A NATIONAL SAMPLE OF HIGH SCHOOL MALES (14, 15)

1 year after 5 years after
Senior year, graduation, graduation,
1969 1970 1974

Ever used--------------------- ----------------------- ---------- 20 35 62
A ny use in prior year. -------------------------------------------- 20 33 52
Daily or weekly sometime in prior year ------------- --- ---------- 6 9 21
Daily use sometime in prior year.---------------- ------------ 1 2 9


TABLE A-4.-PERCENTAGE OF MARIHUANA USE REPORTED IN 22 HIGH SCHOOLS (16)

Junior high school Senior high school
1971 1973 1971 1973

Ever used--------------------------------------- 15 19 38 48
Ever used 60 or more times ---------- --------- ------- 2 4 11 17
Used in past 2 months -------------------------- 11 13 27 36
Used 60 or more times in past 2 months .-- ----------- 1 1 2 4

Percent
Ever used----------------------------------------------------------- 47
Used in last 12 months---------------- --------------- ---------- --- 41
Used in lMst month--------------------------------------- ---- ---- 29
Used 20 or more times in last month---------------------------------- 6
The only regularly conducted national survey of marihuana use
among college students is that prepared by Gallup (9). The percent-
ages reporting having ever used this substance in surveys conducted
between 1967 and 1974 were:
Percent
1967-------------------------------------------------------------- 5
1969-------------------------------------------------------------- 22
1970-------------------------------------------------------------- 42
1971-------------------------------------------------------------- 51
1974-------------------------------------------------------------- 55
One other national student survey conducted in 1974-75 for Drug
Abuse Council found 48% of high school and 64% of college students






20

reported having used marihuana (33, 34). The corresponding percent-
ages for daily use were 6% and 8%. l
One local survey of particular interest is that annually conducted
among high school students in San Mateo County, California since
1968 (4). Table A-5 shows the percentage of ninth and twelfth grade
male students reporting one or more, ten or more, and 50 or more
uses of marihuana during the preceding year.
San Mateo County is adjacent to San Francisco,and thus had an
earlier and more pronounced exposure to the counterculture movement
and associated drug use than did most other areas. This is particularly
evident in the figures for the late 1960's. For instance, one year after
Gallup found only 5% of nationwide college students had used mari-
huana (1967), the comparable percentage for senior males in San
Mateo county high schools was 45%. The percentage of San Mateo
students using marihuana in 1975 is still substantially above the na-
tional level; however, the difference is not nearly so large. It is interest-
ing to speculate on the meaning of this narowing gap. One possibility
is that the apparent plateau may be a ceiling and that the growth of
marihuana use in San Mateo may have reached its limit. It may also
be that other drugs (viz cocaine), not of great interest when the study
began in 1967, are now luring users away from marihuana. Many alter-
native explanations for the San Mateo phenomenon are possible;
whether the phenomenon or its alternate interpretations have any
meaning for the national level is unknown.
In summary, at the national level marihuana use appears to have
significantly increased among youth during the past two years. This
is indicated by the trend in national household surveys as well as
surveys of various high school student populations. This conclusion
is contrary to that suggested in the 1974 Marihuana and Health report,
when data available at that time seemed to indicate a plateau had been
reached (20). It also appears that daily marihuana use has increased
among youth, although the available data on changes in daily use are
fairly limited.
TABLE A-5.-PERCENTAGE OF MARIHUANA USE AMONG MALE SAN MATEO
COUNTY HIGH SCHOOL STUDENTS (4)
1 or more uses in past year 10 or more uses in past year 50 or more uses in past year
9th grade 12th grade 9th grade 12th grade 9th grade 12th grade
1968------------------- 27 45 14 26 NA NA
1969- ------------------- 35 50 20 34 NA NA
1970 ------------------- 34 51 20 34 11 22
1971- ------------------- 44 59 26 43 17 32
1972 ------------------- 44 61 27 45 16 32
1973 ------------------- 51 61 32 45 20 32
1974 ------------------- 49 62 30 47 20 34
1975.... ------------------- 49 64 30 45 20 31

Ifarih uama use among males, age 20 to 30
One of the. most significant recent studies involved the interviewing
of 2.500 selected to be representative of the 19,000,000 U.S. males in the
20-30 age group (23). This group evidences the highest rate of drug
use, and the in-depth interviewing of a relatively large representative








sample provided more reliable information on marihuana and other
drug-using behavior than had previously been available.
The data were collected from October, 1974 to May, 1975 and showed
that 55% of those interviewed had at some time used marihuana. De-
fining as current use any use in the year 1974-1975, the study reported
38% current users. Fifteen percent reported having used marihuana
daily or almost daily at some time. Eleven percent reported using
marihuana 1,000 or more times, and 11% also reported use within 24
hours of the interview. Hashish use at some time was reported by 29%.
and the use of hashish oil by 11%. Surprisingly, 11% of the total
sample and 41% of those described as heavy users reported growing
marihuana for their own use.
When particular age categories within this group are examined, the
data show that 37% of the men who were 29-30 at the time of the
interview had used marihuana in comparison to 63% of the 20-24 age
group. When those described as light or experimental marihuana users
are excluded, the differences are even more, striking; 12% of those 29-
30 reported use in comparison to 37% of those 20-24. These results
indicate that males now in their late twenties are less likely to have
tried marihuana than men five to ten years vouniger, and are con-
siderably less likely to adopt marihuana use as a frequent behavior.
Similar or more pronounced differences probably exist for those over
30. For instance, the 1974 follow-on to the Marihuana Commission
Survey found 7% of males and females aged 34-49 reported having
used marihuana, but only 1% had done so within the past month.
The peak year of first marihuana use for the sample of males be-
tween 20 and 30 was 1969; however, the peak year for any use during
the calendar year was 1974 when the rate for this group reached 37%.
The authors concluded that the data were clearly consistent with an
upward trend in marihuana use.
This study also revealed that the differences in marihuana use as a
function of various demographic characteristics were not as pro-
nounced in the group sampled as those reported in the general popula-
tion. In the male 20-30 age group, 70% of those living in cities of over
1.000,000 population had used marihuana in comparison to 43% of
those in communities of less than 2,500. In terms of education, the
percentage reporting some use of marihuana was almost identical for
tho-e with less than high school education, high school graduates and
college graduates. Those who had attended college without graduating
showed a higher rate. For those aged 20-23 at the time of the inter-
view, the percent having used marihuana was virtually the same for
those still in school and those not. A higher percentage of blacks (65%)
than whites (54%) reported some use, but the inverse relation of mari-
huana use to age was not as apparent in the black group. Blacks and
other ethnic minorities showed a higher prevalence of marihuana use
prior to the late 1960s, but minority youth were less influenced by the
recent epidemic (5).
A synthesis
The overall survey results indicate that marihuana use has not sig-
nificamtly penetrated the portion of the adult population over 30 years
of age. Where use has occurred in this group, the frequency has been






22

mostly of an experimental nature. However, the plateau in current
marihuana use among adults found in national survey results may be
deceptive in predicting future usage. As the more frequently using
younger groups enter the adult age range, the overall rates are likely
to increase.
Results from both household surveys and student studies indicate
that marihuana use is still increasing among youth at the national
level, although usage appears to have stabilized in certain areas which
reached a relatively high level in the early 1970's. Most of the data on
youth also indicate that daily or near-daily usage has increased in the
past two to four years.
If recent marihuana usage in the United States is compared with
that prior to the epidemic which began in the late 1960's or especially
with patterns of use in countries where cannabis use has been indige-
nous for many years, some useful perspectives emerge. It is clear that
much of the recent American usage is quite minimal, both in terms of
frequency of use and amount consumed (21, 27). The patterns of use
often seem to be based more on the adoption of a fad or style than an
attraction to the pharmacological properties of the drug. This is not
to say that, once it is introduced as a fad, marihuana use will not be
sustained because of its pharmacological effects.
Based on currently available survey data, it appears that around
2%c of youth, aged 12-17 or about 8% of those who have tried it, are
currently using marihuana daily. For those 17 years-of-age, around
4 or 5%o are probably daily users and for 17-year-old males the per-
centage is of the order of 6 or 7%, or about 13% of those having'
tried it.
For adults, the overall daily use is probably only 1 or 2%, but a
more meaningful percentage is that for the age groups primarily in-
volved. As described earlier, the percentage of daily use among males
20-30 years of age is around 8 or 9% or 15% of those who have tried
marihuana. For males 20-24 years of age, current daily use is around
10 or 11%, or about 17% of those having ever used the drug.

SOCIAL AND PSYCHOLOGICAL CORRELATES
Research on the social and psychological correlates of marihuana
use may be organized under three headings: 1) pre-use characteristics;
2) factors influencing transition from non-use to use, including the
temporal order of drug-using behavior; and 3) correlates of mari-
huana iise following its adoption. In most instances only statistical
associations, as opposed to casual relationships, can be established.
Pr'e-use characte7istics
This aspect, has been thoroughly covered in earlier research and
recent work lias largely served to confirm prior findings. Aside from
the, association of marihuana with routine demographic variables such
as those mentioned in the previous section, the majority of variables
which pre(lict marihuana use, ranging from a break with traditional
values (7, 10, 19) to more severe behavioral and adjustment problems
(11) are related to lack of conformity. Smith has found self and peer






23


ratings of rebelliousness to be among the best predictors of high school
students who subsequently become marihuana users (29).
Factors influencing transition from non-use to use
In a longitudinal study of high school students, Jessor has shown
that those individuals who will initiate marihuana use can be identified
with considerable accuracy from various personality, belief and atti-
tude measures (13). Furthermore, these measures, such as attitude
toward deviance, value of achievement and friends' approval of drug
use, show significant changes in the direction of the user group during
the period of marihuana initiation. Jessor has found similar results
with regard to the initiation of alcohol drinking and sexual behavior.
Several studies have investigated the role of child-re:arIing practices
and parents' drug-using behavior in the initiation of adolescent drug
use. One recent study found that perceived laissez-faire pa rent-child
relationships led to high marihuana usage among the offspring; an
autocratic relationship led to medium usage; and quasi-democratic or
democratic relationship led to low usage (12). Another study found
higher rates of marihuaria use when the parents showed less dis-
approval of use. and also when the father used prescription drugs (25).
Kandel also found a positive relationship between parents' drug-using
behavior and the child's marihuana use, although her work demon-
strated rather conclusively that this effect wNs minor in comparison to
peer group influence (17). This emphasis on peer influence is in ac-
cord with the thesis of Suchman and others that. student marihuana
and other drug use is largely determined by the integration into a
social subculture in which drug use is a part (31,32).
One social environment, the military, has apparently proved to have
less influence on marihuana and other drug use than was initially be-
lieved. O'Donnell, et al., in their study of 20-30 year old males found
that neither domestic nor overseas service had any effect on marihuana
use (23). Robins has also found that Vietnam veterans' marihuana use
after return was not significantly increased over that for a comparison
group who did not enter the military (26).
Since marihuana use is known to generally precede other illict drug
usage, the question is often raised as to the role of marihuana. in facili-
tating the transition or progression to more dangerous drugs. While
not specifically answering this question, Kandel and associates have
determined that the temporal sequence along the legal-illegal drug con-
tinuum is consistent (18, 28). By conducting longitudinal studies of
two large samples of high school students, they were able to determine
the order in which the various drugs were used. Only 11 of the sample
began using illicit drugs without first using a legal drug. Beer and
wine collectively constituted by far the most common "entry drug"
(28%) with cigarettes accounting for 6% and hard liquor 31. In
addition to the fact that legal drug use virtually always preceded illicit
use, heavy use of both liquor (weekly) and cigarettes (over a pack a
day) resulted in a. high percentage (40%) moving from non-use to use
of illicit drugs in a five month period. Only 2 to 3% of adolescent legal
drug users progressed to other illicit drugs without first trying mari-
huana. If the individual progressed beyond marihuana, the next step






24


was generally pills. Subsequent steps were psychedelics, cocaine and
heroin, in that order; but, of course, only a small percentage progressed
to the higher levels in the sequence. Heavy use of marihuana or other
drugs along the sequence was more often followed by progression to
the next step, and also by a higher probability of moving two or more
steps during a single time period.
Correlates of marihuana we
Although marihuana use has become increasingly common over the
past several years, it is not surprising that those who are less conven-
tional in other respects are more likely to use the drug than are the
more traditionally oriented. In their national study of males, ages 20-
.0, O'Donnell et al., found that those men living in consensual unions
(i.e., with a woman to whom they are not married) were more likely
to be using marihuana than those living independently, or living in
their parental home. Those who were married and living with their
wives were least likely to be using the drug (the percentages of current
use in ascending order were: married, 25%; living with parents, 38%;
living independently, 56%; consensual union, 68%). A similar trend
was found in the use of other drugs including alcohol and tobacco (i.e.,
current drug use of all types was greater by males in consensual unions
than among those who were married). Those unemployed at the time
of interview were more likely to have used marihuana in some time in
their lives than those. who were employed (72% of the unemployed had
ever uieed compared to 52% of the employed) (23).
In this same study both self-reported criminal acts and contacts
with the criminal justice system (some drug use related) were sub-
stantially higher for marihuana users than for the non-users. The
authors caution, however, that "the fact that drug use. sometimes
occurs first and at other times criminal behavior precedes use indi-
cated that if there is a causal connection between drug use and crimi-
nal behavior, it is not a simple one" (23). Similar results have been
reported in terms of arrests by Brill and Christie (1% for non-users
compIared to 10% for regular marihuana users) (6).
An Air Force study of some 4500 men reporting marihuana use
indicated somewhat poorer performance when compared with a control
grop1) of non-users (22). Finally, a longitudinal study of college
freshmen found a strong relationship between marihuana and other
drug use and the choice of unconventional careers (30). There was also
a disproportionate tendency for marihuana. users to change in the
direction of unconventional careers during the two-and-one-half year
follow-up period and the authors concluded, after multivariate analy-
sis, that the results suggest a causal relationship. However, it should
be stressed that, in general, studies relating marihuana use to other
variables have not established more than a statistical association. It is
clear that marilihana usage is frequently part of a larger pattern of
nonconformity, but the existeiice of causal relationships between mari-
Iiniii iuse and other behavior have generally not been determined.













REFERENCES.-EPIDEMIOLOGY OF MARIHUANA USE


1. Abelson, H. and Atkinson, R. B. "Public Experience with Psychoactive
Substances." Princeton, New Jersey: Response Analysis Corporation, August,
1975.
2. Abelson, H., Cohen, R. and Schrayer, D. A nationwide study of beliefs, in-
formation and experience. "Mariliuana: A Signal of Misunderstanding." Na-
tional Commission on Marihuana and Drug Abuse; Appendix Volume II. Wash-
ington, D.C.: Government Printing Office, 1972.
3. Abelson, H., Cohen, R., Schrayer, D. and Rappeport, M. Drug experience,
attitudes and related behavior among adolescents and adults. "Drug Use in
America: Problem in Perspective." National Commission on Marihuana and Drug
Abuse; Appendix Volume I. Wasliington D.C.: Government Printing Office, 1973.
4. Blackford, L. "Student Drug Use Surveys-San Mateo County, California
1908-1975." San Mateo, California: Department of Public Health and Welfare,
1975.
5. Bloom, R., Hays, J. R. and Winburn, M. G. Marihuana use in urban secondary
schools: A three year compa rison. "The International Journal of the Addictions,"
9:329-335 (1974).
6. Brill, N. Q. and Christie, R. L. Marihuaiia use and psychosocial adaptation.
Follow-up study of a collegiate population. "Archives of General Psychiatry,"
31:713-719 (1974).
7. Cunningham, W. H., Cunningham, I. C. M. and English, W. D. Sociopsycho-
logical characteristics of undergraduate marijuana users. "The Journal of Ge-
netic Psychology," 125 :3-12 (1974).
8. Elinson, J. "A Study of Teenage Drug Behavior." NIDA Grant DA 00043.
Columbia University School of Public Health, New York, N.Y., October, 1975.
Personal communication.
9. "Gallup Opinion Index." Volume 109 (Part 4). Princeton, New Jersey:
American Institute of Public Opinion, 1974.
10. Grossman, J. C., Golhstein. R. and Eisenman, R. Tii'ldeLradulate marijuana
and drug use as related to openness to experience. "Psychiatric Quarterly," 48
(1) :86-92 (1974).
11. Halikas, J. A. and Rimmer, J. D. Predictors of multiple drug abuse. "Archives
of General Psychiatry," 31:414-418 (1974).
12. Hunt, D. G. Parental permissiveness as perceived by the offspring and the
degree of marijuana usage among offspring. "Human Relations," 27(3) :267-285
(1974).
13. Jessor, R. Predicting time of onset of marijuana use: A development study
of high school youth. "Journal of Consulting and Clinical Psychology." in press.
14. Johnston, L. 1). Drug use during and after high school: Results of a national
longitudinal study. "American Journal of Public Health" (Supplement), 64: 29-
37 (1974).
15. Johnston, L. D. "Monitoring the Future: Continuinii Study of Life Styles
and Valiies of Youth." University of Michigan, Ann Arbor, October, 1975. Per-
sonal communication.
16. Jn'sephson, E. Trends in adolescent mnrijunaiia use. "Drug Use : Epidemio-
logical and Sociological Approaches." Edited by J.isephson, E. and Carroll, E.
Washington, D.C.: Hemisphere Publishing Corporation, 1974.
17. Kandel, D. Inter- and intragenerational influences on adolescent marijuana
use. "Journal of Social Issues," 30(2) : 107-135 (1974).
18. Kandel, D. and Faust, R. Sequence and stnaPes in patterns of adolescent drug
use. "Archives of General Psychiatry," 32:923-932 (1975).
19. Krug, S. E. and Henry, T. J. Pers-oiiality. motivation, and adolescent drug
use patterns. "Journal of Counseling Psychology," 21(5): 440-445 (1974).
20. "Marihuana and Health." Fourth Annual Report to Congress from the
Secretary of Health, Education, and Welfare. Washington, D.C.: Government
Printing Office, 1974.
(25)


67-062-76-3







26


21. McGlothlin, W. H. Drug use and abuse. "Annual Review of Psychology,"
26:45-64 (1975).
22. Mullins, C. J., Vitola, B. M. and Michelson, A. E. Variables related to
cannabis use. "The International Journal of the Addictions." 10(3) : 581-502
(1975)
23. O'Donnell, J. A., Voss, H. L., Clayton, R. R., Slaftin, G. T. and Room,
R. G. W. "Non-Medical Drug Use Among Young Men in the United States: A
Nationwide Survey." Special Action Office for Drug Abuse Prevention Grant DA
3AC678 and N IDA Grant DA 01121,1975.
24. Opinion Research Corporation, "Use of Marijuana and Views on Related
Penalties Among Teens and the General Public." Commissioned by the Drug
Abuse Council, Washington, D.C., October, 1974.
25. Prendergast, T. J. Family characteristics associated with marijuana use
among adolescents. "The International Journal of the Addictions," 9(6) : 827-
839 (1974).
26. Robins, L. N. "Veterans Drug Use Three Years After Vietnam." Special
Action Office for Drug Abuse Prevention Grant DA 3AC680, NIDA Grant DA
01120, and NIMH Grant MH 36,598, 1975.
27. Rubin, V. and Comitas, L. "Ganja in Jamaica: Medical Anthropological
Study of Chronic Marihuana Use." The Hague: Mouton, 1975.
28. Single, E., Kandel, D. and Faust, R. Patterns of multiple drug use in high
school. "Journal of Health and Social Behavior." 15(4) : 344-357 (1974).
29. Smith, G. E. Early Precursors of Teenage Drug Use. Paper presented at the
36th Annual Scientific Meeting, Committee on Problems of Drug Dependence,
Mexico City, 1974.
30. Somers, R. H., Mellinger, G. D. and Manheimer, D. I. "Drug Use and Career
Choice Aniong University Men." NIDA Grant DA 00137, "Institute for Research
in Social Behavior." 16(1): 63-72 (1975).
31. Suchman, E. The hang-loose ethic and the spirit of drug use. "Journal of
Health and Social Behavior," 9:146-155 (1968).
32. Thomas, 0. W., Petersen, D. M. and Zinggraff, M. T. Student drug use: A
re-examination of the "hang-loose ethic" hypothesis. "Journal of Health and
Social Behavior," 16(1) : 63-73 (1975).
33. Yankelovich, D. Drug users vs. drug abusers-how student's control their
drug crises. "Psychology Today," 9(5) : 39-42 (1975).
34. Yankelovich, D. Yankelovich, Skelly, and White, Inc., New York, N.Y.,
October, 1975. Personal communication.













