are in Research|
and the Dependence Liability of Marijuana
July 11, 1997
Recent research published in the journal Science provides valuable contributions
to understanding the relative dependence liability of marijuana. (Tanda et al,
1997, de Fonseca et al, 1997)
Research by Tanda, Pontieri, and Di Chiara on cannabinoid activation of dopamine
transmission is especially important. E. L. Gardner and this research team have
been reporting on a cannabinoid effect on the brain reward system (Gardner et
al, 1988a; Gardner et al, 1988b) and dopamine transmission for several years (Chen,
et al 1990a; Chen et al 1990b; Chen et al 1993), however until now their results
have not been replicated and similar experiments have been contradictory. (Castaneda
et al, 1991)
Chiara and Imperato have previously associated an effect on dopamine with amphetamine,
cocaine, ethanol, nicotine, and opiates. (Di Chiara, G. and Imperato, 1988) The
key location of dopamine transmission is the nucleus accumbens. Recently a distinction
has been discovered between the shell of the nucleus accumbens, which influences
emotions, and a core, which influences somatomotor functions. (Heimer, L et al,
1991.) Nicotine, cocaine, amphetamines, and morphine have previously been shown
to stimulate dopamine transmission in the shell of the nucleus accumbens. (Pontieri,
F. E. et al 1996)
Abood and Martin note that Gardner's findings were confined to "one strain of
rat" and its application "to human abuse is tentative at best." (Abood and Martin,
1992) This conclusion is also reported by the Office of Technology Assessment,
which attributes the finding to an in-bred quality specific to Lewis Rats. (US
Congress OTA, 1993)
In 1991 a research team of D.E. Moss published "THC does not affect striatal dopamine
release: microdialysis in freely moving rats" (Castenada et al, 1991) which reported
results from in vivo microdialysis on Long-Evans rats. In 1992 Herkenham, using
a lesion-technique, established that there are no cannabinoid receptors in the
dopamine producing areas of the brain. (Herkenham, 1992) These results were consistent
with prior research indicating that animals will not self-administer marijuana.
The Office of Technology
Assessment (OTA) reached the following conclusion about marijuana's abuse potential
in 1993: "While marijuana produces a feeling of euphoria in humans, in general,
animals will not self-administer THC in controlled studies. Also, cannabinoids
generally do not lower the threshold needed to get animals to self-stimulate the
brain reward system, as do other drugs of abuse." (US Congress OTA, 1993)
The conclusion of OTA is based on the pharmacological literature. Abood and Martin
report in 1992 that: "While self-administration of drugs has been taken as an
indication of psychological dependence and/or abuse potential, few reports claim
to have established experimental models for self administration of [Delta -9]-THC
. . . This observation suggests limited potential for development of . . . limited
psychological dependence due to the weak reinforcing properties of [Delta -9]-THC."
(Abood and Martin, 1992)
Herkenham's 1992 review of the literature produces this comment: "Animals generally
will not self-administer [Delta -9]-THC. Cannabinoids did not lower the threshold
for electrical self-stimulation in one study. In another study they did, but apparently
both this phenomenon and the enhancement of basal dopamine efflux from the [nucleus
accumbens] by [Delta -9]-THC are strain-specific, occurring only in Lewis rats."(Herkenham,
show more pronounced neuroadaptations to many drugs of abuse, not just cannabis.
(Nestler, 1993) However these specific adaptations draw attention to specific
neurosystems contributing to an animal's inherent responsiveness to drugs of abuse.