CHAPTER 2


CHEMISTRY AND METABOLISM
Because the drug abuse problem involves marihuana, the study of
the pharmacological and toxicological properties of the drug must be
pursued; cannabis, however. is a complex mixture of variable amounts
of numerous, potentially active substances. The chemistriy of mari-
huana, is, therefore. of paramount importance to the investigator. and
the recently reported development of relatively simple analytical pro-
cedures for the separation and quantitation of the major cannabinoids
in marihuana is a significant advance. The effects of marihuana can
now begin to be more meaningfully compared in different laboratories,
and many of the past problems of conflicting data will be avoided
simply by knowing the chemical composition of the sample at hand.
Indeed, the United Nations has recommended that all nreearch reports
on the properties of marihuana include a quantitative account of the
major cannabinoid content of the preparation involved.
Another notable contribution in the field of c iiinabinoid chemistry
was the introduction of a refinement in the synthesis of delta-9-THC,
the major psvchoactive drug in ca 1 abis. In recent v. ITs, the sy-nthesis
of delta-9-TIiC, as -wvell as of other cannabinoids, bas been subjected
to extensive investigation, which has resulted in a continuous simplifi-
cation of the synthetic procedures. Such developments have reduced
the cost of synthesis and thereby increased the availability of these
important drugs for scientific investigation. The long-term significance
of the recent refinement must be viewed in the perspective of a long
list of many contributions to our understanding of the chemistry of
cannabis and its constituents. In the past few years the chemical study
of cannabis has resulted in the isolation, characterization and synthesis
of numerous constituents of marihuana, thus providing biologists with
the opportunity to study the pure drugs. In a classical sense, the chemi-
cO.l advances represent the basis for the rational investigation of the
pharmacology and toxicology of marihuana.
New reports of the isolation and identification of some of the metabo-
lites of marihuana continue to represent the most important aspect of
research in the area of metabolism. In the human, for example, can-
nabinol has now been reported as a metabolite, and several new ones
have been isolated from urine. It is essential to pursue the identifica-
tion of marihuana metabolites because the question of what accounts
for the pharmacological and toxicological activity of marihuana can
only be answered by a study of the constituents of cannabis and their
respective metabolites. The importance of metabolism was first demon-
strated a few years ago when 11-hydroxy-delta-9-THC, a major
metabolite of delta-9-THC, was found to be as active as, or more
(27)






28


active than, the parent compound. In the current Marihuana and
Health report, the study of the anticonvulsant activity of the can-
nabinoids has revealed that another metabolite, 8-alpha, 11-dihydroxy-
delta-9-THC, is also a very active substance. It is not unreasonable to
assume that still other marihuana metabolites will be found to produce
significant pharmacological and toxicological effects.

'DRUG SOURCES
The detailed chemical analysis of cannabis has been extended to
yield more components (4, 43, 44), and investigators have recently
identified a new spermidine alkaloid called cannabisativine in an alco-
holic extract of the root of Cannabis sativa' L. (24).
The importance of the influence of smoking marihuana on the nature
of its chemical constituents continues to be recognized (14, 18, 19, 20,
37). A detailed analysis of the pyrolytic products of cannabidiol
(CBD) has demonstrated that one of the principal volatile products
formed is olivetol, a pharmacologically active chemical precursor of
the camiabinoids (19).
The cannabinoids are potentially unstable compounds and their
stability in chloroform, a commonly used solvent for extraction and
storage of cannabinoids, has been re-examined (51) : The results of a
three-month storage study support a previous assessment that either
synthetic or naturally occurring cannabinoid mixtures are reasonably
stable. Other investigators have determined the influence of pH on
stability by describing the kinetics of the degradation of delta-9- and
delta-8-tetrahydrocannabinol (delta-9-THC, delta-8-THC) at differ-
ent pH values (12).
More new cannabinoids have been synthesized and examined for
pharmacological activity (8,22, 52), and the synthesis of delta-9-THC
has continued to be refined with the introduction of a one-step reaction
using either chrysanthenol (35) or p-mentha-2,8-dien-l-ol and olivetol
(34).
ANALYTICAL TECHNIQUES: DETECTION
At the present time four principal methods are used for the analysis
of cannabinoids: gas-liquid chromatography (GLC), thin-layer chro-
matograpliy (TLC), mass spectroscopy (MS) and radioimmunoassay
(RIA). The chromatographic procedures remain the most useful be-
cause they offer either simplicity, as in the case of TLC, or the best
combination of sensitivity and selectivity, as in the case of GLC. The
GLC methods have been especially useful in the separation and quanti-
tation of cannabis constituents (31). One of these methods, which in-
volves the formation of silyl derivatives of 2% OV-17 chromatog-
raphy columns (49), has been extremely valuable for the elucidation of
the major components of cannabis. This method, referred to in the 1974
Marihuana and Health report (25), demonstrated that previous GLC
analyses of cannabis failed to separate CBD from cannabichromene
(CBC); hence, some CBD samples used in pharmacological studies
were. probably significantly contaminated with CBC. The recognition
of 1he prevalence of CBC in some cannabis samples should prompt a
re-evaluation of the pharmacological effects of pure CBD and an evalu-






29


ation of the pharmacological properties of CBC, alone and in combina-
tion with CBD.
The variability in cannabis composition has led the United Nations
to recommend that all scholarly reports on the effects of cannabis in-
clude a quantitative analysis for CBD, cannabinol (CBN), and delta-
9-THC content; the GLC method described above was recommended
for this purpose. Subsequently, the same research group published
another GLC method which does not require derivatization, but still
provides satisfactory separation of CBD and CBC (50). The relative
simplicity of this procedure suggests that it is the current method of
choice for the analysis of cannabis for its principal cannabinoid
constituents.
New TLC methods for the cannabinoids continue to be developed (9,
16, 17, 29, 48). A two-dimensional TLC system has been described as
capable of slparatinm 27 constituents of hashish resin, including CBD,
CBN, delta-9-THC and CBC (29). This technique uses silica-gel
plates and the solvents n-pentane-diethyl ether-ethyl acetate (90: 8: 2)
and n-pentane-aceton (90' :10). In another report a new procedure for
cxIraclting irl enables the cannabinoid metabolites to be separated
into neutral, weak and i ;-ton, acid frictions. which can be ealilv frac-
tionated further by TLC (17'). In addition, the use of methanol to
extract delta-9-THC and its metabolites from tissues was found to
yield higher recoveries than other common extraction methods (38).
Finally, the factor- that influence the stability and color intensity of
the chromogen- a n nabinoi(id products have been identified as chronmo-
gen ba i city. residual :zol vent and chromogen dyeltuff (9).
High pressure liquid chromatograpIy (HPLC) repre-ents a new
and potentially usvtful technique for cannabinoid analyses. The great
separatory capability inherent in IiPLC should lend it-.lf well to the
general problem of ie.-olving complex can.nabhinoid mixtures. A recent
report has desi-ribed the use of dansyl derivatives for the fluorometric
detection of cannabinoids separated by ITPLC (1). The results ob-
tained from the analvsi- of c!iiinabinoid standards illustrate that the
combination of dansyI derivatives and HPLC provides a, method with
the sensitivity and selectivity of GLC and mass fragment togra phy.
This method has recently been used effectively in an examination of
cannabinoid metabolites in dog feces (23). Furthermore, it is interest-
infy to note that TIPLC has been used to separate quantitatively drlta-
9-THC from other plasma heptane extractable substances (e.g., lipids)
that can interfere with the GLC analysis of such extracts (11).
Since the pioneer mass spectroscopy work with cannabinoids by
Agurell, et al. (56). which was summarized in the fourth Marihuana
and Health report (25). the technique has played an important vole
in the identification of individual cannabinoids. The inherent sensi-
tivity of the technique lends itself well to the potential measurement
of cannabinoids in biological samples; and workers at the. Re,-,arch
Triangle Institute have developed a method for the quantitative anal-
ysis of human plasma for concentrations of delta-9-TITC as low as 0.5
ng/ml (58). Mass fragmentographic methods have also been uimd in
a number of other studies (16,23,29,43,44,57).
Several reports have also appeared describing the use of RIA for the
detection af cannabinoids, particularly in body fluids (13, 26, 46, 47).






30


In addition, two new immunoassay techniques are under consideration:
homogeneous enzyme immunoassay (36) and free radical immunoassay
(6). The most appealing feature of immunoassay is its great sensi-
tivity, but limited selectivity continues to restrict its applicability.

METABOLISM
The continuing study of the biological disposition of the cannabi-
noids has yielded a greater understanding of factors affecting their
metabolism, the nature of their metabolites, their distribution in the
body and, finally, the routes of their excretion. Research into hepatic
iMicrosomal metabolism was designed to define the optimal in vitro
conditions for the metabolism of delta-9-THC (40). The influence of
several cannabinoid vehicles on delta-9-THC metabolism was evalu-
ated. and apparent Km and Vmax values were determined. The pat-
tern of metabolite production was followed as a function of duration
of incubation.
Twenty-four hours after oral administration, crude cannabis resin
was found to increase both pulmonary and hepatic aryl hydrocarbon
hydroxylase activity in male rats (42). The stimulus for this effect
may have been the trace quantities of benzo-(alpha)-pyrene found in
cannabis resin. In another experiment, the rate of delta-9-THC metabo-
lism both in vivo and in vitro was increased by the daily pretreatment
of rats with phenobarbital (39). Despite an increased rate of metabo-
lism, neither the apparent Km nor Vmax was altered. The pheno-
barbital effect was compared with the response in tolerant animals:
In vitro, the rate and pattern of metabolism was unchanged, and, in
vivo. the amounts of cannabinoid in tissue and its disappearance from
blood was also unaffected. The data suggest a functional, rather than
a dispositional, basis for tolerance.
Various druas have been examined in terms of their effects on the
in vitro and in vivo metabolism of delta-9-THC (41): Pentobarbital,
phenobarbital, SKF 525-A, amphetamine and meprobamate all in-
hibited delta-9-THC metabolism in vitro; under similar conditions
morphine and mescaline had no effect. In contrast to these general
findings, only SKF 525-A affected delta-9-THC metabolism in vivo.
It appears, therefore, that the in vivo interactions between delta-9-THC
and other centrilly acting drugs cannot be explained by an alteration
in delta-9-THC metbolism.
Recent ex-minations of the delta-9-THC biotransforination prod-
ucts of rabbit and dog? liver microsomes have revealed the presence of
1.h-ep~x)hexaiLIydio(Taa)in~od (3, 55) ; and a comparison of metabo-
lites from the perfused dog lung and from dog hepatic microsomes
has led to tlie rlscovery of side-chain hvdroxylated derivatives (55).
Moreover, tliere is now evidence that CBN and its oxidized derivatives
ar, normal metalwoites of delta-9-THC. CBN has been identified in
human plasma following miarihuana smoking (27), in rat bile (54)
and iii rat blood (28) after intravenous injection of delta-9-THC.
Oxidized metabolites of CBN have also been identified (2, 5); and a
new lnetal)olite containing two carboxyl groups h)as been isolated from
rabbit urine (30). Both rat and rabbit liver microsomes were found
to convert CBN into a number of side-chain hydroxylated compounds







(53). In addition, marihuana metabolites in human urine have been
extracted by a new method which separates them into neutral, weak
and strong acid fractions (17).
Various aspects of the distribution of the cannabinoids in the body
have been investigated: Thus, one research group has found that the
properties of delta-9-THC in plasma are a function of the method of
administering the drug (10). In this study, delta-9-THC was admin-
istered either intravenously in polyethylene glycol or in rat serum,
or in the form of cannabis smoke. Plasma disappearance curves varied,
depending upon the method of administration, and, compared with the
other two means of administration, injection in serum resulted in a
slower elimination from plasma., a lower proportion of metabolites rela-
tive to delta-9-THC and a different distribution of binding to plasma
proteins.
Other investigators found that the plasma-protein distribution of
delta-9-THC after intravenous administration differs in female and
male rats (7) ; and at all doses tested, the response in females was more
pronounced. The latter finding correlated with that of higher tissue
concentrations of delta-9-IIIC and its wetabolites in the female;
therefore, the enhanced activity of delta-9-THC in the female rat mav
be due to the higher tissue cannabinoid concentrations in the brain.
The relationship between tissue-drug concentration and pharma-
cological activity was extended in a comparative study of the effects
of delta-9-THC and dimethylheptopyran (DMHP) on mouse im-
mobility (21). Like delta-9-THC, the brain concentrations of DMTHP
and its hydroxylated metabolite correlated with the behavioral effect
(21). Despite DMHP's greater potency, the fraction of the dose in
the brain was smaller than that of delta-9-THC; thus, the potency dif-
ference between delta-9-THC and DMJHP appears to be a consequence
of the latter's greater activity at the site of action.
Plasma concentrations of delta-9-THC. 11-hvdroxv-delta-9-THC,
CBN and CBD were measured by radiommunoassav as a function of
time after their intravenous administration in the rabbit (45). Delta-
9-THC was unlike the other drugs, because plasma values for reacting
substances rose for several minutes after injection, presumably due to
the rapid formation and re-entry of the 11-hydroxy metabolite into the
plasma. In humans, this metabolite leaves the plasma more rapidly than
does delta-9-THC (33) ; an observation that has been confirmed in mice
(32).
In a study of lactating ewes, both delta-9-THC and its metabolites
were recovered from the milk for as long as 96 hours after administra-
tion of a single, intravenous low dose (15). Other investigations have
shown that biliary excretion in rats accounts for the elimination of
60% of an intravenous dose of delta-9-THC (3mg/kg) (40), that
biliary excretion remains unchanged when tolerance to THC develops
(39), and, finally, that most of the metabolites in the bile are highly
polar substances.















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norcannabinoid. "Journal of Medicinal Chemistry," 17: 1234-1235 (1974).
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by radioimmunoassay. "British Medical Journal," 3:348-348 (1975).
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Wall, 2M. E. The rate of penetration of (delta-9-tetrahydrocati;ilbinol and 11-011-
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International Congress; of Pharmacology, Helsinki, Finland, 1975.
33. Perez-Reyes. M., Timmons, 1M. C., Lipton. 21. A., Christepii-en, LI. D., Davis,
K. H. and Wall, -M. E. A comparison of the pharmacological activity of delta-
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entia," 29:1009-1010 (1973).
34. Razdran, R. K., Dalzell, H. C. and Handrick, G. R. Hashish. A simple one-
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35. Razdan, R. K., Handrick, G. R. and Dalzell, H. C. A one-step synthesis of
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International Congress of Pharmacology, Helsinki, Finland, 1975.
38. Schoolar, J. C., Ho, B. T. and Estevez, V. S. Coinpa rison of various solvent
extractions for the chromatographic analysis of delta-9-THC and metabolites.
Paper presented at the Sixth International Congress of Pharmacology, Helsinki,
Finland, July, 1975.
39. Siemens, A. J. and Kalant, H. 'Metabolism of delta-1-tetrahydrocannahinol
by rats tolerant to cannabis. "Canadian Journal of Physiology and Pharma-
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40. Siemens, A. J. and Kalant. H. Metabolism of delta-1-tetrahydrocannabinol
by the rat in vivo and in vitro. "Biochemical Pharmacology," 24:755-761 (1975).
41. Siemens, A. J., deNie, L. C., Kalant, H. and Khanna, J. TN. Effects of
various psychoactive drugs on the metabolism of delta-1-tetrahydrocannabinol
by rats in vitro and in vivo. "European Journal of Pharmacology," 31: 136-147
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34


42. Skelton, F. S. and Witschi, H. P. Aryl hydrocarbon hydroxylase activity
induced by cannabis resin: Analysis for polycyclic hydrocarbons. "Toxicology
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44. Stromberg, L. Minor components of cannabis resin V. Mass spectrophoto-
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45. Teale, J. D., Clough, J. M., Piall, E. M., King, L. J. and Marks, V. Plasma
cannabinoids measured by radioimmunoassay in rabbits after intravenous injec-
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CHAPTER 3


TOXICOLOGICAL AND PHARMACOLOGICAL EFFECTS
The toxicological research reviewed in the present Marihuana and
Health report is the result of the continuing need to identify and
evaluate the toxicological properties of marihuana. To fill this need,
a series of inhalation toxicity studies have made two major contribu-
tions. First, in the absence of detailed pathological studies in humans,
marihuana has been administered to numerous species in a wide range
of dosages by a variety of routes-including inhalation. The report
that chronic adininist ration of low doses by smoke inhalation results
in a toxicity comparable to that elicited by other routes of administra-
tion serves to validate the conventional animal toxicity studies which
are based on either the oral or parenteral route. Accordingly, the mass
of animal data collected in the past few years leads to the conclusion
that, to date, regardless of the route of administ rat ion, the ob-irved
toxicity of marihuana is not :vzociated with any serious pathological
changes.
Secondly, until the inhalation studies, most cannabinoid toxicity
research was restricted to the principal psychoactive constituent of
cannabis, delta-9-TJIC: now. however, cainizibidiol and caiinabi-
chromene-both formerly considered pharmacologically inactive-are
known to contribute significantly to the toxicity and lethality of
marihuana. Clearly, future toxicological evaluations of cannabis con-
stituents must be extended to all the major, naturally occurring canna-
binoids. both alone and in various combinations.
Another important aspect of toxicological research arises from the
reported effects of marihuana on such cellular components and prod-
ucts as lipids, proteins, nucleic acids, hormones and neurochenical
transmitters. An association between some of these effects and animal
behavior has now been made: most, but not all, of the changes apipea V
to be readily reversible. These cellular effects and their implications
are not easily understood, but they may reflect subtle alterations in
function independent of any gross pathological changes. With chronic
drug exposure, however, these subtle changes may evolve into signifi-
cant toxicological factors.
The study of the pharmacological properties of marihuana is impor-
tant for at least three reasons: (1) to define its effects, particularly
its possible toxic effects: (2) to determine the potential interaction
of its effects with various pathological states (e.g., coronary artery
disease, liver disease, epilepsy) : and (3) to evaluate the potential
therapeutic uses of the cannabinoids. During the past year there have
been sicnifica nt. contributions to the attainment of all these objectives.
Several studies have recognized the ability of the cannabinoids to
interact, not only with one another, but more importantly, with other
(35)






36


drugs; the interaction in some instances results in the enhancement of
a drug effect, in others in an antagonism. Such a complex set of effects
has been described in the case of the barbiturates, the amphetamines
and alcohol. The significance of this interaction potential is obviously
not limited to drugs used only for illicit purposes: From the reported
interaction effects, the concurrent use of marihuana with licit drugs
could conceivably result in an increased toxicity, a diminished thera-
peutic effectiveness or, even, an enhanced therapeutic effectiveness.
Another report of a potentially significant drug interaction centers
on the delta-9-THC blockade of the morphine-abstinence syndrome.
If this effect, is confirmed. then the characteristics and consequences
of the interaction should be defined further, particularly with refer-
ence to other drugs known to block the opiate-abstinence syndrome.
The pharmacological studies included in the present. Marihuana
and Health report reveal the toxic influence of marihuana. on pre-
existing pathological states (62) : Thus, the clinical description of
the adverse effect of smoking marihuana on cardiac function in
patients with coronary artery disease. is a significant contribution
toward a more comprehensive picture of the toxicity of cannabis.
There are also reports of animal data indicating that, the use of mari-
huana may adversely affect the control of seizures. This interpretation
is bhi ed on several observaat ions of marihiana's central-nervous-system
excitatory properties and on the hyperexcitability following with-
drawal from repeated delta-9-THC treatment. These potentially
unfavorable interactions with epilepsy may be independent of the
anticonvulsant properties of marihuana, as is the case with some
antiepileptic drugs, such as phenobarbital.
The Report (62) contains descriptions of two pharmacological
effects that have definite clinical potential: The decrease in intraocular
pressure and the anticonvulsant activity, both of which are described
in sufficient detail to warrant serious consideration of their therapeutic
application. Furthermore. the quantitative evaluation of the relative
anticonvulsa nt, and neurotoxic activity- of several cannabinoids has
demonstrated that a potentially useful therapeutic effect of cannabi-
diol is at least partially separable from the motor toxicity of mari-
huana. a finding which is further supported by the report of
cannabidiol's complete lack of psychotoxicity in humans. A compar-
-able pharmacological selectivity for other cannabinoid effects deemed
potentially valuable clinically is thus a distinct possibility. Finally,
the introduction of numerous synthetic cannabinoids presents an
opportunity to search for the most appropriate agent for any given
desired effect.
TOXICOLOGICAL EFFECTS
Investigators have continued to evaluate the toxicity associated with
chronic exposure to the cannabinoids using various routes of adminis-
tration and several different. species. Experiments have been of two
basic types: those. designed to study lethal effects produced by the
chronic administration of massive doses. and others designed to study
sublethal toxicity produced by relatively low doses, such as those
commonly used by humans. The chronic low-dose work now includes
rat studies of toxicity following smoke inhalation (71) : The daily
doses given to 1-, 5- and 23-day exposed animals were analogous to






37

those taken by humans, and the results indicate that inhalation of
delta-9-tetrahydrocannabinol (delta-9-THC) can produce the char-
acteristic marihuana central-nervous-system (CNS) toxic effects
(depression and excitation) elicited by other routes of administration.
These effects, like those associated with other routes of administration,
appeared in the absence of any pathological changes, and tolerance
ultimately developed to most of them. In a study of the inhalation
toxicity of Turkish marihuana (high in cannabidiol and canimbi-
chromene and low in delta-9-THC content) rats were daily exposed
to smoke 5 days per week for 25 days (72). This treatment resulted in
various manifestations of CNS depres-ion and in a dose-related lethal
effect-respiratory arrest; such results demonstrate that cannabidiol
(CBD) and cannabichromene (CBC) can contribute to the toxicity
of marihuana.
Massive oral doses of delta-9-THC or crude marihuana ext racot
administered to rats daily for 28 to 91 days have been used to deter-
mine toxic neurochemical effects (59) : After 28 days of treatment,
signific:int, decreases were observed in total] brain protein, ribonuleiec
acid (RNA) and acetylcholinesterase activity. Thes1 neurochemical
changes in rats coincided with the appearance of the CXS stimulation
(fighting behavior and convulsions) characteristic of chronic mari-
huana treatment, and. like neurotoxicitV, were partially reversed by
91 days of continued administration.
In a study similar to that described immediately above, neurochem-
ical changes were evaluated in rats treated for as long as 180 days: in
this instance, however. the dose>, were relatively low-2, 10 or 50
mg/kg/day orally (60). The two lower do-es of delta-9-THC were
again analogous to the (dlrug content of the marihuana and hashish
consumed by humans. (This work is the counterpart of a low-do-e,
chronic-toxicity study (74) referred to in the 1974 Marihuana and
Health report (62). Neurochemical analyses of four areas of the brain
(frontal cortex. parietal cortex, subcortical regions and cerebelltun)
were made at various times after the initiation of chronic treatment
and generally showed neurocheinicail changes comparable to those
produced in the massive-dose study described above. In the lower-doze.
study, however, changes required longer periods of treatment to appear
and varied in the different areas of the brain. Some of the behavioral
and neurochemical changes were sex-linked, and several occurred after
the development of tolerance to the behavioral effects. Furthermore,
a few of the neurochemical alterations were reversible, even after a
30-day recovery period.
Neurotoxicity and EEG, effects of chronic oral treatment of rats
and rhesus monkeys have also been described (79. 80). In riits acute
treatment with 10 mg/kg delta-9-TIIC increased the frequency of
surgically induced polyspike activity, while chronic treatment resulted
in subcortical spike bursts with concomitant seizureii. In the rhesus
monkey chronicilly treated with crude marihuana extract equivalent
to 12.5 mg/kg delta-9-THC or more. the neurotoxic manifestations
always preceded and outlasted the effects on the EEG, and tolerance
developed more rapidly to the EEG effects than to the neurotoxicity.
The results suggest that the neurotoxic effects become manifest at
lower doses than the characteristic EEG effects, findings similar to
those previously reported in humans.






38


Monkeys treated intravenously (i.v.) with delta-9-THC exhibited,
at the injection site. such toxic reactions as edema, necrosis, ulceration
and fibrosis (83). In order to elaborate the local toxicity findings, the
drug was chronically administered subcutaneously (s.c.) to rabbits in
doses ranging from 15.9 to 153.4 mg/kg/day. The dermal responses,
which were generally dose-related, included erythema, edema, ulcera-
tion and nodule formation. These results illustrate that the use of
marihuana i.v. may be accompanied by local toxic reactions. The
chronically treated animals displayed dose-related decreases in body
and liver weights, in glycogen content of the liver, and in blood sugar
and alkaline phosphatase activity; serum potassium concentration was
elevated. As in other chronic toxicity studies from this group, no
pathological tissue effects-other than those at the injection site-
were discernible.
A study of the influence of different routes of administration and
vehicles on the lethal dose 50 (LD50) values of delta-9-THC has also
been made. (73). The oral LD50 for delta-9-THC in an aqueous emul-
sion of sesame oil and polysorbate 80 was similar to that obtained
with a pure sesame-oil vehicle, indicating that the composition of the
emulsion did not affect the LD50. Furthermore, the i.v. LD50 for the
same aqueous formulation was essentially identical to the inhalation
LD5O. In general, the results established the validity of the i.v. route
of administration in the investigation of the pharmacology and toxi-
colocry of marihuana-like substances.
The continuing interest in the carcinogenic potential of marihuana
smoke has brought forth a report that marihuana tar painted on
mouse skin produced a variety of effects on squamous cells, including
metaplasia of sebaceous glands (20). This good correlation with the
established carcinogenicity of tobacco smoke led the investigators to
conclude that cannabis smoke will also be carcinogenic, a conclusion
which is supported by bioassays of marihuana tar on mouse skin. Both
tumorgenicity and tumor-promoting activity were revealed although
at levels significantly lower than those resulting from tobacco smoke
(41). This contrasts with in vitro observations on human hlng explants
which suggest that cannabis smoke may be more carcinogenic than
tobacco smoke (91).
In another investigation, marihuana. smoke produced a dose-
dependent depression of the bactericidal activity of pulmonary alveo-
lar macrophages: the effect was related to a water-soluble constituent
in the smoke rather than to delta-9-THC (23). It is possible that, the
toxicity of marihuana smoke to the alveolar macrophage may impair
the ability of this cell to function in the host-defense mechanism of
the lung.
Numerous reports have appeared describing the effects of delta-9-
THC on the endocrines. The main thrust of research in this area has
aimed at pituitary and gonadal hormones. (See Appendix G "Human
Effects" for a detailed review of the latter.) One of the previously
reported effects of heavy marihuana use in humans was gynecomastia
(37). This effect has now been produced in rats given 1 mg/kg delta-
9-THC s.c. for two to three weeks (38). In a related study, delta.-9-
TITC in male rates increased pituitary weight, total pituitary prolactin
and the concentration of prolactin in serum (24), but in a similar






39


study, delta-9-THC decreased, rather than increased, serum prolactin
concentrations (57). The discrepancy in these results may be due in
part to differences in dosage: The effect in the former study was
obtained at 16 mg/kg. In humans, marihuana use has had no apparent
effect on serum prolactin. The gynecomastia described above was asso-
ciated with normal serum hormone values, while another group of
chronic marihuana users was also normal (56).
Research into the effect of delta-9-THC on other pituitary hormones
has indicated that in rats delta-9-THC in doses of 5 to 20 mg/kg
inhibited growth hormone and stimulated adrenocorticotropic hor-
mone secretion; daily administration of 20 mg/kg for 20 days did not
produce tolerance to these effects (55). The findings suggest that delta-
9-THC acts as a stress stimulus of the hypothalamicpituitary axis. A
similar response to delta-9-THC in the mouse was evidenced by an
increase in corticosterone concentration in plasma (69), although tol-
erance to the effect on steroid secretion rapidly developed in this
species. The work of one group of investigators has shown an
inverse relationship between plasma corticosterone and the amount of
5-hydroxytryptamine in whole brain. A positive correlation between
the steroid value and aggressive behavior in ovariectomized rats fol-
lowing chronic cannabis treatment was found (66). Aggressiveness
was abolished by estrogen treatment, suggesting that previously
described sex differences in response to cannabis may, in part, have
been due to female variability during different phases of the estrus
cycle.
The inhibitory effect of delta-9-THC on the secretion of growth
hormone also manifested itself in prepuberal male rats (17), but in
adult female rats high doses of the drug (50 mg/kg) elevated serum
growth hormone values (28). In a study of male mice chronically
treated with delta-9-THC, growth was depressed in a way similar to
that seen in estradiol treated animals, suggesting that delta-9-THC
can exert an estrogen-like effect (78).

PHARMACOLOGICAL EFFECTS
The similarities in psychological actions between the liqueur
absinthe and cannabis have led to a molecular structural comparison
of their active principles, thujone and tetrahydrocannabinol (26).
Because the substances have a similar molecular geometry and similar
functional groups, they may exert their psychic effects by interacting
with a common receptor in the CNS. The receptor should have a bind-
ing site for oxygen, a planar region for the allyl group and pockets,
or cavities, for fitting with alkyl and hydrogen groups that are com-
mon to both drugs. The importance of the phenolic hydroxyl group in
tetrahydrocannabinols in eliciting delta-9-THC-like activity in ani-
mals has also been established (86).
Studies of the effects of delta-9-THC on sleep-wakefulness patterns
referred to in the 1974 Marihuana and Health report (62) have been
expanded to include the male squirrel monkey whose patterns are simi-
lar to those of the human (1). Chronic treatment reduced slow-wave
sleep time, which failed to return to normal, even after a 30-day
recovery period. In addition to this change in sleep pattern, the time






40


spent in Stage 1, or drowsy sleep was increased in treated animals and
this change also persisted throughout the recovery period.
The analgesic activity of delta-9-THC has now been described in
the dog, as well as in the rat, mouse and rabbit (54). Tolerance, which
has been found to develop to such other effects in the dog as ataxia and
sedation, also developed to the analgesic effect. Two cannabinoid-free
extracts (an aqueous extract and a volatile oil) of marihuana also
were found to elicit analgesia in mice. The analgesic potency of the
extracts was much lower than that. of delta-9-THC, but the nature of
the analgesic material and its interaction with delta-9-THC are still
unknown.
Many cannabinoids, in addition to delta-9- and delta-8-THC, are
known to be anticonvulsants: These include cannabinol (CBN),
dimethylheptylpyran (DMHP) and some of its isomers; 11-hydroxy-
delta-9-THC (46); 8-alpha, 11-dihydroxy-delta-9-THC (45); and
some new benzopyrans (70). Moreover, the activity of CBD has been
confirmed and the compound subjected to a variety of seizure tests
which have demonstrated that in its anticonvulsant properties the drug
more closely resembles diphenylhydantoin (DPH) than does delta-9-
THC (44, 49, 85). The interaction of CBD with other anticonvulsant
drugs has also been described in studies that generally show that, in a
maximal electroshock test in mice, CBD clearly enhances the potency
of delta-9-THC, DPH and phenobarbital (PB). The determination
of the protective indices (toxic dose/anticonvulsant dose) of several
cannabinoids in mice indicates that motor toxicity is a separable effect
from anticonvulsant, activity (46); for example, compared wVitli delta-
9-THC, DMHP is relatively more toxic and CBD significantly less
toxic. Furthermore, the separation of toxicity from anticonvulsant
activity is dramatically illustrated by the report that massive i.v. doses
of CBD in humans do not produce either the marihuana-like psycho-
toxicity or tachycardia (68).
In rats and mice subjected to a maximal electroshock test, tolerance
to the protective effect of delta-9-THC and CBD rapidly developed
(46, 47), but a similar response to repeated treatnientt was associated
with DPH and PB (47); in addition, tolerance to delta-9-THC or
CBD involved cross-tolerance to DPH and PB (47). Tolerance has
also been described for the antiseizure activity of delta-9-THC in the
gerbil, but in this case it did not develop to the neurotoxic effects (82).
It should be noted, however, that a study of the. influence of repeated
daily drug treatment on the results of several anticonvulsant tests
indicates that tolerance does not develop to all the anticonvulsant
properties of the cannabinoids (48). In fact, in some tests anticon-
vul sant activity increased, rather than decreased, with repeated treat-
ment. Similar results were obtained with DPH but not with PB. Tho
evidence suggests that. the tolerance observed is not a dispositional but
a functional adaptation. For example, in one study tolerance to pro-
tection 1,raginst. a mnaxi mal elect roshock developed concurrent with an
accumnulat ion of cannaibi iioids in tlhe CNS and increased sensitivity to
caiinalbirloids in certai ]I aniticonvulsa]it tests, while no change occurred
in plasma delta-9-TJIC concept ration or in barbiturate sleep time (48).
Previous reports mintioiied descriptions of some excitatory prop-
ert ies of delta-9-111C, especially in coniijiiuiction with toxicity produced








by chronic, high-dose treatment. Withdrawal from repeated treatment
with anticonvulsant doses of delta-9-THC also resulted in CNS hyper-
excitability, as measured by a decre-ise in the 6-Hz-electroshock thresh-
old test for minimal seizures (49, 50) ; no such withdrawal increase
manifested itself in the case of CBI) or DIPH. On the other hand,
withdrawal hyperexcitability to delta-9-THC could not be demon-
strated when pentylenetetrazol (PTZ) was used to elicit minimal
seizures (11). Following low-dose, i.v. administration, convulsant
effects of delta-9-TIIC have been observed iii a special train of rabbits
(19). Furthermore, delta-9-THC administered i.v. to the photosensi-
tive baboon Papio papio resulted in an epileptiform EEG response.
3/sec rhythmic spikes and waves (63) ; no dose were anticonvulsant
against the photically elicited myoclonic activity, but high dc--s (1-5
mg/kg) enhanced seizure respoi,-es in some ea-es.
In the area of cannabinoid hypothermic activity, one recent study
compared several cannabinoid preparations with chlorpromazine in
mice (58) and ranked them in order of decreasing potenicy as follows:
chlorpromazine, marihuana extract, distillate. DMIIP. delta-s- and
delta-9-THC. Tolerance to the effects of both delta-9-THC and chlor-
promazine rapidly developed, although more rapidly to the former
drug. Antipyretic activity for delta-9-THC, suggested by previous
reports, have now been confirmed in mice (16). Additionally. with
respect to the mechanism which lowers body temperature. the results
from direct and indirect cal orimetrv measurements suggest tb at delta"
9-THC-induced hypothermia is associated with both a decrease in heat
production and an increase in heat loss (4, SS). In brain, some wivesti-
gators have found a decreased tissue metabolic rate following in vivo
drug administration and a subsequent tolerance (64). Such an effect
on metabolic rate could be mediated bv either a direct or indirect action
of the cannabinoids: A direct effect of several cannabinoids on tisue
oxygen consumption in vitro has been described by another research
group (14) who reported that the cannabinoids depress the oxygen
consumption of homogenates of liver, heart, brain and 4 elettal muscle.
Moreover, mitochondrial preparations from the latter two tissues were
studied further and their metabolic rates were also depressed. The
dose-response data from the oxygen consumption research indicate
that hypothermic doses of delta-9-THC yield tissue-drug concentra-
tions sufficient to depress metabolic rate directly.
Recent research into the cardiovascular effects of marihuana has
yielded a number of studies on various facets of this subject (cf. 15).
For example, it has been found that in rats tolerance does not develop
to the bradycardia. commonly associated with chronic marihuana treat-
ment (53). In addition, the effect of delta-9-TH{C on cardiac function
has been described in pentobarbital-anesthetized dogs with an elec-
trically maintained constant heart rate (9). In this study. the drug
decreased aortic blood pressure, cardiac output, left ventricular peak
pressure and left ventricular end-diastolic pressure, but the contractil-
ity index was not affected. The decrease in cardiac output could be
restored to normal by elevating left ventricular end-diastolic pressure
with an expansion of plasma volume. In dogs with a maintained con-
stant cardiac output, delta-9-THC decreased blood pressure and total
peripheral resistance, but increased ilitravascular blood volume. These


67-i1 )-76-4





42


results indicate that the delta-9-THC induced decrease in cardiac out-
put in the presence of constant cardiac rate is due to a decreased venous
return, rather than to a decrease in myocardial function.
In a study using spinal preparations, delta-9-THC exerted no cardio-
vascular effects; hence, the role of the CNS in mediating delta-9-
THC's effects on heart rate and blood pressure was investigated in cats
anesthetized with chloralose (87). Spinal transaction (C1-C2) abol-
ished the drug-induced bradycardia and hypotension. The delta-9-
THC-ca used bradycardia was also blocked by the surgical removal of
tone to the heart, but neither heart-rate nor blood-pressure effects were
modified by bilateral vagotomy. Sympathetic outflow in the inferior
cardiac nerve decreased after delta-9-THC administration although
peripheral sympathetic functions were unaffected; thus, the cardio-
vascular effects of delta-9-THC appear to be due to a CNS action which
results in a decrease in sympathetic tone.
Other investigators have examined the relationship between the
sympathetic nervous system and delta-9-THC's cardiac effects in terms
of changes in the uptake of noradrenaline by the heart and have found
that delta-9-THC, like cocaine, can decrease in a dose-related manner
the uptake of noradrenaline by the isolated, perfused rat heart, al-
thouffh cocaine. appears to be about ten times more potent than delta-
9-THC (32). The significance of such effects is not yet clear, but of
great interest is the report that smoking marihuana can adversely
affect cardiac function in patients with angina pectoris (3). In these
patients, smoking one marihuana cigarette containing 19.8 mg delta-
9-THC decreased exercise performance significantly more than smok-
ing one placebo cigarette.
The cannabinoids' ability to decrease intraocular pressure is still
inciting investigation and several congeners of delta-9-THC, admin-
istered either systemically or topically, have now been tested. These
are listed in order of decreasing efficacy: 11-hydroxy-delta-9-THC;
delta-9-THC; 8 alpha, 11-dihydroxy-delta-9-THC; SP111A; other
derivatives (33). Delta-9-THC can decrease the pressure in the rabbit
eye by 25% and increase outflow capacity by 70% and the role of the
sympathetic nervous system in mediating these effects has been estab-
lished (34, 35, 36). The alpha-response is an enhanced total outflow
facility and the beta-response is a vasodilatation of the efferent ves-
sels from the anterior uvea, thereby causing a decrease in the forma-
tion of aqueous humor. Part of delta-9-THC's effect on intraocular
pressure appears to be mediated through these actions on sympathetic
receptors; but most arises from a central effect.
The influence of cannabinoids on biogenic amines continues to be a
focal point for studies of their mechanism of action. In a rat study of
repeated delta-9-THC treatment on brain metabolism of 5-hydroxy-
tryptamine (5-HT) and norepinephrine (NE), the products of metab-
olism were isolated from whole brain following the intracisternal
administration of radiolabelled 5-4T or NE (40). Chronic treatment
yielded a decrease in the metabolism of 5-HT but an increase in that
of NE. In another study in the rat, the effect of hypothermia doses of
delta,-9-THC on the metabolism of 5-HT and NE in the hypothalamus
and brainstem was reported (89), and these results show that there are
no changes in either the amount or the turnover of these amines in the





430


two parts of the brain investigated. Several cannabinoids have been
examined for their effect on the uptake of NE, 5-11T, dopamine (DA)
and gamma-aminobutyric acid (GABA) by synaptosomes derived
from various regions of the rat brain (6). The findings indicate that
camnabinoids can inhibit the uptake of NE, 5-HT and GABA by
hypothalamic synaptosomes; in addition, a discussion of the structural
requirement for these effects is included. Delta-9-THC can also aug-
ment the release of NE from the isolated rat vas deferens (32), an
observation which has led to the suggestion that the release of trans-
mitter from peripheral stores may, in part, account for the hypotensive
activity of delta-9-THC. Delta-9-THC can decrease the uptake of DA
by crude striatal synaptosomal preparations (42) ; however, ampheta-
mine is more potent in this regard. Delta-9-THC also appears to alter
the intraneuronal disposition of DA without any effect on its metabo-
lism (65). It is possible that these effects are related to delta-9-THC's
known interaction with amphetamine.
Studies of the mechanism of action of delta-9-THC have been
expanded to include its effect on cyclic adenosine. 8'.5'-monophos-
phate (cyclic AMP), and investigators have found that low doses of
delta-9-THC (0.1-1.0 mng/'kg intraperitoneally) cause a 50-160c
increase in brain cyclic AMP. whereas higher dosz- (2.0-10 mg/kg)
depress cyclic AMP 30-CO'- (27). This biphasic. response apparently
correlates with other previously reported biphasic responses in bio-
genic amines, temperature regulation and behavior.
The influence of tetrahydrocaimabinols on brain acetvlcholine con-
tent has also been ilive-tigatv-d (5). The intravenous administration
of 5 mg/kg delta-9- or delta-8-THC was found to decrease bin in
acetylcholine content, while 11-hydroxy-delta-9-THC, a metabolite,
was ineffective. Delta-8-THC did not appreciably alter either acetyl-
choliinesterase or choline acetvltransferase. The decrezas-e in acetvl-
choline was not observed in rnts treated with 6 mg/kg intraperitoneally
(90). In contrast to the results described above for acute experiments.,
chronic oral cannabinoid treatment produced a decrease in brain
acetvlcholinesterase activity, as well as a decrease in total protein and
RNA (59) ; however, no changes were observed in brain lipid. glyco-
lipid or cholesterol concentration. In the chronic study. the neuro-
chemical changes coincided with the onset of neurotoxicity; further-
more, both were partially reversed during continued drug treatment.
The mechanism of some of the anticholinergic effects of the canna-
binoids remains to be elucidated.
The relationships between cannabis and prostaglandins have been
studied further and it has been confirmed that cannabinoids inhibit
the formation of prostaglandins PGE1 and PGE2 but they also stim-
ulate PGF production (22). In another study, eugenol. a minor vola-
tile constituent of cannabis. was found to be a more active inhibitor
of PGE1 synthesis than was delta-9-TIHC. This observation, com-
bined with a demonstration of pharmacological activity in the essen-
tial oil fraction (76), indicated: a need to consider the role of these
substances in the pharmacology of cannabis. The release of PG-like
substances by delta-9-THC from both rabbit kidney and guinea-pig
lung has been reported (52) : These substances produced renal vaso-
dilation and pulmonary vasoconstrictiion. responses which were blocked






44


by aspirin. The former effect may account for the diuretic property
ascribed to delta-9-THC, while the delta-9-THC-caused release of
PG-like material may be related to the increase in PG synthesis re-
ferred to above (22).
An examination of the influence of acute and chronic delta-9-THC
treatment on the lipids of rat brain subeellular fractions has revealed
the following effects: Acutely, the lipid content. of the mitochondrial,
synaptosomal and myelin fractions decreased, but in the microsoinal
fraction all major lipid components increased; chronically, these
changes tended to return to normal (75). Other reports have, noted
a lvsis of rat liver lysosomes in vitro by high concentrations of delta-
9-THC (8), and the uptake of delta-9-THC in vivo by the. lysosomes
(43).
Numerous interaction studies of marihuana constituents have been
undertaken since the last report and the interaction between canna-
binoids, particularly between delta-9-THC and CBD, has received a
great deal of attention. CBD's ability to antagonize some of the be-
havioral effects of delta-9-THC has been established and studies have
been extended to the investigation of other effects. In one such study,
prior treatment with CBD blocked the delta-9-THC induced catatonia.
corneal areflexia and aggresiveness in REEM sleep-deprived rats (51).
In addition, CBD potentiated the delta-9-THC analgesic effect and
impairment of rope climbing. In another study, pretreatment with
apparently inactive doses of CBD reduced the depressant effects of
delta-9-THC on body temperature, on heart rate and on respiration
(7). CBD also reduced the depressant effects of delta-9-THC on
variable-interval and fixed-interval schedules of food reinforced oper-
ant behavior (25). In these tests, high doses of CBD did affect these
behavioral parameters, suggesting that CBD can function as a partial
a(ronist. A comparison of the interaction of CBD and CBN with delta-
9-THC showed that CBD intensified delta-9-THC's effects on animal
motility, on food and water intake, on body temperature, oil catalepsy,
and on hexobarbital sleep time (30). CBX, in general did not alter
the activity of delta-9-THC, except in the barbiturate sleep-time test.
In this case, CBN, in contrast to CBD, blocked the delta-9-TIIC
prolongation of hexobarbital sleep time, thus corroborating an earlier
report of CBN antagonism. The evidence presented suggests that. CBD
heightens the effects of delta-9-THC by a metabolic interaction at the
level of the hepatic drug-metabolizing enzymes; on the other hand, the
observed antagonism between CBN and delta-9-THC on sleep time
appears to be a central interaction (29). The ability of CBD to poten-
tiate the anticonvulsant activity of delta-9-THC was described above
(85). An in vitro potentiation has also been reported (2). Both delta-
9-TJC and CBD were found to depress intestinal motility, but delta-
9-THC was more potent. Inactive doses of CBD increased lthe depres-
sant effect of (delta-9-THC, demonstrating that potentiation was not
necessarily mediated by a CBD blockade of delta-9-TIIC's metabolisIu.
The interaction of CBN with depressant, excitatory and peripheral
effects of delta-9-T1IC lias also been described (81) : Inactive doses of
CBN appeared to enhance the depressant, effects and slightly inhibit
excitatory effects, while having no effect on a peripheral response to
d( lta-9-THC.






45


Additional studies have focused primarily on the interaction of can-
nabinoids with other drugs. Acutely, delta-8-THC, in a dose-related
manner, prolonged alcohol sleep time, but tolerance developed to this
interaction with repeated cannabinoid exposure (31). The enhanced
sleep time produced acutely cannot be attributed to an altered rate of
alcohol metabolism (31). The possibility that some of the effects of
delta-9-THC are mediated by an action on chemical transmitters has
been pursued by measuring the cannabinoid's influence on the LD)0s
of certain drugs. It was found to intensify the toxicity of some cholin-
ergic drugs but to attenuate the toxicity of others; the toxicity of
adrenergic drugs was significantly reduced by the pretreatment with
delta-9-THC and, finally, delta-9-THC increased the. toxicity of a
5-HT-blocking drug (77).
The interaction studies of cannabinoids and barbiturates have been
expanded to include ether anesthe-ia (13, 61). Cannabis extract. pro-
longed the duration of both barbiturate and ether anesthesia. How-
ever, after repeated treatment, tolerance developed to the interaction
with ether but not to that with pentob1 rbital. CBN also prolonged the
duration of ether anesthesia, but CBD tended to antagonize ether. The
investigators su ggested that the failure of others to observe any such
effect on ether anesthesia may have been the consequence of the variable
cannabinoid composition of cannabis extracts.
A study of the interaction of delta-9-THC pretreatment with
d-amphetamine in aqrirl,-ated mice, indicated that cannial)inoid ire-
treatment can potentiate motor activity and lethality without affection
hyperthermia (21) : these effects were a1-1Zociated with a decree -e in
the amount of amphetamine in the brain. The influence of a combined
treatment of (letla-9-THC and inethamphetamine on the EEG and on
bR-11avior has been described by other investiU;itors v\ ho reported meth-
amphetamine reversed the delta-9-THC effects o ndie EEG. but the
combination of drugs produced some striking behavioral disturbii ices,
which appeared to be a potentiation of methamphetamine toxicity
(18). An interaction between delta-9-THC and a naloxone-preeipitated
abstinence in morphine-dependent rats appears to exist for a sin le
delta-9-THC pretreatment can block in a do-e-related manner the
naloxone-induced abstinence signs. Pretreatment with 10 mg/kg CBD
failed to produce any such effect (39).
It should be noted that two comprehensive reviews (67, 84) on the
general subject of the pharmacology of marihuana have appeared since
the 1974 Marihuana and Health report (62).














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December, 1974.












CHAPTER 4


PRECLINICAL EFFECTS: UNLEARNED BEHAVIOR
As the studies reviewed in the four previous Marihuana and Health
reports (44, 45,46,47) have shown, the cannabinoids produce a variety
of effects on unlearned behavior in different animal species. The litera-
ture pertaining to cannabis and unleariied behavior is now quite volu-
minous. Consequently, this appendix focuses primarily on the relevant
literature which has appeared since the last report, although some
attempt is made to consider this literature in light of previous findings.
Furthermore, for the sake of exposition the appendix is organized
around four categories of unlearned behavior: gross behavior; activity
and exploration; consummatory behavior; and aggressive behavior.

GROSS BEHAVIOR
Much of the early preclinical research with canabinoids investi-
gated the effects of these drugs on the gross behavior of a wide range
of animal species. As has been discussed in previous Marihuana and
Health reports and recent reviews of the animal literature (e.g.. 53)
a variety of gross behavioral changes are induced in animals by the
cannabinoids. Included among these effects are: catalepsy, ataxia, ab-
normal body post urges, hypers'ei sitivity. and hyperactivity. Subsequent
to this earlier work on gross behavioral changes. much of the preclini-
cal work with cannabinoids pertained to learned rather than un-
learned behavior. Most recently, however, there has been a renewal of
interest in the gross behavioral changes induced in animals by canna-
binoids. The primary reason for this has been the recognition that
complex pharmacological interactions may occur among the canna-
binoids.
The majority of cannabinoids r-ozearch on unlearned behavior has
used delta-9-THC or delta-8-THC since these particular cannabinoids
have been established as the major active components of cannabis
samples (49). However, several re-earchers reported that the phar-
macolorical activity of cannabis s:nmples was not always entirely ex-
plained by the tet rahydrocannabinol content of the samples (7, 36. 55).
This led to the suggestion that interactions between THC and other
cannabinoid constituents of cannabis. namely cannabidiol (CBD) and
cannabinol (CBN), may be important. This suggestion was supported
by findings that CBD inhibits the metabolism of delta-9-THC (25,
35, 42).
Experiments dealing with interactions of cannabinoids on gross
unleariined behavior are still few in number. However, those inter-
actions which have been observed appear. at this time. to be complex
and are not always consistent among experiments. For example, in
(51)






52


testing the effects of cannabinoids on catalepsy in rodents, investi-
gators have found CBD and CBN administered alone to be either
active (37, 61) or inactive (24). Moreover, when administered in com-
aination with delta-9-THC, CBN has been reported either to have no
effect on catalepsy (24) or to potentiate delta-9-THC induced cata-
lepsy (61). Finally, CBD in combination with delta-9-THC has been
reportedd to prolong (24) or to enhance (37) catalepsy induced by
ielta-9-THC.
The interactions between the cannabinoids on drug-induced loss of
the righting reflex (anesthesia, sleeping-time) seem to be particularly
,omplex (14, 15, 25, 37, 41, 43, 61). For example, CBN antagonizes
ielta-9-THC effects on pentobarbitone- (41) and hexobarbitone- (2-5)
induced loss of the righting reflex but potentiates delta-9-THC-ether
affects on the same unlearned response system in the same animal
species (43). The complexity of these and other interactions (14) will
most likely be better understood with additional research-especially
research which can distinguish between drug interactions involving
CNS activity and those involving cannabinoid-induced changes in
tetrahydrocannabinol metabolism.
As would be expected, THC interacts with drugs other than the
cannabinoids to affect, unlearned gross behavior. Recent experiments
have shown that delta-8-THC potentiates the loss of righting reflex
induced in rats by alcohol (27) while delta-9-THC potentiates some,
and antagonizes other, amphetamine-induced postural and activity
behaviors in rats (30) and rabbits (16).

ACTIVITY AND EXPLORATION
Based on the research available at the time, the 1974 Marihuana
and Health report (47) concluded that cannabinoidss generally sup-
press the spontaneous motor activity and exploration of animals,
although findings regarding these effects are limited, as always, by
driug route, time-effect. and drug-response considerations" (20, 26).
The suppression effect of delta-9-THC on spontaneous motor activity
hirs been confirmed by two recent studies (6, 56). In one of these (6),
oral doses of delta-9-THC ranging from 1.25 mg/kg to 40.0 mg/,kg
were administered acutely to mice. The lowest drug dose produced a
significant. increase in activity while the remaining drug doses pro-
duced a dose-dependent suppression of activity. Other mice were used
to investigate tolerance to the suppressive effects of 40.0 mg/kg of
delta-9-THC (p.o.) on spontaneous activity. Complete tolerance
developed after one dose and had a duration of less than four days.
Another aspect of this latter study (6) deserves mention. Specif-
ically, the, activity of mice that had been previously habituated to
the experimental apparatus was not suppressed by a 40.0 mgY/kg dose
of delta-9-THC. This finding is in accord with other research (17, 19)
which shows that prior habit nation to an experimental situation can
alter the effects of THC on motor activity in animals.
Delta.-9-THC doses of 30.0, 60.0 and 120.0 mg/kg were administered
subctitaneoiisly to pregnant rats on the fourth day of gestation (66).
It was found that. delta-9-THC produced an increase in abnormal
pregnancies but that it had no significant effect on the locomotor activ-








ity of the offspring. This latter finding is at odds with a previous
experiment (7) in which effects were observed on the unlearned
behavior of offspring from pregnant rats that had been administered
delta-9-THC subcutaneously during the tenth to twelfth days of
gestation. Additional research is needed to determine whether delta-
9-THC has a direct action on the developing fetus which becomes
manifest in the unlearned behavior of offspring.
The spontaneous activity of rats was additionally used to study the
drug interaction between delta-9-THC and phencyclidine (56). It
was found that an increase in activity produced by 5.0 mg/kg intra-
peritoneal injections of phencyclidine was antagonized by oral doses
of delta-9-THC, ranging from 2.5 to 10.0 mg/kg, in a dose-related
manner.
Exploratory behavior and performance on simple unlearned motor
tasks have also been used recently to study the interactions of delta-
9-THC with other cannabinoids. First of all, it has now been reported
that CBD and cannabichromene (CBC), in inhaled doso? from 1.0 to
2.0 mg/kg decreases exploratory behavior of rats in a dose-related
manner (57) while CBN (10.0 mg/kg: i.p. injection) significantly
increased exploration-ambulation in rats (61). However, CBD did not
affect the motor coordination of mice over a wide range of i.p. doses
(62). In combination with delta-9-THC. both CBD (37) and CBN
(61) produce a pharmacological interaction on exploratory behavior
in rats, although delta-9-THC and CBD do not seem to interact to
affect motor coordination in mice (62).

CONSUMER BEHAVIOR
Prior to 1973 delta-8-THC, delta-9-THC, hashish resin, and pyra-
hexyl were all shown to produce reductions in food and water intake,
with a consequent weight loss, in animals. Research appearing since
that time, much of which was reviewed in the fourth Marihuana and
Health (47) report, has generally confirmed and extended these find-
ings for delta-8-THC and delta-9-THC (3. 28, 32, 33, 39, 59, 60). In
addition, inhaled doses of CBD and CBC have been recently shown to
reduce the rate of growth in rats and to decrease their food and water
consumption in a dose-related mariner (57). On the other hand, neither
CBN nor CBD were found to affect food and water consumption over
a range of i.p. doses up to 80.0 mg/kg (24). However, in this latter
study, CBD, but not CBN, was found to enhance the suppressive ef-
fects on consummatory behavior produced by delta-9-TIIC.
The general findings of cannabinoid-induced suppression of con-
summatory behavior stands in stark contrast to the findings that mari-
huana or hashish will increase the human appetite for food (1, 31).
Several possible explanations have been offered to account for this
discrepancy. Sofia and Barry (60) have suggested that since pure
delta-9-THC has not been used with humans, the appetite-timul ant
effect of marihuana might be due to a constituent other than THC.
The recent findings regarding CBN, CBD and CBC reported above
(24, 57) seem to make this suggestion less likely. It has also been sug-
gested that, since most animal studies have not taken continuous meas-
urements of consummatory behavior, increases in consumption may


t5)3








have been overlooked. However, in recent experiments with rats where
such continuous ineasures have been taken (32, 60), dose-related delta-
9-THC decreases in food and water intake have been confirmed. There
is some evidence (28) to support the contention (22) that the discrep-
ancy between animal and human consummatory behavior is due to the
higher cannabinoid doses, relative to body weight, used in animals
than in humans. Furthermore, the possibility that the discrepancy is
related to humans' adaptation to a long-term deprivation regimen
whereas most animals used as either nondeprived or acutely deprived
has also received empirical support, (29). Nevertheless, the discrepancy
between animal and human experiments is inadequately explained.
There is, of course, the possibility that the differences are due solely to
between-species differences. If so, consummatory behavior will stand
as a rare instance in which animal research with cannabinoids has not
served reliably as a predictor of cannabinoid effects in humans.
AGGRESSIVE BEHAVIOR
If aggression is taken as a uniform behavior of threatening or
attacking another animal, then conflicting findings regarding the
effects of cannabinoids on aggressive behavior exist in the literature.
However, a variety of procedures has been used to study the aggressive
interactions between animals under the influence of cannabinoids, each
of which tends to involve a different kind of aggressive behavior. In
fact, when separated by aggression paradigms, the literature reward-
ing cannabinoid effects on aggressive behavior is quite consistent. In
general, the conclusion from both the last Marihuana and Health
report (47) and a recent extensive review of the cannabis and aggre-
sion literature in animals (2) is that cannabinoids suppress aggressive-
ness in nonstressed animals but increase stress-induced aggression.
While one recent study (51) has demonstrated an increase in aggression
following long-term administration of THC to rats which were not
apparently stressed, the above conclusion applies to the acute cannabi-
noid experiments on animal aggressiveness which have appeared since
the last report. For the sake of discussion, the new experiments ANill be
divided into categories of stress-induced and nonstress-induced aggres-
sion, with the latter category being subdivided into isolation-induced
aggression, competitive aggression and predatory aggression.
Sfres i-nd(uced aggression
As indicated, when stressed animals are put under the influence of
cannabinoids the usual outcome is an increase in aggressiveness. This
outcome seems to be independent of the nature of the stressor used.
Increased aggression under cannabinoids has been reported for such
stressors as: starvation (13), low temperature (12), REM sleep depri-
vation (5, 11), withdrawal from morphine (10), septal lesions (21),
elect ric shock (9) and most recently, ovariectoomy (54).
Takahashi and Karniol (61) have investigated the interaction
between CBN and delta-9-THC with respect to stress-induced aggres-
sion. Generally, this experiment produced results comparable to a simi-






55

lar previous investigation of the interactive effects of CBD and
delta-9-THC on aggression induced by REM sleep deprivation (37).
Intraperitoneal injections of 20.0 mg/kg delta-9-THC and 80.0 mg/kg
CBN induced aggre-siveness in the stressed rats. Interestingly, how-
ever, when the same doses of CBN and delta-9-THC were administered
together, the amount of aggressiveness was less than that produced by
delta-9-THC alone (61).
I co at'on-ind-w-d aggiY on
Several experiments have shown that delta-9-THC and cannabis
extract will suppress isolation-induced aggression in rats which have
not also been subjected to stre.-s (e.g., 21. 58). Other studies have
shown that this cannabinoid-induced suppression of aggre_ion is not
a result of motor impairment (38) nor does it exhibit tolerance (C')).
The interaction between delta-9-THC and CBD on isolation-induced
aggres-ion was inve-tigated this year in mice (62). Intraperitoneal
dose? of 2.5 mg/kg delta-9-THC and 40.0 mg/kg CBD individually
suppressed aggreIivenes although the interaction between these two
ca nnabinoids was not significant.
Competitive aggrc*ss?.ion
Recent findings are in accord with previous results (34, 52, 64. 65)
showing that delta-9-THC reduced dominance and social competition
in animals. For example, Cutler et al. (18) administered cannabis
resin to mice in i.p. doses ranging from 4.0 to 100.0 mg/kg, then placed
the mice with unfamiliar partners. These researchers found that the
drug did not affect nonsocial behavior, social investigation or sexual
behavior. However, dose-related increases in immobility and flight rela-
tive to aggression were obtained.
Ely et al. (23) demonstrated the importance of the existing social
structure in their examinations of cannabinoid effects on aniiimal ag-
gression. Doses of 0.5, 2.0 and 20.0 mg/kg of delta-9-THC were intra-
venously injected into mice whose dominant or subordinate status in
their colonies was either relatively stable or whose dominance was
threatened either by a rival or an intruder. In the stable colonies the
only behavioral change noted was a limited period of reduced activity
by the dominant males. Dominant mice confronted with a rival ex-
hibited a reduction of activity and a consequent loss of their dominant
status. Dominant mice confronted with an intruder made fewer attacks
on the intruder than nondruoged dominant mice, but their aresnive-
ness returned to the pre-drug baseline level after 24 hours.
Dose effects of delta-9-THC on aggressive behaviors of resident and
intruder rats were examined by Miczek (50). This investigator varied
i.p. dose level from 0.125 to 4.0 mg/kg and found that as the do-e was
increased, attack and threat behaviors of the dominant resident rat
decreased. Only at the highest dose level of 4.0 mg/kg did delta-9-THC
interfere with the defensive and submissive behaviors of the intruder.
Predatory aggres . on
Research appearing before the last report (47) supported the con-
clusion that cannabinoids reduce predatory aggression in nonstressed






56
animals (2, 21, 48). Although one study (4) indicated that THO
could produce. muricidal behavior in rats which did not previously
display such behavior, it was not possible to conclusively determine
whether stress induced by food deprivation or the administration of
the cannabinoid over a 40-day period was responsible for this result.
However, a recent study by Miczek (51) indicates that the long-term
administration period may have been the crucial factor. This investi-
gator found that during an administration period of 60 days, pre-
viously nonmuricidal rats given sufficient food and water so as not to
lose weight and an intraperitoneal delta-9-THC dose of 10 or 20
mg/kg/day developed mouse-killing behavior.













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effects in rat at high doses. "Science," 175:911-912 (1972).
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26. Fried, P. A. and Niernan, G. W. Inhalation of cannabis smoke in rats.
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30. Gough, A. L. and Olley, J. E. Cannabis and amphetamine-induced sterotypy
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4-1-M8 (1971).
32. Huthsinz, K., Fetterolf, D. and Ferraro, D. P. Modification of drinking
behavior and water intake by delta-9-tetrahyclrocaniiinainol in rats. Paper pre-
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33. Jarlw, T. IU. C. and Henriksson, B. G. Acute effects of two tetrahydrocanna-
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34. JTnes-, B. C., Clark, D. L., Consroe. P. F. and Smith, H. J. Effects of (-)-
delta-9-tr n s-tetrah ydroca n nal iunols on social behavior of squirrel monkey dyads
in a waiter competition situation. "Psvch opharmacologin," 37: 37-43 (1974).
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45: 375-377 (1972).
36. Karniol, I. G. and Carlini, E. A. The content of (-)-delta-9-trans-tetrahydro-
eannabinol does not explain all biological activity of some Brazilian marihuana
sanimpl(q. "Journal of I'hnrnamey and Phrrnmacology," 24: 833-835 (1972).
37. Karniol, I. G. and Carlini. E. A. Pharmacologic interaction between cnnna-
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(1973).
3A. Killby, M. M. The effect of delta-9-tetrahydrocannnibinol on innate and in-
'4 runi"~~i 1i 'tiglItihIg lijl:i ;Vi' r in the m(ise. Pd p)er presentedl at the Southwestern
PsyciolorTical Association, 1971.
;30. TKiliey, M. M., Forhes, W. B. and Olivetti, C. L)elta-9-tetrahydrocannabinol:
Inhib~ition of deprivatifin and ca rbacol-indueed water consumption in the rat
after f-cntral ,ind( peripheral administration. "Behavioral Biology," 8:679-685
(1973).
40. Killicv, M. M., Moore, J. W. and Hall, M. Delta-9-tetrahydrocannabinol
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31: 157-16G (1573).
41. Kraintz. J. C., ]Rerger, H. J. and Welch. B. L. Blockade of (-)-trans-delta-
8-tetr.aihvydr(i-.innalhinol depressant effect. by canna-binol in mice. "American Jour-
nal of Pharmacology," 143: 149-152 (1971). .
42. Kupfer, D., Levin. E. and Burstein, S. H. Studies on the effects of delta-i-
tM-rahydroca nnahi nol (delta-i-THC) and DDT on the hepatic microsomal meta-
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43. Malor, R., Jackson, D. M. and Chesher, G. B. The effect of delta-9-tetra-
hydrocannabinol, cannfibidiol and cannabinol on ether anaesthesia in mice. "Jour-
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Department of Health, Education, and Welfare. Washington, D.C.: Government
Prilltin,- Office, 1971.
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Secretary of Health, Education, and Welfare. Washington, D.C.: Government
Pi inting Office, 1972.
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48. McDonough, J. H., Manning, F. J. and Elsmore, T. F. Reduction of predatory
aggres-,ion of rats following administration of delta-9-tetrahydrocaniabinol. "Life
Sciences." 11: 103-111 (1972).
49. Mechoulman, R. Marihbliai i chemistry. "Science," 168:1159-1160 (1970).
50. Miczek, K. A. A behavioral analysis of age.-ssive behaviors induced and
modulated by delta-9-tetrahydrocannabinol, pilocarpine, d-aniphetamine and L-
DOPA. "Activitas Nvi-vo-a Superior," in press.
51. Miczek, K. A. Moiius-1-killing and motor activity: Effects of chronic delta-9-
tetrahydrocannabinol and pilocarpine. "Psychopharipacolo~ i." in press.
52. Miczek. K. A. and Barry, H., I11. Delta-9-tetralydrocaniiabinoI and aggres-
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54. Palermo Neto, J., Nunes, J. F. and Corvalbo, F. V. The effects of chronic
cannabis treatment upon brain 5-hydrox ytryptamine, plasma corticosterone and
aggressive behavior in female rats with different hormonal status. "Psycho-
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55. Poddar, M. K. and Ghosh, J. J. Effect of cannabis extr:ict, delta-9-tetra-
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cal Pharmacology," 21 : 3301-3303 (1972).
56. Pryor, G. T. and Braude, M. C. Interactions bWiween delta-9-tetrshydroean-
i;-ibinol (THC) and plihencyclidine (PC). "The Pharmacologi-f. 17: 18-2 (1975).
57. Ro:viTikranz, H. and Braude, M. C. Rat inhalation of Turki ih miarihuana.
"The Pharmacologi t," 17: 181 (1975).
58. Santos M., Smpi Jo, M. R. P.. Fruiaiidt-, N. S. and Carlini. E. A. Effects of
'iw)llHt 1iis -.tiai (nimriliuana) on the fighting behavior of mice "Pyychopharma-
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59. Sjoden, P. 0., Jarbe, T. 17. C. and Henriksson, B. G. Influence of tetrahydro-
cannabinols (delta-8-T(C and delta-9-T. 1C) on body weight, food. and water
intake in rats. "Pharnu ie' 'logy Biochemistry and Behavior," 1: 395-399 (1973).
60. Sofia, R. D. and Barry, 11. Acute and chronic effects of delta-9-tetrahy(iro-
cannabinol on food intake by rats. "Psychopharmacoiogia, 39: 213-222 ('1974).
61. Takahashi, R. N. and Karniol, 1. G. Pharmacological interactions between
catia1 iinol and delta-9-tetrahy(drocannlabinol. "Psychopharma cologia,"' 41: 277-
284 (1975).
62. Ten Ham, M. and Da Jong, Y. AlC.-ence of interaction between delta-9-tetra-
hydrocannabinol (delta-9-THC) and cannabidiol (CBD) in aggression, mniiile
control mind body temperature experiments in mice. "Psychopnarmacologia." 41:
169-174 (1975).
63. Ten Ham, M. and vanNoordwijk, J. Lack of tolerance to the effect of two
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(1973).
64. Uyeno, E. T. Effects of delta-9-tetrahydrocannabinol on dominance behavior
of the rat. "Federation Proceedings." 32: 725 (1973) .
65. Uyeno. E. T.. Del ta-9-tetranylroannabinol and the competitive behavior of
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66. Uyeno, E. T. Delta-9-tetrahydro-an nal inol administered to pregnant rats.
"The Pharmacologist," 17: 181 (1975).
67. Sa'zsenrath, E. N. and Chapman, L. F. Tetrahydrocannabinol-imiduced mani-
fet4ations of the "marihuana syndrome" in group-living macaques. "Federation
Proceedings," 34: 1666-1670 (1975).















CHAPTER 5
PRECLINICAL EFFECTS: LEARNED BEHAVIOR
A review of the previous four Marihuana and Health reports (40,
41, 42, 43) reveals that an extensive array of procedures and contexts
have been used experimentally to study the effects of cannabinoids on
the performance of learned behavior in animals. These preclinical
behavioral experiments have provided a framework for, and guided
the design of, subsequent human experimentation. Compared to pre-
vious years, only a few experiments pertaining to cannabinoids and
learned behavior have appeared this year. By and large these more
recent experiments confirm previous findings; no particularly novel
procedures have been employed nor have there been dramatically
unpredictable results. In part, the decrease in activity in cannabinoid
preclinical animal research on learned behavior is one sign of an
increase in human cannabinoid-learning investigations.
Several detailed taxonomies of learned behavior are possible. How-
ever, for the purposes of the present report, learned behaviors will be
categorized into those involving: avoidance learning and aversive con-
trol; reinforcement schedules and maze learning; and discrimination
learning.
AVOIDANCE LEARNING AND ADVEPSIVE CONTROL
Whether or not cannabinoids enhance, depress or fail to affect the
acquisition of avoidance behavior depends importantly on the canna-
binoid time-course of action (45) and dose (22), as well as on the
particular cannabinoid (28) and type of avoidance task used (52).
However, when the behavior investigated is performance, rather than
acquisition, of a learned avoidance task, cannabinoids have been reli-
ably found to have disruptive effects (e.g., 9,27,28,47).
Additional reports of cannabinoid-induced impairment of estab-
lished avoidance behavior have come from Tayal et. al. (53) and
Pryor and Braude (51). In the latter study (51), it was further
reported that delta-9-THC had a more than additive interaction with
phencyclidine, over a wide range of doses for both drugs, in impairing
conditioned avoidance behavior. The Tayal et. al. (53) experiment also
found that tolerance develops to the disruption in avoidance perform-
ance induced by an alcoholic extract of cannabis. This finding of tol-
erance confirms and extends previous reports of cannabinoid tolerance
development under learned avoidance tasks (e.g., 27, 39). However, no
new research has appeared to add to the finding (47) that delta-9-
THC is cross tolerant with ethyl alcohol but not with morphine or
chlorpromazine in a shuttle box avoidance task.
With respect to aversive control situations other than avoidance
learning, there have been several reports that cannabinoids reduce the


(61)






62


conditioned emotional response of animals to a stimulus previously
associated with an unavoidable electric shock, regardless of whether
an appetitive or aversive situation is used to maintain baseline re-
,ponding (e.cr., 23, 27). The usual interpretation given to this finding
is that cannahinoids act to reduce fear or anxiety. However, a fear-
reduction interpretation does not always gain support from research
with humans (50).
Moreover, Ferraro and Bruce (16) have argued that previous con-
ditional emotional response experiments have been, in part, con-
founded by drug-state changes which occurred between the training
and testing phases of thes' experiments. Indeed, when they compared
the conditioned emotional respon.-es of rats who had received all of
their trainicr and testing under 2.0 mcr/ko delta-9-THC (intraperi-
toneal injection) with nondrug control rats, delta-9-TIIC was found to
increa e. the conditioned emotional response (14).
Another factor which may be. considered to temper the interpretation
that cannabinoids reduce fear in aversive control situations is that
delta-9-THC has been found to have an analgesic effect in animals
(35) ind humans (48, 49). This was demonstrated by Dykstra and
McMillan (12) who used a titration procedure to determine the in-
ter.-itv at which monkeys would maintain a continuously applied
electric shock. It was found that an injection of 15.0 mg/kg delta-S-
TIJC caused the monkeys to adjust the shock to a higher intensity than
they had in the absence of the drug.
In still another aversive control context. Corcoran et al. (8) ha've
extended previous findings thr't dclta-9-TIIC (1f) and hashish extiraet
(7) produce. "bait shyness" in rats when paired with novel tastes. In
the Corcovan et a]. (8) study, delta-8-TITC, CB1), and canlnalbidcrol
(CBG) all produced 1) it shyness. However, cannabichromene (CBC)
did not produce a conditioned taste aversion in this aversive control
situation.

REINFORCE(lMENT SCHEDULES AND[ MAZE LEARkNING
Both operant and instrumental oonditionmg paradigms have been
11'Z('d to study thf1 effect^ of cannabinoidrs on apietitivelv reinforced
learned behavior in animals. In the opnrant conditioning context.
-ebpdiilp of rtinlforeenient have r, cepiv.l the most stu idy. In the instru-
mental conditioning context, mf'7p or aillv l(ezir ing has been the usual
har.'1 inc for determining cannabinoid AT(. .t.z-
Following the outline established ii the fourth Marihua na and
Hefialth report (-13), experiments deziliiT i w (ilmhbinoid-reinfotcC-
rnmnt scedl(lule interactions will be ci4epnrized n two major types:
Typ' I experimeutM-; which focus on changes in sef)difule controlled
respolv-'-p. and Type ITI experiments in which such responses merely
provide a baseline for the study of drug-relbtoed parameters.
TIn bulk of the vnrlier caninbinoid re-earch with reinforcemeiit
s.edules wvas of the' first type (cf., 40, 41, 42, 43). What little research
of this type there hIs been in the past two years (e.g., 9, 20, 55) has
miilily telded to replicate and confirm the findings from the earlier
resa rchi evenii where more complicated reinforcement schedules have
beii used (2). Taken all together, the research demonstrates that





63


behavior under reinforcement schedule control is reactive to delta-9-
THC and delta-8-THC as well as to other constituents of cannabis
(10, 21). In general, such behavior is depressed in a dose-related
manner by cannabinoids, although under schedules which tend to
generate low response rates, a bi-phasic dose-response function or an
alternation between periods of no responding and increaised rates of
responding are sometimes observed.
Although only limited attention has been given to the effects of
^nnnabinoids on the acquisition and extinction of operant behaviors
(18), the now very extensive literature on the relationship between
cannabinoids and performance of schedule controlled responses has
stimulated the use of such responses as baselines in Type II studies of
drug-related parameters.
Among other things, reinforcement schedule baselines have been
used in the past two years to study: Between-ca nitabinoid comparisons
(36) ; cross-tolerance between cannabinoids and other drugs (47) ; and
differences between drug vehicles and routes of cannabinoid adminis-
tration (1, 15, 17). An operant paradigm has also been used to investi-
gate the interaction between delta-9-THC and cannabidiol. Davis and
Borgen (10) found that intrniperitoneal injections of 3.0 mg/kg delta-
D-THC suppressed schedule controlled responding in rats while 25.0
mg/kg CBD did not. Similarly, intramuscular injection of 1.0 mg/kg
delta-9-THC suppres-ed responding in pigeons while 50.0 mg/kg CBD
did not. However, when animals were pretreated with their respective
CBD doses, the THC induced suppresion of responding was reduced.
An instance of the Type II reinforcement schedule experiment was
recently performed by Dykstra et al. (13) These researchers injected
pigeons responding under variable interval, fixed ratio, and fixed in-
terval schedules with a range of delta-9-TIIC and SP-111 doses (.3 to
18.0 mg/kg intramuscular injection administered either one or two
hours before the start of the experimental session). SP-111 as a water
soluble ester of delta-9-THC which bears a basic amino function (56).
Both drugs prodciced a d(cIe-related suppression of reinforcement
schedule responding although delta-9-THC was three to six times more
potent than SP-111 and had a faster time of onset.
A large number of both types of reinforcement schedule experi-
ments have, investigated the development of tolerance under the can-
nabinoids (e.g.. 1, 2, 20, 36, 38. 47). These experiments have uniformly
shown that tolerance readily develops in animals to cannabinoid-
induced suppress int effects on operant responding. However, two
studies have shown that, in this situation, tolerance development to
delta-9-THC is due to the animals respondinii under the influence of
the drug rather than to the mere exposure of the animals to delta-9-
THC (5, 38). Moreover, Frankenheim (20) observed that repeated i.p.
injections of delta-8-THC (10.0 and 17.8 mk/kg) tended to increase
the sensitivity of rats to a response rate-increasintr effect of the drug
under a differential reinforcement of low rate schedule of reinforce-
ment. This increased sensitivity was likened by Frankenheim (20) to
the reverse tolerance sometimes reported for marihuana effects in
humans.
Compared to operant reinforcement schedule research, the effects of
cannabinoids on the acquisition and performance of instrumental maze





64


or alley-way responding have not received extensive study. A Cana-
dian study, not yet published, has found that permanent impairment
of maze learning ability in rats occurred following six months of treat-
ment with oral doses of either ethanol or cannabis extract. While the
doses of THC and alcohol were both relatively high (20 mg THC/kg)
the authors point out the animals were visibly intoxicated for "only
about four hours after each dose, gained weight normally and were
in good general health throughout the experiment." Based on the de-
gree of intoxication, they argue that the research may be relevant to
possible learning impairment under conditions of unusually heavy
human use (57). Based on previously published literature, it may be
concluded that the cannabinoids impair reinforced and latent learning
in a variety of instrumental conditioning situations including the Y
maze, T maze, Lashley III maze and straight alley (11,29,44,46, 54).

DISCRIMINATION LEARNING
The effects of cannabinoids on discrimination learning were re-
viewed for the first time in the previous Marihuana and Health report
(43) under two subtopics: 1) the effects of cannabinoids on the per-
formance of discrimination based on exteroceptive stimuli, and 2)
the acquisition of stimulus control of behavior based on the presence
or absence of cannabinoids.
As there have been few experiments published since the last report
which describe the effects of cannabinoids on discrimination learning
with exteroceptive stimuli, only a brief summarization of the existing
literature will be made herein.
In general, the effects of cannabinoids on established stimulus dis-
criminations are influenced by the same variables as determine the
effects of other psychotropic drugs on discrimination performance
(cf., 43). More specifically, disruption of discrimination performance
by cannabinoids is more likely if the discrimination is complex rather
than simple and if the. discrimination is successive rather than simul-
taneous. The typical cannabinoid-induced disruption of discrimination
performance is the result of dose-related decreases in responses to the
stimulus associated with reinforcement and corresponding increases in
responses to the stimulus associated with nonreinforcement. Finally,
and in accord with the effects of most other psychotropic drugs, during
generalization testing delta-9-THC reduces total response output but
does not typically alter the slope of the generalization gradient.
It is now well established that animals can learn to discriminate
between the presence of cannabinoids and a vehicle-control solution
(3, 4, 19, 25, 31, 32, 33, 37). Jarbe et. al. (33) used an experimental
procedure which is prototypic of research on this topic. Gerbils trained
in a T maze were required to make discriminative choices based on
whether delta-9-THC or drug vehicle alone had been injected prior to
the training session. As is the usual outcome in cannabinoid stimulus
studies of this sort, Jarbe et. a]. (33) found that the delta-9-THC
discrimination was acquired in a dose-related manner (from 0.5 to 16.0
mrg/ kg, i.p.), Furthermore, decreasing the dose or increasing the
injection-test. interval from that used in training led to a decrease in
delta-9-TIIC associated choices. One final aspect of this study which






65


is unique is that pentobarbital (20.0 mg1/kg) interacted in a more than
additive fashion with delta-9-THC to determine drug versus control
solution choice responses.
The delta-9-THC discrimination paradigm has also been used
recently to compare the potency of different routes of drug administra-
tion (3, 32). As compared to intraperitoneal administration, delta-9-
THC administered orally or by inhalation had stronger stimulus prop-
erties while lesser stimulus properties were manifest after intravenous
administration of delta-9-THC.
Although some quantitative differences exist, it now appears that
the stimulus properties of delta-9-THC are interchangeable with delta-
S-THC, 11-OH-delta-8-THC, cannabis extract, and hashish smoke (3.
32). However, neither CBD or CBX seemingly produce TIC-like
stimulus properties (32). Furthermore, a wide range of drugs from
several pharmacological clauses have been shown not to be interchange-
able, in terms of stimulus properties. with delta-9-THC. Thus, there is
support for a hypothesis that the active cannabinoids may have a
unique mode of pharmacological action.
One final aspect of the cannabinoid-stimulus discrimination para-
digm merits further study. Of concern is whether or not tolerance
develops to the drug-stimulus properties of delta-9-THC. There have
been three studies which address this concern. One study supports the
development of tolerance (26), one provides indirect evidence support-
ing tolerance development (30), and finally, one provides data in-
directly supporting a lack of tolerance development (6). Until addi-
tional experiments are performed it seems appropriate to conclude
tentatively that a slow and perhaps partial, tolerance develops to the
stimulus properties of delta-9-THC.
State-dependent learning refers to the phenomenon that animals per-
form better if trained and tested under the influence of a drug than if
a drug-state change occurs between the training and testing phases of
an experiment. State-dependent learning has been shown for delta-8-
THC and delta-9-THC (cf., 45). However, it is not clear from the
THC literature whether or not symmetric disruptive effects are ob-
tamied between a change from a drugged to a nondrugged state (D-
ND) and a change from a nondrugged to a drugged state (ND-D).
Both symmetric and aisymin i-ietric state-dependent effects have been re-
ported for THC (24). In the case of asymmetric effects. a change from
the ND to D state (22). Johansson et al. (34) have shown that delta-8-
THC will reliably induce asymmetric state dependency of this latter
type if animals are first made tolerant to the acute disruptive effects
of the drug.
















REFERENCES.-PRECLINICAL EFFECTS: LEARNED BEHAVIOR


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*t ltyd ro';i iniiahinol on operant behavior. "Research Communications in Chemni-
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and sVitpiilnfhinne on continuous spontane'ms alternation in the Y-maze. "Psycho-
pha rmacii log1.-" 32 :171-1 S2 (1973).
12. Dykstra. L. and McMillan. D. E. Shock-intensity adjustment by squirrel
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or (-hlorprorliazine. "Federation Pri.-eedijigs," 33: 516 (1974).
13. Dykstra, L. A., McMilIan. D. E. aind Harris, L. S. Effects of delta-9-THC
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orally ad inist'-trod (lflta-9-TIIC (in interval schedule performance of the rat.
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ditki'ivid eniiionril respioiwu. Paper iresent41 "I at. Rlie RiK'ky Mountain IPsycho-
bigical Assoeintion, SSalt Lake. 1975.
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on reyier nft. reinforrenient svliiedifle ;erforin-a nce in ratis. "Pliarmiacology,"
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of v-ariible interval wcliePll behavior by rats under delta-9-tetrahydrocannabinol.
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19. Ferraro, D. P., Gluck, J. P. and Morrow, C. W. Temporally relay ted stimulus
properties of del ta -9-tetrahydroca miabiniol in monkeys. "Psychopharmacologia."
35: 305-316 (1974).
20. Frankenheim, J. M. Effects of repeated rosess of L-d& ta-8-trans-tefrallydro-
canna1iinol on schedule-controlled temporally-spaced respondigii of rats. "Psycho-
pharmacologia," 38: 125-144 (1974).
21. Frankenheim, J. M., McMillan, D. E. and Harris, L. S. Effects of delta-9-
and delta-8-tetrahyd i' jcan aiii 1inoI and cannabinol on schedule-controlled behavior
of iiigeons and rats. "Journal of Pharmacology and Experimental Therapeutics,"
178: 241-253 (1971).
22. Goldberg, M. E., Hefner, M. A., Robichaud, R. C. and Dubinsky, B. Effects
of delta-9-tet.rahydrocannii iaiiiiioI (THC) and chlordiazepoxide (CDP) on state-
dependent learning: Evidence for asymmetrical dissociation. "Psychoph arma-
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23. Gonzalez, S. C., Karniol, I. G. and Carlini, E. A. Effect of cannabis sativa
extract on conditioned fear. "Behavioral Biology," 7: 83-94 (1972).
24. Henriksson. B. G. and Jarbe, T. The effect of two tetrahydrocaiinabinols
(delta-9-THC and delta-8-THC) on conditioned avoidance learning in rats and
its transfer to normal state conditions. "Psychopbarniacologia," 22 : 23-30 (1971).
25. Henriksson, B. G. and Jarbc', T. Delta-9-tetrahydrocannabinol used as a
discriminative stimulus for rats in position learning in a T-shaped water maze.
"Psychononuie Science," 27: 25-26 (1972).
26. Hirscliorn. 1. I). and Joecan... A. Morphine uid delta-9-tetnihydro-
cazinabinol: Tolerance to the stimulus effects. "Psychopiiarmintcologia," 36: 243-
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27. Houser, V. P. The effe'-t of delta-9-tetrahydrocanzi ibinol upon fear-moti-
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(1975).
28. Izqnierdo, I. and Nai-e.-1o, A. G. Effects of cnwiiii'bidiol and of diphenyl-
hyda ntloin on the hippocamipus and learning. "Psychop Iliarmacologia," 31:321-
332 (1973).
.1). Jarb L. T.. C. (\ nil II<'srikss()on. B. (1. Effects of delta-S-Ti1(1 and (elth!-9-
THC on the acquisition of a djisc4riminated positional habit in rats. "'Psycho-
phurmacolo~gia," 31:9321 --;:-;2 (19731).
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29: 1251-1253 (1973).
31. Jarbe, T. U. C. and Ienrih-.-cn. B. G. State dependent learning with tetra-
hydrocannabinols and other drugs. "Ciencia E Cultural," 25: 752 (1973).
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duced with hashish, tetri.Jydro.- ;;iinibiinols (delta-8-THC and delta-9-THC) and
other drugs. "Psychophiarmacologia," 40: 1-16 (1974).
33. Jarbe, T. U. C., Johansson, J. 0. and Henriksson, B. G. Delta-P-tetraliy dro-
cdi.;)ilhinol and pcitoI1rhit;l "r.; (1iscrii1i1ii1tive c(ues in the Monol1ian _i-1
(Meriones ung iculatus). "Pharmacology Biochemistry and Behavior," 3:403-
410 (1975).
34. Johanssnn, J. 0., Henriksson, B. G. and Jarbc, T. U. C. Effvcts of delta-8-
THC on d(is.)ociation of conditioned avoid 2 lice responding in tolerant and non-
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68

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LSD-25 and scopolamine on non-spatial single alternation performance in the
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Personal communication.












CHAPTER 6


PRECLINICAL CHRONIC EFFECTS: UNLEARNED AND LEARNED BEHAVIOR
There is no unequivocal answer to the question of whether or not
tolerance develops to cannabinoid-induced effects on unlearned and
learned behavior. In certain response systems, tolerance clearly de-
velops and is characterized by its rapid development and large magni-
tude. Indeed, in the past two years tolerance has been demonstrated for
both unlearned and learned responses in a range of animal species
under a variety of drug conditions in studies examining: unlearned
motor responses in rats (4) ; spontaneous activity in mice (3) ; condi-
tioned avoidance performance in rodents and monkeys (30, 39, 46) ;
analgesia in dogs (31); and reinforcement schedule performance in
pigeons, monkeys and rats (2,5,21,32).
In addition to demonstrations that tolerance to the cannabinoids can
develop in unlearned and lea rned behavioral situations, there have been
several experiments which serve to elucidate some of the determinants,
both pharmacological and extrapharmacologica!, of tolerance develop-
ment to the cannabinoids. These latter experiments encompass a wide
variety of situations and paramneters and, in some JMi ftmces, suggest
constraints on the generality or pervasiveness of tolerance to the can-
nabinoids. The studies described below are representative of these
experiments.
Abel et al. (1) have shown that tolerance to the effects of delta-9-
THC on reinforcement schedule responding develops in pigeons at
about the same rate. after intramuscular, intravenous, or peroral ad-
iiiiinistration. Tolerance also follows a similar course for delta-9-THC
and its metabolite 11-OH-delta-9-THC (32). However, Fernandes et
al. (13) have sugjrested that CBD interacts with T1IC to enhance the
tolerance development to THC.
Barns and Fried (4) have shown that the age of the subject at the
time of first exposure to delta-9-THC interacts with later tolerance
development. Rats first received delta-9-THC when immature de-
veloped tolerance more rapidly as adults than did rats who were adults
when first drugged.
Rate of tolerance appears to depend as well on: the amount of prior
training on a learning task (40) ; and the type (39), parameter values
(19, 24, 30), and complexity of the learned task (16, 43). In general,
as the amount of prior training is decreased and the difficulty of the
learned task is increased, tolerance develops more slowly or does not
develop at all. Another behavioral variable that seems to determine
the rate of tolerance development is the behavioral consequences pro-
duced by delta-9-THC (14, 36). For example, in one experiment (36)
tolerance developed to delta-9-THC much more rapidly if delta-9-
THC acted to increase the number of shocks received by rats working
(69)






70


under a conditioned avoidance task. In this same learning context,
it appears that the development of delta-9-THC tolerance in appetitive
reinforcement situations is facilitated if animals are given the oppor-
tunity to respond under the influence of the drug rather than being
given mere exposure to the drug. This latter finding has been reported
for rats (7), pigeons (5), monkeys (35), and chimpanzees (18).
On the basis of findings such as the above, Ferraro (15) has
followed the lead of others (12, 25) in proposing a behavioral model
of marihuana tolerance. The' essence of this position is that learning
or drug-behavior interactions account, in part, for some of the char-
acteristics of tolerance development to delta-9-THC. The. pharma-
cological mechanism underlying tolerance development to the canna-
binoids is not definitely known (cf., 37). However, there is evidence
which suggests that the development of tolerance to delta-9-THC may
proceed by more than one pharmacodynamic mechanism of action.
For example, Anderson et. al. (3) found that both the time of onset
and the duration of tolerance to delta-9-THC differed in mice with
respect to drug effects on intestinal motility, temperature, and loco-
motor activity. As these researchers concluded, it seems unlikely that
any one mechanism, such as metabolic tolerance, could account for the
obtained differences in tolerance development over so wide a range
of response systems. Other experimenters have provided data which
suggest thliat. delta-9-THC tolerance is not solely metabolic or drug dis-
tributional (10, 38). Obviously, additional research will be necessary
in order to specify just what pharmacodynamic and learning factors
are important in determining the development of tolerance to
ma rihuana.
Admittedly, it is not possible to make direct comparisons between
different cannabinoid tolerance experiments since they often differ in
nonsvstematic ways with respect to such variables as number, level and
distribution of drug doses, behavioral task and species of subject.
Nevertheless, it must be noted that the literature contains a fair
number of experiments where a lack of tolerance development to the
cannabinoids has been reported. This result has been found for rodents
in such situations as: open-field behavior (42) ; isolation-induced
aggression (11); food and water intake (23, 44) and discrimination
learning based on exteroceptive (20) or drug-produced stimuli (6).
By contrast. Frankenheim (22) has recently reported that repeated
injections of delta-S-THC produce an increased sensitivity to some of
the effects produced by this drug on reinforcement schedule-controlled
responding in rats. This increased sensitivity was likened by Franken-
heim (22) to a reverse tolerance effect.
With respect to other chronic effects of the cannabinoids, two experi-
ments have failed to find any residuial effects on learned behavior fol-
lowing discontinuanne of delta-9-TIHC previously administered for
1O consecutive days (18) or periodically for seven months (17). And,
with the exception of one experiment (41), animals have not been
observed to se(1f-administer cannabinoids. More specifically, monkeys
do not self-administer delta-9-TIIC after receiving the drlig for a
montli or when offered it as a substitute for cocaine (26). Rats forced
to drink cannabis extract or hashish suspensions for long periods of
time (up to 126 days) reject, the drug in favor of a control solution






71


(9, 33). Finally, mice are reluctant to consume food pellets containing
delta-9-THC even after subsisting on the pellets for over two months
(34).
It is noteworthy that no behavioral symptoms of abstinence or with-
drawal were reported in the above experiments at the termination of
the forced drug regimens used (cf., 26, 33). One further experiment
by Chesher and Jackson (8) reported the absence of an abstinence syn-
drome after withdrawal of cannabis extract admiinistered in oral doses
equivalent to up to 80.4 mg/kg delta-9-THC for 11, 13, and 28 days.
In this study, mice were tested for their convulsive thresholds to pen-
tylenetetrazol between six hours and six days following termination of
the cannabis drug regimen. No differences were obtained between drug
and control animals.
Despite the above evidence to the contrary, there were two reports
last year that were suggestive with respect to delta-9-TIIC-produced
dependence and abstinence symptoms (29, 45). In the better controlled
of these experiments (45), rats were administered naloxone hydro-
chloride after a five-week pretreatment period with delta-9-THC (8.0
to 32.0 mg/kg, intraperitoneal injection). The rats exhibited narcotic-
like withdrawal symptoms including diarrhea, teeth chattering and
"wet dog" shakes. Two additional experiments published this year
(27, 28) demonstrated that delta-8-THC and delta-9-THC, but not
CBD, reduce the abstinence symptoms precipitated by naloxone hvdro-
chloride in niorphine-dependent rats. In the first of these (27), delta-
9-TTIC doses of 5.0 and 10.0 mng/kg administered by the intraperi-
toneal route one hour before naloxone administration significantly
reduced the frequency of wet shakes and diarrhea in the morphine
treated rats. On the basis of their data, Hine et al. (27, 28) concluded
that the tetrahyldrocannabinols may have some therapeutic utility in
clinical narcotic detoxification programs.















REFERENCES.-PRECLINICAL CHRONIC EFFECTS: UNLEARNED AND LEARNED
BEHAVIOR
1. Abel, E. L., McMillan, D. E. and Harris, L. S. Delta-9-tetrahydrocannabinol :
Effects of route of administration on onset and duration of activity and tolerance
development. "Psychopharmacologia," 35: 29-3S (1974).
2. Adams, P. M. and Barrett, E. S. Effects of acute and chronic marijuana
on the performance of a complex reinforcement schedule in the squirrel monkey..
"Clinical Toxicology," 7:267-268 (1974).
3. Anlerson, P. F., Jackson, D. M., Chesher, G. B. and Malor, R. Tolerance
to the effects of delta-9-tetrahydrocannabinol in mice on intestinal motility,.
temperature, and locomotor activity. "Psychopharmacologia," 43: 31-36 (1975).
4. Barnes, C. and Fried, P. A. Tolerance to delta-9-THC in adult rats with
differential delta-9-THC exposure when immature or during early adulthood.
"Psychopblarmacologia." 34:181-1190 (1974).
5. Bruice. P. D. and Ferraro, D. P. Learned tolerance to delta-9-tetrahydro-
cannaibi niol in pigeous. Papter presented to Rocky Mountain Psychological Asso-
ilation, Salt, Lake, 197.).
6. Bueno, 0. F. A. and Carlini, E. A. Dissociation of learning in marihuana in
tolerant rats. "Psychopharmacologia," 25: 49-56 (1972).
7. Carder. B. and Olson, J. Learned behavioral tolerance to marihuana in.
rats. "Pharmacology Biochemistry and Behavior," 1:73-76 (1973).
8. Clipsher, G. B. and Jackson. D. M. The effect of withdrawal from cannabiAs
on pentylenetetrazol convulsive threshold in mice. "Psychopharmacologia,"
40: 12f-k135 (1974).
9. Corcoran, 1. E. and Amit Z. Reluctance of rat to drink hashish suspen-
sions: Free-choice and forced consumption, and the effects of hypothalamie
stiiniilation. "Psycliopharmacologi a." 35:129-147 (1974).
10. Dewey, W. L., McMillan. D. E., Harris, L. S. and Turk, R. F. Distribution
of radioactivity in brain tolerant and nontoleraut pigeons treated with 3H-delta-
9-tetraliyd rocannaiinol. "Biochemical Pharmacology," 22.:399-405 (1973).
11. Dubinshy, B., Roliiehiaid, R. C. and Goldberg, M. E. Effects of (-)-delta-
9-tr'i ns-tetrahi r(KAn;imihbin(pl and its selectivity in several models of aggressive
behavior. "Pharmacology," 9: 20-2116 (1973).
12. EIsnmre, T. F. Effects of (lelta-9-tetrahydrocarnaininol on temporal and
aiiditory discrimination performance of monkeys. "Psychophairmacologia." 26:
62-72 (1972).
13. Fernandes, M., Schbharek, A., Coper, H. and Hill, R. Modification of delta-
9-THC-aetions by eniuunbinol and cannaabldiol in the rat. "Psychopharmacologia,"-
38: 321-33S (1974).
14. Ferraro, D. P. Effects of delta-9-tetraliydrenniaiiibinol on simple and comn-
lplex lea rmed behavior in animals. "Current. Research in Marijuana." Edited by
Lewis. M. F., New York: Academic Press. 1972.
15. Ferniro, D. P. A lieliaviorni model of inn rihuiina tolerance. "Pharmacology
of Mmrihutann." Editeil by Braude, M. C. and Sazara, S. (in press).
16. Ferraro, D. P. and Grilly, D. M. Lnck of tolerance to delta-9-tetrnhydro-
canu ribini'l in (binlpil izees. "'Science," 179:490-492. (1973).
17. Ferraro, D. P. and Grilly, D. M. Marihumana extract in chimpanzees:
A bs'ncc of ltinur-terin effects on operait. behavior. "Psychological Report.s,"
32: 473-474 (1973).
18. Ferraro, D. P. anmd Grilly, D. M. Effects of chronic exposure to delta-9-
t't almydroi icnnlbi ol on delayed matcliig-to-sniuple in chimpanzees. "Psycho-
pbmwrinuieoblgia," 37:127-138 (1974).
19. Ferraro, D. P., Grilly, D. M. and Grisham, M. G. Delta-9-tetrahydro-
call 0i, ii mitiiol fud dlelfyed in atehing-to-sn mple in chimnpanzees. "Drug Addiction";
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(72)







73

20. Fetterolf, D. J. and Ferraro, D. P. Retardation of the acquisition of a
successive discriliii na tion by delta-9-tetrahydrocannabinol in rats. Paper pr'-
sented to the Rocky Mountain Psychological Association, Salt Lake, 1975.
21. Frankenheiin, J. M. Effects of repeated di'st-s of levorotatory-delta-8-trans-
tetrahydroca iifn a inol on schedule-controlled temporally-sliaced responding of
rats. "Psychopharnrimologia," 3s: 125-144 (1974).
22. Frankenichim, J. M., McMillan, D. E. and Harris, L. S. Effects of delta-:i-
and delta-8-tetrahydrocannabinol and cannabinol on schedule-controlled behavior
of piigeonis and rats. "Journal of Pharmacology and Experimental Therapeutics,"
178: 241-253 (1971).
23. Gluck, J. P. and Ferraro, D. P. Effects of delta-9-THC on food and water
intake of deprivation experienced rats. "Behavioral Biology," 11: 395-401 (119)74)
24. Grilly, D. M., Ferraro, D. P. and Marriott, R. G. Long-term interactionsi of
marijuana and behavior in chimpanzees. "Nature," 242:119-120 (1973).
25. Harris, R. T., Waters, W. and McLendon, D. Behavioral effects in rhesus
monkeys of repeated intravenous do-ses of delta-9-tetrahydrocannabinol. "Psychu-
pharmacologia," 26: 2197-306 (1972).
26. Harris, R. T., Waters, W. and McLendon, D. Evaluation of reinforcing
capability of delta-9-tetrahydroca nnabinol in rhesus monkeys. "Phychoph arma-
cologia," 37:23-29 (1974).
27. Hine, B., Fried man. E., Torrelio, M. and Gershon, S. Morphine-dependent
rats.: Blockade of precipita teil abstinence by tetrahydrocannabinol. "Science,"
187: 443-445 (1975).
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attenuate'1 abstince and induced rotation in morphine-dependent rats: Pos Ide
involvement of dopamine." Neuropharmacology," 14: 607-610 (1975).
29. Hirschhorn, I. D. and Roseiicrains, J. A. Morphine and delta-9-tetrahydro-
cannabinol: Tolerance to the stimulus effects. "Psychopharmacologia," 36: 243-
253 (1974).
30. Houser, V. P. The effects of delta-9-tetrahydrocannabinol upon fetar-morn-
vated behavior in squirrel monkeys. "Physiological Psychology," 3: 157-161
(1975).
31. Kaymakcalan, S., Turker, R. K. and Turker, M. N. Analgesic effect of delta-
9-tetrahydroca innalbin'il in the dog. "Psychophalirrinmologia," 35:123-128 (1974).
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nabinol and 11-hydroxy -delta-9-tetrahydrocannabinol: Behavioral effects and tol-
erance development. "Jouiiral of Pharimacology and Experimental Therapeutics,"
189:61-65 (1974).
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"Psychopharinacologia," 36: 133-145 (1974).
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Behavior," 2: 603-607 (1974).
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on free-operant shock avoidance. "Federation Proceed inis." 33: 481 (1974).
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hydrocniin;iuiiizdl tolerance. "Anials of the New York Ac:idiiiy of Sciences.'"
191:89-99 (1971).
38. MeMillan, iD. E,, Dewey, AV. L., Turk, R. F., Harris, L. S. and McNeil. J. ITI.
Blood levels of 311-delta-9-tetrahydro ann-ii a 1 nol and its metabl,: ites- in tolera n;
and nontolerant pigeons.- Biochemical PharMin ologmy." 22 :2'-37 (1,073).
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chives Internationales de Pharmacodynamie," 207: 254-259 (1974).
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of amount of prior training. "Pharmacology Biochemistry and Behavior," 22: 243-
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74


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Behavior," 1: 243-249 (1973).
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cannabinol on food intake by rats. "Psychopharmacologia," 39: 213-222 (1974).
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niaihuana extract: EEG and behavioral effects of chronic oral administration
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"Indian Journal of Experimental Biology," 12:375-376 (1974).














CHAPTER 7


HUMAN EFFECTS
ACUTE F!2FECTS
A person ingesting or smoking cannabis experiences a fair-IV pre-
dictable sequence of physiologic ard psychologic changes which last
a few hours and then gradually disappear. Although dose admin-
istered and individual differences in personality, expectations., setting
and past drug experience all contribute to varied consequences from a
given do-e of cannabis, the variability in acute effects from cannabis
seems no greater than with any other psychoactive drug. A number of
reviews and collections of papers have appeared during the past year
which attempt to cover the vast amount of information accumulating
about the acute and chronic effects of cannabis (71 27. 43. 70, 82. 114).
Some authors have attempted to consider the i'elearch findings in the
context of political-social decisions (43, 13.5) and point out the lacunae
in the data as well as the well established facts (43). The continuing
research efforts this past year have attempted to fill some of the gaps.
Emphasis has been placed on the chemistry of cannabis constituents.
less obvious effects such as hormonal changes and the initial studies of
acute drug effects in populations other than those made up of self-
selected marihuana users.
Activity of 9natIllw7 and synthclif can nabno;ds
Detailed pharmacokinetic studies of delta-8-FHC in man using mass
fragmentogiaphic techniques indicate a similar time course and clear-
ance pattern to that seen with delta-9-TH(' (103). A very rapid alpha
phase was followed by a slower phase. While blood levels did not al-
ways predict physiological and psychological effects, they paralleled
heart rate changes well.
D)MHP, a synthetic cannabinoid. differs from delta-9-THC by hav-
ing a double bond in the 6a. lOa positions. Intravenous administration
in man produced profound cardiovascular effects but only minimal
psychological effects (102). As is the case with natural cannabinoids.,
hydroxylation seemed to be the major metabolic pathway.
Metabolism of can nabfboid. and biochem i;.try
Jfetabolites.-Although studies of a major metabolite of delta-9-
THC. 11-hvdroxv-THC, indicate it is pharmacologically active, some
question remains whether it is the only metabolite or whether delta-
9-THC needs to be hydroxvlated to 11-hydroxv-THC before the THC
is active (72). In an attempt to clarify these issues, Hollister sorted
people. into fast and slow hydroxylators on the basis of antipyrine
(75)






76


and phenylbutazone plasma disappearance rates. THC and these drugs
are metabolized by the same liver microsomal enzyme system (169)..
There was no difference in speed of onset, intensity or duration of
effects after intravenous injection of delta-9-THC when the two groups.
were compared (72). Such results suggest 11-hydroxy-THC may not
be. the sole source of delta-9-THC effects. Another group of investi-
gators found 11-hydroxy-THC to leave the plasma more rapidly than
THC, suggesting THC may, in fact, be more potent (133).
A number of additional marihuana metabolites have been reported
in a series of studies (83, 84, 85) and for the first time, unchanged
delta-9-THC was identified in the urine using conventional thin layer
chrom atographic techniques in amounts estimated at .0 1-.005 % of
the dose (74). New extraction procedures revealed a previously
ignored fraction containing abundant metabolites (83) including
many polar metabolites (84). The exact identity and activity has yet.
to be determined. In a review of structure activity relationships of
cannabinoids in man, Hollister concluded that the potency of the THC
molecule. is altered by changing length of side chains, or by metabolic
hydroxylations. No material has yet been formed in nature in cannabis
itself or in THC metabolites which differ qualitatively from THG
(71). There is now evidence indicating the human small intestinal
mucosa, as well as the liver, can hydroxylate THC (59).
Cannabinoid interactions.-Studies of the possible. interaction be-
tween delta-9-THC and the. other two major cannabinoids of mari-
huana-cannabinol (CBN) and cannabidiol (CBD)-are not com-
pletely consistent in their conclusions. Hollister found only slight
interaction between THC and CBD. After CBD, there was a delayed
onset and prolonged effects of THC that were slightly more intense
(73). The magnitude of the interactions was so small as to be clinically
insignificant. However, other experi ments in man with different1
samples of innrihiiana plant material containing varied amounts of
CBN and CBD found differences in effects, possibly due to differing
proportions of CBN, CBD and TIIC(18). A subsequent study by the
same group found large doses of CBD to block many, of the effects
of THC (86). A possible complicating factor in cannabinoid inter-
action studies is the issue of instability of various synthetic and natu-
rally occuirrin g cfnnanbinoids (165).
mtarbrom ? with other drnw.-Besides CBD and CBN, other drug
interactions with THC have been invest i ga te(d in man. Secobarbital
and smoked marihuana had additive eflects on subjective responses
and psychomotor impairment. (32). Siubjects had difficulty distin-
guishing 150 E incg of secobaribital from '25 micrograms of TIIC/kg.
When amphet fluiiie :iid smioked marihuana, were combined, additive
effects of heart iite and blood p1re)IcLire and subjective symptoms were
ols)eTved. but,110 no interaction effect on psychomotor performance was
found (47). hised on the :ismsmption that THC interferes with
cholinergic brain mechanisms, physostiirmi inc decreased the. tachy-
cardina and eonjiuictiv al injection, but had little effect on psychological
chi nge-- (51). Little potentnin lion of narcotic drug effects was noted
in a ,hiudy eva!hating THIC as a pr)-nesthetic qent (77). Animal
stUldies indicate that wht ee\'r the (Iru1r combination the depressant
(ffccts of UIIC tend to predolominate (13S).








Assay techngques.-A great deal of effort has gone into the develop-
ment of practical assays of cannabinoid levels in man. Such measures
are needed not only for research purpo-zcs, but would be liceful clin-
ically and in law enforcement (particularly in cases where intoxication
while driving an automobile is an issue). A number of techniques
using saliva and TLC with mass spectrometry (81). radioimmuno-
.-ay of blood and urine (105. 160), and gas chromatography of blood
(106) have been reported but still are not sufficiently sensitive, specific
and reliable for widespread practical application. The tight binding
of THC to plasma protein (170) is only one of the many problems in
the development of sensitive reliable tissue level assays (cf. Analytical
Techniques, Detection).
Cardiov ascdular effects
Cannabis has long been known to have marked cardiovascular effects
(21, 143). Last year's report reviewed some preliminary data which
resulted in some expressed concern about electrocardiographic changes
during acute intoxication. The subsequent publication of a number
of studies wiiere cardiovascular dynamics were studied some time
after administration of large doses of THC indicates that cannabis
produces only minimal EKG changes in young healthy subjects (77,
8. 22, 104). Nonspecific P or T wave changes are most commonly noted.
Occasional premature beats also occur. Tachycardia, continue; to be
the most common and prominent physiological response to acute do-es
(145). In a study of prolonged administration of oral doses of 30 mg
delta-9-THC given every four hours, heart rate slowing and blood
pressure drops developed (8). Blunting of peripheral vascular reflexes
developed along with plasma volume expansion. Although tolerance
developed to the orthostatic hypotension. the supine hypotensive
effects persisted throughout the period of drug admininist ration. These
changes commonly seen in laboratory animals but not previously noted
in man suggest a biphasic action of THC in humans with an increase
in svm pathetic activity involving the heart and peripheral blood
vessels at low doces and a centrally mediated sympathetic inhibition
at higher doses (65). The slightly increased supine blood pressure
would be consistent with this mechanism (22, 77, 104). Forearm blood
flow increases and total peripheral resistance decreases slightly with
acute doses (104, 77) consistent with beta-adrenergic stimulation. The
great individual variability in response to large intravenous doses has,
however, led one group to suggest. an indirect episodic activation of
the sympathetic system secondary to psychological arousal in addition
to the beta-adrenergic stimulation (101). Cardiovascular and psycho-
logical mechanisms of action may be independent as is suggested by
the observation that DMHP, a synthetic cannabinoid, produces pro-
found cardiovascular but few psychological effects (102).
A series of reports on the cardiovascular effects on cannabis smok-
inz in persons with coronary disease are consistent with the prelim-
inary report cited last year (137, 4, 3). Smoking either marihuana or
high nicotine cigarettes decreased exercise performance prior to the
onset of angina by increasing myocardial oxygen demand and decreas-
ing myoceardial oxygen delivery (4). Cardiovascular hemodynamics
were evaluated by echocardiography (137). After marihuana, stroke








index decreased and ejection fraction was greater. Carboxyhemo-
globin made for some changes after both marihuana and placebo.
These. studies demonstrate that marihuana effects may differ in indi-
viduals with pre-existing disease than in normals. Most research
studies thus far have, of course, been done on youthful selected, normal
volunteers.
PIulmonary effects
Because smoking is the most common means of cannabis consump-
tion in this country, the effects of cannabinoids and marihuaa smoke on
pulmonary function has been of continuing interest. The. fourth Mari-
huana and Health report described bronchodilating effects with pos-
sible therapeutic implications after marihuana smoking. Previous
reports have described mainly adverse findings in frequent chronic
cannabis smokers including bronchitis, obstructive pulmonary defects,
and chronic cough (62).
Two groups publishing the promising reports described last year
have continued and extended their studies (149, 156, 157, 168). Acute
administration of either smoked marihuana or oral doses of THC
produced statistically significant increases in bronchodilation and re-
versed experimentally induced bronchospasm in young adults with
bronchial asthma (156, 157, 168). Indications are that the. mechanism
is independent of beta adrenergic or antimuscarinic effects (149). In
contrast to these promising reports, a British group (34, 58) found
that measures of forced vital capacity, peak expiratory flow rate and
other clinically useful measures of pulmonary function did not im-
prove in a group of patients with reversible airway obstruction given
10 ing doses of oral THC. One possible reason for these discrepant
findings may be that the groups (149,156) reporting cannabis-imndced
brow hodilation are using whole body plet hysmography, an exceed-
invglv sensitive measure that will detect very small chances in pid-
monary function, whereas the less optimistic reports come from a group
using less sensitive, although clinically relevant measmremient
techniques.
Chronic smoking may produce different and less useful effects tihan
acute administration as indicated by pulmonary function changes dlr-
ing periods of chronic administration (109). Mendelson found si rnifi-
cant jinpairmients in pilmnonary function tests (vital capacity, or FEN
1.0) in a group of chronic marihuana, smokers (109). Further reduic-
tion in pulmonary function test performance developed dinring this
study in which the volunteers smoked three to ten miarihuana cigarettes
(l.aily for 21 days. An outpatient study of young adults with varyin(
tobacco cigarette, habits found more improvement in pulmonary fujnc-
tion during an eight week period of no smoking in the cannabis smoker
S i1)croup (5). An in. v;tio study suggests that the wNater soluble compo-
nents of inariluana smoke may contain substances toxic to the defense
network of the lung other than delta-9-THC or other cannabinoids
(31). Studies using high doses of TIIC given intravenously noted only
modest changes in minute ventilation and the. ventilatory response to
C02 equivalent to that prodlued by 5 mrg doses of morphine (77, 104).
A study of the respiratory effects of smoked marijuana and orally
ingested delta-9-THC has examined the effects of the drugs on the
respiratory response curve. Both the synthetic and natural material






79


produced a respiratory depression in a group of previously chronic
users. Although the effect was found to be slight, the authors recom-
mend further study because of the possible relevance of this effect to
patients with chronic lung disease or central nervous system impair-
ment of respiratory regulation (172).
EndoYrine and metabolic effects
The report of depressed plasma testosterone levels in chronic mari-
huana smokers (98) and the report of a failure to find such a change
in marihuana smokers receiving the drug daily over a 21-day period
(110) have led to further studies and discussion (55. 93. 96. 97. 99 100,
101). Kolodny has reviewed the numerous problems confounding the
study of the hypothalamic-pituitary-testicular axis in man (96) and
discusses possible biologic implications of lowered testosterone levels.
He presents data (97, 100) showing significant drops in plasma tes-
tosterone levels and luteinizino hormone levels two and three hours
after smoking a single marihuana cigarette. In a chronic administra-
tion study, subjects showed no significant drop in levels after four
weeks of daily marihuana smoking; but, then. with continued smokiy g
they had significant drops in luteinizing hormone, followed by falling
testosterone levels and follicle stimulating hormone levels. Thus. the
data from research finding no marihuam a-related hormone changes
(93, 110, 144) are quite consistent with studies that do (97, 98, 100) if
the different time periods of marihuana u-c are taken into account.
The biological significance of these chagiires is unclear and Kolodiy is
appropriately cautious in his interpretation of their importance (96).
In most cases the plasma hormone levels remain within the us,,ally
accepted normal limits. Such alterations might be expected to ae minor
important for prepubertal or pubertal males or males with already
impaired sexual functioning. There might also be adverse effe Its on
sexual differentiation of the fetus of mothers usingz cannabis. In the
al;senice of clinical evidence for these consequences, such concern is at
present. speculative.
One surgeon has attempted to link such hormonal changes to tie
development of gynecomastia in niale, lmriluana users (66, 69)). le
was able to stimulate the developnmel;t of rat breast tissue by delta-9-
THC administration (66). Other investig } tors (101) have not fouid
changes in serum prolactin levels in men given THC experimentally.
The a bseiice of prolactin changes is surprihin r since many centrally
acting drugs alter prolactin levels. The reported gynecomastia was
postulated to result from a prolactin dependent mechanism.
In last year's report a study described glucose intolerance in a small
group of subjects given intraxvenous doses of delta-9-THCi (75). A
lower dose of THC given a smoked hashish liad no effect on blood
glucose though blood lactic aci(d Iecreased ( GIQ)) (4luco-" efflux from
human erythrocytes was inhibited by THC and cannabidiol, suggest-
ing some drug effects on glucose transport mechanisms (146). It would,
however, be quite speculative to try to relate these changes to the crav-
ing for sweets often reported by cannabis users.
Sexual functioning
Reports discussed in the section on "Endocrine Effects" describe sex
hormone changes related to cannabis use. Although anecdotal accounts






80


describe cases of sexual dysfunction possibly associated with such
changes, properly controlled studies are needed to confirm them (96,
100). A number of accounts report enhanced sexual activity associated
with cannabis use (11, 20, 51, 63, 93). However, the psychological,
social and pharmacologic factors associated with sexual activity prob-
ally interact in complicated ways as is true with most other drug effects
on sexual behavior (20, 93). For example, with cannabis, as with alco-
hol, dose is important. Small to moderate doses appear to be most effec-
tive as releasers of inhibitions (93). Larger doses and/or chronic use of
marihuana may actually diminish sexual interest and potency in males.
Adequate data elucidating the effect of marihuana use on sexual func-
tioning are not yet available.
Neurological effects
Perceptual, cognitive and mood changes are presumably reflected in
changes in nervous system activity. As with any psychoactive drug,
however, simple one-to-one correlations between behavioral changes
and brain activity are rare (78). The most important questions have
to do with how long the effects persist: for hours, days, weeks or are
they permanent?
Most of the new studies are extensions of or attempts to replicate
findings reported last. year. Smoked cannabis produces acute, revers-
ible, dose-related changes in brain waves as measured by computer-
analyzed EEG (49, 91). Following ordinarily used doses, the changes
are modest, consisting mostly of alpha wave slowing and are not in-
dicative of any particular pathology. Cannabis does not appear to have
unique qualities among CNS active drugs as measured by scalp EEGs.
Clianges in EEG recorded from deep brain structures, consisting of
slow wave and spiking activity, have not, however, been seen with any
other drug (67). These changes have been well-described in monkeys.
Similar changes have been reported in a small number of humans (67).
The behavioral significance of these neurological changes is yet to be
determined (78). A recent review of possible neural mechanisms of
cannabis stiigests the hippocampus and other deep structures may be
important sites of action (41), at least in animals.
Scalp EEG and evoked potentials showed marked changes in sub-
jects given very large smoked doses of TUC or marihuana (158,159).
Alpha abundance increased with posterior slow wave, activity becom-
ing prominent. Ataxia, hypersoninia, increased deep tendon reflexes.
tremor, tonic muscle contractions and myoclonus followed these 1 mg/
kg doses of THC.
Loss of REM sleep appears to be a predictable effect of cannabis
(159. 159). Total sleep time increases. Stage 4 or slow wave sleep is
relatively unaffected. In this respect cannabis is unlike any sedative-
hypnotic drug studied thus far (48). When the drum is stopped after
a period of prolonged administration, REM sleep stace and eye move-
ments show a marked rebound above baseline levels. In contrast to the
relatively small changes in waking EEGs after the drurr is given, sleep
EEG changes are very dramatic and large-both when the drug is
acutely and chronically administered (48).
Changes in the slow cortical potentials recorded from the scalp
(contingent, negative variation or CNY) after cannabis are of particu-








lar interest since this measure is said to be sensitive to changes in
motivation and attention deployment, among other factors. A recent
study of the CNV obtained somewhat different results from tho-c
reported last year (10). Like many neurophysiologic measure-, it
appears the CNV is far more complicated than was originally assumed.
It appears the CNV may get larger or smaller after cannabis, depend-
ing on the level of intoxication, the task demands, the motivation of
the subject and changes in attention. To view the cannabis-induced
CXV changes as any direct measure of attention deployment or moti-
vation is probably an oversimplification (10).
Effects on cell-mediated immune response
Conflicting opinions as to the possible effects of caniabis on the
cell-mediated immune response continue to appear (148). In the fourth
report, the observation that chronic marihuana users had decreased
in vit ro lymphocyte response to allogeneic cells and to a mitogen was
described (118). This original observation has led to extensive in vitro
and animal studies described elsewhere in this report. Related studio.
in humans published this past year provide partial support for the
notion of an immune system or thymus-derived cell alteration in
people who smoke marihuana (30, 118, 134). However, other investi-
gators using an in vivo skin testing procedure found no evidence of
impairment of cell-mediated immunity in chronic marihuana users
(151). Marihuana smokers had less T cell response to phvtohemag-
glutin stimulation and decreased PMX phagocytic capacity (184).
The authors of the latter study caution that the clinical signifcl..) Ce
of these findings is uncertain. In possibly related in vivo studies, the
white blood cells from both cannabis users and non-users showed m':"1ii-
lar dose-related inhibition of migration when exposed to THC and
extracts of cannabis (147). Substances other than THC in the crude
extract may have effects on this test system.
Administration of THC or cannabis to controlled populations, v-ith
before and after testing, is underway and may provide useful infor-
mation in clarifying the etiology of the cell-mediated immune effects
(125).
Other physiologic effects
Previous reports associated cainabis intoxication with decreases in
int raocular pressure. The possible therapeutic implication of this unex-
pected effect is discussed in the section on therapeutic applications.
More extensive studies in normal volunteer subjects indicate a non-
dose-related pressure drop lasting from four to five hours (68). The
magnitude of the eye pressure decrease (about 30%) was the same
whether the person smoked one or 22 marihuana cigarettes. Effects on
other aspects of eye physiology (acuity, refractive error, biomicros-
copy, fungus changes, visual fields. ophthalmodcvnamometry, electro-
ret inography and orthoptic evaluation) were minimal or absent. Other
investigators concluded that the observed eye pressure decreases were
more likely a consequence of drug-induced relaxation and sedation
rather than specific cannabis effects on the eye, since other sedative
drugs produced similar changes in eye pressure. (52). Results of studio-
of the effects of smoked marihuana on galvanic skin response are con-
sistent with drug-induced reduction in level of autonomic nervous sys-






82


tern arousal (25). However, recent findings seem to contradict this
interpretation (cf. Therapeutic Aspects).
Intravenous administration of a water infusion of cannabis resulted
in gastroenteritis, hypoalbuminemia, hepatitis, and many cardiovascu-
lar changes secondary in part to hypovolemia (131). It is not entirely
clear what symptoms were cannabinoid effects or, more likely, the non-
specific effects of injected foreign plant material.
Acute effects on mental and psychomotor performance
As in previous years a host of studies have reported impaired func-
tioning on a variety of cognitive and performance tasks while mari-
huana intoxicated. For the most part, impairments were dose-related.
The investigators who gave the smallest doses generally reported the
fewest, effects. Impaired memory (9, 33, 38, 39, 167), altered time sense
(9, 167) and decrements on performance on a number of tasks-suoh
as those involving reaction time, concept formation, learning, percep-
tual motor coordination, attention and signal detection-are commonly
described (9, 24, 25, 32, 35, 37, 115, 116, 119, 120, 121, 150, 162). A
number of discussions of the locus of the memory impairment have
appeared (33, 39, 164). There is a growing consensus that the memory
defect is due to a storage problem rather than acquisition or retrieval.
There has been concern that cannabis may increase the. suggestibility
of those using it. However, in laboratory studies marihuana smoking
had no effect on hypnotic susceptibility (6).
Effects on sensory function
One of the more commonly reported effects of cannabis is a sub-
jective change in sensation. A number of groups investigated drug
effects on various aspects of sensory functioning. Although subjective
impressions of changes in skin sensitivity are commonly associated
with cannabis intoxication, no objective or measurable change in
cutaneous sensitivity using a number of measures was noted (115).
The decrease in auditory signal detection while intoxicated appeared
to be d(ie to a decrease in sensitivity rather than a change in criteria
(120). This finding contrasts with the usual subjective reports of en-
liaiwed auditory sensitivity. THC given to patients suffering from
pain demonstrated mild inilgesic effects but. 20 mg doses orally pro-
dIiced many unplevasunt side effects-somnolence, dizziness. ataxia,
blurred vision, etc. (126, 127). The experience. of experimentally in-
dwced pain in normal subjects was also diminished by smoked mari-
hiuna (130). Pain secondary to spinal cord injury was decreased by
(:ilunabis use, (42). The. characteristics of preferred tone frequency
were, shifted while intoxicated (35).
Autom obile dr'rb performance
MJore evidence has accimiulted indication tha6t drivinqr ability and
relaftid skills aire impaired 1Iv c:mnabis at dopeS likely to be. commonly
ii'4ed in the iTnited States (90, 89, 119, 44). Despite. their commonly
expreTsed belief that their driviiin ability is impaired when intoxicated
(90, 163, 32), more cannabis users appear tn drive today while intoxi-
eritoed than was the caso a. few years a-co. In limited surveys 650% to 80%
of the users questioned reported driving soon after marihunana use (90,
15.1). The use of alcohol in combination with marihuana before driv-






83


ing was reported by 64% of one sample and during driving by 20%
of the sample (90). As the risks of arrest for possession decrease, one
might expect more users will take the chance of being caught while
intoxicated and driving (154).
A more detailed report of a Canadian driving study discussed last
year (89) has appeared (90). The data clearly demonstrate that mari-
huana in relatively low doses (cigarettes containing approximately 5
and 8 mg of TI-C) typically had a detrimental effect on driving skills
and performance not only on a test course but also under more usual
city driving conditions. However, as is true with alcohol, effects were
not uniform with all drivers. Some, particularly at the lower dose,
actually improved their performance. Thus, the problem of individual
differences that has complicated developing and enforcing "drunk
driving" laws will probably recur when discussions of the minimal
allowable dose or blood level of cannabinoids come up.
Compared to most of the behavioral tasks studied in the laboratory,
automobile driving is more complex. The relative importance of the
various perceptual, cognitive and psychomotor functions in determirn-
ing driving ability is not completely understood. For example, in some
situations the cognitive impairment produced by cannabis may have
only limited impact on actual driving performance due to concomitant
drug-induced changes in risk acceptance or feelings of aggression. In
a laboratory simulation of driving, cainnabis-intoxictited subjects took
longer to decide whether to pass another car seemed less likely to accept
the risks of passing and seemed less aggressive than alcohol-intoxic.-ted
subjects (40, 45). Other laboratory simulator studies have found that,
while some driving skills are relatively unaffected by marilhuana. there
is a dose-related impairment in the ability to attend to peripheral
stimuli while driving (119). Such an impairment might interfere with
a driver's response to a car suddenly emerging from a side street.
Because of the many inherent inadequacies of laboratory driving
simulator studies (90), cannabis-related driving risks will ultinmately
have to be assessed on the basis of studies of actual accident rates for
users compared to non-users. This has been difficult in the study of
aIlcohol. It promises to be still more difficult with cannabis because of
the difficulties of measuring tissue levels of the cannabinoids, the
longer excretion times, the more complicated metabolism and the often
combined use of cannabis and alcohol -while driving, making the rela-
tive contribution of either drug uncertain (90, 154).
Flying an airplane demands still more complex skills than does
driving. There is little information concerning poshjIble pilot error
or impairment in performance as a result of having used marihuana.
A preliminary study has shown that under flight simulator test con-
ditions experienced pilots showed marked deterioration in perform-
ance following smoking marihuana containing 6 mg. of TIHC (108).
More detailed studies are planned to follow up these initial
observations.
Nonpharmacologic determInants of subject b'c reSPonse
Sociocultural factors (128) appeal mr to interact with such pharma-
cologic aspects as dose and route of administration so as to modify
marihuana's subjective effects. Some of these factors were explored in






84


studies published this past year. Laboratory studies are often criticized
because a sterile, scientific laboratory setting may alter the response
to the drug so that findings have little relevance to more typical con-
ditions of use. A group of subjects were randomly assigned to smoke
marihuana (16 mg THC) and were tested either in a typical medical
research laboratory or a private living room designed to facilitate a
pleasurable drug experience (76). Although there were great differ-
ences between subjects in their subjective responses to the smoked
marihuana, the effect of the very different settings was negligible.
A similar study using only a subjective level of intoxication as an
index of drug effects found a psychedelic environment was -associated
with greater intoxication at intermediate dose levels, but not at the
highest (16 mg THC) dose employed (14). Another attribute of the
setting in which cannabis is often used is the possible effect of other
intoxicated friends on a person's "high." However, in a study testing
the effects of modeling, subjects smoking marihuana for the first time
were relatively unaffected by the presence of an actor modeling a
marihuana high (17). The results of this study suggest that previous
experience with cannabis is a complicated socialization process in
which individuals learn from friends and others to discriminate and
label various aspects of the drug state (17). The mood one is in before
smoking is sometimes thought to interact with the drug effects to
produce varied outcomes. A laboratory study found no difference in
subjective response to low doses of smoked marihuana and no difference
in level of anxiety in groups of subjects made anxious by exposure to
laboratory stresses (136). Finally, in a study mentioned in last year's
report, but which had not yet been published, it was found that the
dose of cannabis consumed in an experimental laboratory setting was
determined by many factors (size of cigarettes, past drug experience)
other than pharmacologic potency of the drug (15). A similar study
by the same group (14) found that controlling the amount of drug
consumed in accord with its varying strength was difficult for subjects,
again suggesting that nonpharmacologic considerations are important
in affecting the amounts consumed.

CANNABIS AND rSYCIIOPATHOLOGY
The association of cannabis use with psychiatric illness raises com-
plex questions for which no completely satisfactory answers are yet
available. Two reviews of past research point out the many methodol-
ogical and theoretical shortcomings of existing work (64, 112). A
variety of psychiatric disorders are clearly associated with the use, of
cannabis-however, whether the psychopathology is an antecedent to
use, a consequence or a mere coincidence is still very much open to
question. A best guess is that cannabis use like that of many other
psychoactive drugs will sometimes be an antecedent, a consequence or
coincidental to psychopathology, depending on the person and many
other variables (112).
As is often true in medicine, the ambiguity in diagnostic classifica-
tion and definition adds to the confusion concerning adverse psycho-
logical reactions associated with cannabis use. The following classifi-
cation has been adopted in imposing some order on the literature (64,
112).






85


Acute panic anxiety reactions
The acute panic anxiety reaction has been noted by many reviewers
to be the most common adverse reaction to cannabis use (64, 112). The
symptoms and signs are usually exaggerations of normal cannabis
effects more generally described by users. Anxiety is often focused on
fears of "going crazy." This reaction appears most likely to occur in
novices and after consuming more potent materials. Personality vari-
ables that make for poorer coping skills play a role. The symptoms
diminish with authoritative reassurance or in a few hours when the
immediate drug effects have worn off. A number of reports in the past
year illustrate these considerations (1, 87, 117, 124, 127, 164. 166).
Patients with chronic pain (127) and depression (1,139) given low
doses of THC in therapeutic trials had far more dysphoric and acute
panic episodes than would be expected if the same doses were given
to typically youthful cannabis users. These older people presumably
found it difficult to accept the drug-induced mental changes as desir-
able. Younger but equally inexperienced "cannabis experimenters"
often react similarly (164, 117).
Cannabis-induced mild paranoid feelings in student and "counter
culture" users of marihuana are common and usually not a source of
undue concern to them (87). About two-thirds of a student group and
95% of a counter culture group studied described suspicion of being
subjected to a police raid or having friends tricking them while intoxi-
cated. Inability to reality test concerning these suspicions was reported
by over half of the subjects. Another field survey found that indi-
viduals with a tendency to use paranoid defense meclhnisnms experi-
enced fewer acute anxiety reactions after cannabis (124). The authors
thought that the more sophisticated defenses represented in paranoid
functioning may be effective in preventing acute adverse reactions. The
same study found that persons with high scores on the schizophrenia
subscale of the MMPI tended to have more problems with adverse
psychological reactions indicating (as have a host of previous studies)
that pre-existing psychopathology is an important factor in such
reactions.
Cannabis induced acute-brain syndrome or toxic de~tiblai
The clinical features of the acute brain syndrome associated with
cannabis intoxication-such as clouding of mental processes, disorien-
tation, confusion and marked memory impairment-are similar to
tho-e. produced by other exogenous toxins (64, 112). The syndrome is
mo-t. likely to occur at high doses and to be dose-related, whereas the
panic reactions may occur at any dose unfamiliar to the user (64, 112,
79). The toxic delirium is likely to follow the time course of other drug
effects. This syndrome appears to be relatively rare in the United
States.
Prolonged reactions
Possible prolonged psychological effects of cannabis use are an area
of serious concern and controversy. These include not only psychic
reactions but also personality change, change in life style, a possible
motivationall syndrome," "flashbacks" and a possible causal rela-
tionship between marihuana use and use of other drugs. Here it is






86


even more difficult to establish precise cause and effect because the close
relationship between ingestion of the drug and acute effects is lacking.
Descriptions of a specific long lasting cannabis psychosis appear
largely in the Eastern literature, and thus are largely drawn from
a culture where use is generally more frequent, and at higher dose
levels, than normally is typical for the United States. This acute
"cannabis psychosis" is generally associated with very frequent. use
and reportedly lasts one to six weeks or longer (64, 112). Recent studies
abroad in Jamaica (141), Greece (155) or Costa Rica (23) where
frequent users of high potency cannabis were examined failed to docu-
ment the existence of a specific cannabis psychosis. However, small
sample sizes were involved and such a relatively rare occurrence could
wvell have been missed.
A few years ago a, clinical report by Kolansky and Moore (95)
described eisrht psychotic reactions in a group of 39 marihuana
smokers in this country and attempted to demonstrate a cause-and-
effect relationship to their marihuana use. A more recent clinical study
demonst rates how correlations between various behaviors and subse-
quent psychiatric disorders can be misleading (2). Consecutive first
cd:-nissions to a psychiatric hospital were evaluated. Thirty-eight
patients who had used marihuana prior to the onset of psychiatric
problems were studied. Indeed, apathy, poor judgment, confusion and
depression followed marihuana smoking, but the correlations between
marihuana use and subsequent illness was less than with such causally
unrelated variables as having masturbated, having experienced sex
education, and having drunk beer. In this clinical study marijuana
use could not be singled out as a prime factor leading to psychiatric
illness.
Marihuana flashbacks-spont aiweous recurrences of feelings and per-
ceptions similar to those produced by the drug-continue to be re-
ported (12). The etiology of such flashbacks remains obscure, but those
wh- experienced them seem to require minimal treatment, if any.
iYo' d 0'of prolonged adverse reactions
Su"veys of user and Pon -ter po0iulations provide somn informal *on
as to 'ieurop- vcho]c'-cral changes, chances in life style and the so-called
aimot'vational syndrome associated bv some with canmnabis ui:e. In
an ,ll too rnrp prospective study, Culver and King (2q) compared
jroims of T .SD-inescaline users with marihuana-hashish uoers and
non-drivr uiinzr controls. The investigators wsed a sophisticated p'vco-
lorieal test battery inclucndini the Halsted-Reitan tests, the Weciwler
Adult Intelligence Scale and tests of spatial perceptual abilities. When
tested a. ynar later the LSD-mescaline ground scored least well on the,
trail m.kinT( test, but the performance of all three groups fell within
normal limits. No evidence could bIe found for the existence of a neuro-
psychological deficit with either light or frequent. cannabis use.
Another study of heavy drug users usina a similar test battery arrived
at similar conclusions (13). However, the authors of the study remind
their readers that one should not conclude that no organic changes
occurred since psychological test data is inferential and definitive
statements as to organic changes can only be based on radiological or
pathological evidence. One study of multiple drug users in the Navy
found a large number of psychiatric symptoms reported by them on-,








the Cornell Medical Index but because of the variety of drugs habit-
ually used it was impossible to single out marihuana use as an impor-
tant factor (61).
The possible effects of cannabis on student performance his been a
major concern because of the extensive use by that group. A longitudi-
nal study of a sample of 1,970 college students examined the relation-
ship between cannabis use and psychosocial adaptation and academic
periornance (11). Users and non-users did not differ in grade point
ave rage or in educational achievement, but the marihuana uers signed
to have more difficulty in deciding on career goals and dropped out of
college more often to reassess goals. A smaller percentage of regular
users planned to seek advanced or professional degrees. There was, in
the opinion of the users themselves, a poorer academic adjustment
among the most frequent users than among infrequent or non-users.
Only 6-0 of non-users reported a worsening of their emotional state
since. beginning college but 20% of the long duration users reported
negative changes in emotional state. A problem with the study was
that a significant percentage of the initial simple was lost over the
three. year period. If the loss was from the group who failed out or
dropped out, those most likely to show loss of motivation or intellec-
tual functions may have been automatically excluded from the study-
Also, the study merely reported the students' own ;iof-c ent 01 their
adaptation since -no interviews were attempted. Other questionnaire
surveys reported differences between users and non-users but the qiues-
tion of causation remains and the mental health significance of some
of the findings are unclear. Non-users scored higher on needs for
achievement and order and not surprisingly had higher grades (152).
Other surveys found marihuana users to be more dissatisfied. disillu-
sioned and alienated (29), more oriented towards the past (88)., but
to be more creative and adventuresome (60). They also had lower levels
of achievement (16).
The ability of cannabis users to work in other contexts has been
examined in attempts to see if a measurable "amotivational syndromle"Of
exists (113, 111). In a study of frequent and infrequent use:'/ smokinT
cannabis while living on a research ward, work output decre.'sed as
marihuana consumption increased (111). However, the inves ticgators
noted that. "motivation" is a function of situatioinl variables as well
as drug factors. To term the decrement in work output "amotivational"
would imply that the users in the experiment had lost interest. in work-
ing for money. However, if the work decrement re-ulted from a drug-
induced impairment of performance, it would not be proper to term it
a motivation effect. In a similar- Canadian study (113) a fall in pro-
ductivity (making stools) followed the smoking of cannabis. The
decreased productivity appeared to be due to less time spent working
rather than to decreased efficiency. The authors interpret this as indica-
tive of an motivationall syndrome." To the extent that these types of
studies involve artificial work conditions and tasks dissimilar to more
usual employment, it is hazardous to draw more general conclusions
regarding the role of cannabis in a more generalized amotivational
picture. Moreover, these studies involved intensive daily use. Their
relationship to episodic or less frequent use in altering motivation is
unknown.






88


An assumed relationship between cannabis use and the use of other
drugs (mainly opiates) has been a source of concern. The progression
hypothesis is a good example of a theoretical construct repeated so
many times that it has become verified by repetition rather than by
facts (161). The patterns of the shifts from one drug to another seem
to be changing with more of a "progression" to "polydrugs" other than
heroin (57). In a military population the pattern of drug use and
selection of drugs was determined more by availability, peer pressure
and drug use fads than by pharmacologic or personality variables
(123). Cannabis users are, however, very likely to use other licit and
illicit drugs with a positive correlation between level of cannabis use
and the variety of drugs used (122).
Criminal and aggressive behavior
The often discussed possible link between cannabis use and crime
or aggressive behavior was the topic of reviews (56, 92) and experi-
mental studies (26, 107, 142). Both reviews (56, 92) concluded that
evidence showing marihuana to cause crime is virtually nonexistent.
Young prisoners who varied in their degree of marihuana use were
compared using a number of personality measures (e.g., MMPI, CPI)
(107). Non-users and occasional users had typical criminal profiles.
Regular users of only marihuana were better socialized and adjusted,
though more deviant, than collegiate marihuana users. Prisoners who
used marihuana plus other drugs were the most deviant.
In addition to concern about marihuana use and criminality, the
association between marihuana intoxication and hostile human be-
havior lias been a topic of great interest and discussion. The results of
observations and self-reports of hostile, aggressive feelings from re-
search subjects intoxicated acutely or chronically with cannabis sug-
2est. the usual effects are to decrease expressed and experienced hos-
tility (80, 109,142).
CHRONIC EFFECTS
T'ooeyrance
Marked tolerance to the effects of cannabis doses commonly con-
sumed in this country is not usually evident, presumably because of
relatively infrequent use and the generally low doses of active mate-
rial. However, as data accumulate from countries where more frequent
use of high doses is common (23, 49, 141, 155), it is apparent that tol-
erance must develop to many of the psychological and physiological
effects. In controlled experimental situations where prolonged admin-
istration of THC or marihuana to volunteer subjects has been under-
taken. what appears to be dose-related tolerance. develops rapidly (8,
s3, 80,109, 111) as judged by behavioral, psychologic and physiologic
measures.
In outpatient studies where frequent and infrequent users or other
populations with differing drug histories are compared in their re-
sponse to a given dose of cannabis., the. results are less consistent.
Marked tolerance to measured effects is rarely obvious, if evident at
,ill (94, 132, 140, 155). However, when sensitive and reliable, measures
,re used, even infrequent use may produce evidence. of some degree
of tolerance on outpatient laboratory tests (9, 24). Tolerance in man
i- apparently a dose-related effect as it is in animals (36).






89


Depe ndcwce
When volunteers were given 30 mg doses of THC orally for 10-20
days, sudden cessation of the drug was associated with the appearance
of irritability, restless decreased appetite, marked sleep disturb-
ance (including sleep EEG alterations), sweating, salivation, tremor,
weight loss. nausea and vomiting, diarrhea and, in general, a clinical
picture similar to that following chronic administration and moderate
doses of many sedative-hypnotic drugs (8, 48, 80). Such psychologic
and physiologic changes have not been commonly observed in other
chronic administration studies in this country. Restlessness and weight
loss was reported by Mendelson in an inpatient volunteer study at the
end of a 21-day smoking period (109). Drug-seeking behavior has not
been associated with the withdrawal syndrome, but the presence or
ab)SOhnce of such behavior is difficult to assess in the laboratory. A with-
drawal syndrome has not been described in recent investigations of
chronic users abroad (23, 49, 141).
Field studies of chronic users
Several field studies of populations of frequent long-term users have
searched for possible adverse or other effects associated with chronic
use (23, 49, 94, 141). These all were concerned with user in countries
where high potency cannabis is more readily available than in the
United States.
The results of a chronic user study discussed in two previous reports
were recently published in book form (141). The 30 experimental sub-
jects had been smoking high potency cannabis almost daily for ten
years or more. Few psychological or physiological differences between
the cannabis smokers and nonsmokers were evident. There was no
evidence for liver, kidney or cardiovascular malfunction. While no
differences in chromosomal abnormalities were found, the results must
be regarded as inconclusive because of various technical deficiencies
of the study. Modest decreases in pulmonary function and altered
hemoglobin levels were the only physiologic difference( evident. The
impact on these findings of tobacco use by the subjects is uncertain.
After smoking cannabis. a small group of workers produced less work
(weeding, hoeing, digging) with more movements, but otherwise
showed no evidence of "amotivation." The importance of cultural
differences in the interpret ition of drug effects is evident in that people
in Jamaica did not find their appetite increased by cannabis, nor their
hearing enhanced nor their time sense altered, and in fact said they
used cannabis so as to work better. Although reassuring, the findings
should also be judged in perspective. They were derived from a small
group of selected users, so that rare consequences (if they did occur)
such as brain atrophy or psychosis might not have been detected. The
subjects were laborers and farmers in a very different culture. so that
intellecual impairment may have been relatively difficult to detect.
A similar although larger and more complex study is underway in
Costa Rica. Coggins presented a preliminary report (23). Eighty
dailv marihuana users and matched nonca nabis-using controls were
evaluated with extensive medical examinations, laboratory studies,
X-rays, EEG, EKG and neuropsychological testing. Although the


67-6(2-76--7






90


study is still in progress, no evidence for a greater incidence of disease
or deterioration has yet to be found.
In studies of Greek and chronic hashish users approximately 47
chronic users were compared with 40 control nonusers on a variety
of EEG, echoencephalographic, neuropsychologic and experimental
laboratory tests (49, 94, 155). Conventional clinical measures of brain
damage (EEG, echo-EEG) showed no evidence of abnormality in the
chronic users. Tolerance to administered doses rapidly developed on
the EEG indices. No evidence of withdrawal symptoms after three
days of chronic administration was evident. When given high doses
of THC, some of these very experienced subjects developed unpleasant
psychological symptoms when their tolerance. level was exceeded.
These were all outpatients so no precise control over drug use outside
of the laboratory was possible. A slightly higher incidence of per-
sonality disorders in the hashish-using group was better explained by
psychosocial variables than by marihuana use.
Thus, these three field studies of users abroad do not report brain
damage, psychosis or an "amotivational syndrome." However, the
cultures are different, and the sample populations are relatively small
so such drug effects can not be ruled out. They may be simply uncom-
mon or difficult to measure.
Chronic effects-laboratory studies
A number of groups have studied the effects of daily cannabis use
in paid volunteer subjects consuming cannabis for up to 72-day periods
while hospitalized (8, 48, 53, 80, 109, 111, 113). Although even 72 days
is not really chronic use. such studies complement. the more commonly
performed acute outpatient studies. In general. in all these. chronic
or subchronic studies, subjects have tolerated the drug treatment phase
well and very few dropouts, psychoses, or other blatant manifestations
of distress were revealed. Except for the pulmonary function changes
noted in one study (109), drug effects on mental, behavioral and
physiologic functions appear to disappear rapidly on cessation of
drug administration and have been, in general, similar to those seen
in acute studies. Tolerance is evident at lower doses (53, 109) and
obvious at high doses (80).
Adverse physiologic effects associated qLith chronic use
Mention has already been made of the endocrine and immunologic
changes reported in some populations of users. Mutagenesis and terato-
genesis is discussed elsewhere in this report. A discussion of the report
of brain ventricle changes was presented in a previous report. A paper
describing the same group of subjects appeared this past year (46),
but no similar reports have yet appeared. The difficulty of performing
pneulfloencej)halograilis in neurological ly normal volunteers makes
survey studies impossible. A number of groups are testing cannabis
users with noninvasive techniques for measuring brain ventricle size
(computerized tomography) and preliminary results should be avail-
able soon. An investigator who reported the electrical changes in the
deep brain structures of a human smoking marihuana has now com-
pleted chronic studies in monkeys, finding similar electrical changes.
The. slow wave activity persists for months after the cessation of a
chronic period of smoking. The behavioral and biological significance
of the changes in man is uncertain.















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