(Gardner and Lowinson, 1991; Nestler, 1992) The research of Gardner and his colleagues
on marijuana's interaction with the brain reward system, while noting that their
findings are strain specific to Lewis Rats, has demonstrated that cannabinoid
drugs enhance electrical brain stimulation and presynaptic dopamine levels at
meaningful low doses. (Gardner and Lowinson, 1991) They also noted that the effect
on dopamine was reversible upon application of the opiate antagonist naloxone,
and concluded that marijuana modulates two opiate receptors, mu and delta. (Gardner
and Lowinson, 1991)
The pioneering work of Gardner and his colleagues in this area generated valuable
hypotheses about marijuana's affect on the dopamine system. A 1988 article by
Di Chiara and Imperato set a standard for establishing that a drug stimulates
dopamine production in the nucleus accumbens of a rat. (Di Chiara and Imperato,
1988) Until the June 1997 article by Di Chiara and colleagues this standard had
not been met with regard to marijuana, and Gardner's work was still considered
unreplicated and strain specific. Di Chiara et al note in the June 1997 article
that previous findings in this area had been inconclusive, citing both Moss' and
Gardner's results. (Tanda et al, 1997) However there findings replicate many of
those made by the Gardner team. Di Chiara's 1997 Science article provides evidence
that meaningful low doses of cannabinoids have an indirect effect on dopamine
transmission in the shell of the nucleus accumbens by way of their modulation
of the mu opiate receptor. (Di Chiara, 1997)
Generally an effect on dopamine transmission is associated with compulsive self-administration
in animal models. Further evidence that cannabinoids are poor reinforcers in animals
was produced in 1994 in a study utilizing rhesus monkeys. (Mansbasch et al, 1994)
The relative dependence liability of marijuana compared to other drugs has been
long recognized. (Hollister, 1986) Di Chiara is quoted in an editorial in Science
on the relevance of his recent findings. "I would be satisfied if, following all
this evidence, people would no longer consider THC a 'soft' drug. I'm not saying
it's as dangerous as heroin, but I'm hoping people will approach marijuana far
more cautiously than they have before." (Wickelgren, 1997)
Cannabinoids are considered promising analgesics because they activate portions
of the opiate system providing pain relief but do not cause the physical dependence
of opiates. (Segal, 1987; Melvyn and Johnson, 1987) Cannabinoid receptors, for
example, do not influence heart and lung activity. (Herkenham and Lynn, 1990)
Activation of the
locus coeruleus, the major noradrenergic nucleus in the brain, is one of the major
physical causes of opiate withdrawal symptoms. (Nestler, 1996) "Dopamine does
not play an essential role in the reinforcing properties of opiates." (Di Chiara,
1995) The recent Science article reports that Delta-9-THC and Heroin both increase
dopamine levels in the shell of the nucleus accumbens by approximately 25 - 50%.
(Tanda et al, 1997) Cocaine increases dopamine output in the shell by approximately
100%, amphetamine by 75 to 150%, and morphine increases dopamine output in the
shell by approximately 50 to 60%. (Pontieri, et al. 1995) Jianping Chen, one of
Gardner's colleagues, notes: "It is also of interest that naturally occurring
rewarding behaviors also appear to correlate with a dynamic enhancement of DA
[dopamine] overflow in the nucleus accumbens. For example, extracellular DA levels
in the nucleus accumbens were found to increase 37% during level pressing for
food reward [Hernandez and Hoebel, 1988], and copulation in male rats was found
to cause a 200% increase in extracellular accumbens DA overflow. [Pfaus et al,
provides context for research findings on the neuroadaptations caused by drugs:
"Substance use, substance abuse and substance dependence are separate, definable
entities in most formulations. An important challenge for nuerobiological research
is to understand how the transition occurs between controlled drug use and the
loss of control that defines addiction or substance dependence and what molecular,
cellular, and system processes contribute to the development of drug dependence."
(Koob, 1996) One of the benefits of further research on marijuana's affect on
neural systems will be the development of treatments for individuals with marijuana
dependency problems, such as medication to eliminate the mild withdrawal symptoms
following cessation of heavy use.
It has been long reported that heavy marijuana use followed by abstinence produces
a mild withdrawal syndrome characterized by irritability and sleeplessness. (Hollister,
1986; Abood and Martin, 1992) Corticotropin-Releasing Factor (CRF) is a chemical
released in the amygdala associated with stress and negative consequences of withdrawal
from alcohol, cocaine, and opiates. (Koob, 1996) F. R. de Fonseca, Koob, and colleagues
have demonstrated that withdrawal from cannabinoids, induced by use of an antagonist
to shut down cannabinoid receptor sites, results in the production of CRF. (de
Fonseca et al , 1997)
Koob and associates have developed an opponent-process model for explaining the
drug dependency, particularly withdrawal symptoms. Such symptoms are thought to
be due to residual deficits from neural adaptations, sensitization of the brain
reward systems through the development of positively emotional cues, or both.
Residual deficits can be due to both within-system adaptations (such as those
in the locus coeruleus that contribute to opiate withdrawal) or between-system
adaptations (such as the role of CRF). (Koob, 1996)
The recent findings in Science (Tanda, et al 1997; de Fonseca et al, 1997) establish
that among the drugs of abuse marijuana's effect on dopamine transmission, while
relevant, is indirect, and the withdrawal symptoms associated with cannabis use
are due to modest between system adaptations rather than extreme within system
adaptations. This supports the argument that cannabis dependency is influenced
far more by the secondary effects of long-term use rather than the reinforcing
actions of occasional recreational use. While low doses of cannabis provide a
similar high as both opiates and food consumption, it is other factors, such as
set and setting (which contribute to sensitization) that determine its dependence
of these studies suggest that their findings may give support to consideration
of marijuana as a gateway drug. (Tanda et al, 1997, de Fonseca et al, 1997) The
general theory of gateway drugs was developed by Kandel. (Yamaguchi and Kandel,
1984) The general theory is that gateway drugs (such as alcohol, marijuana, and
tobacco) introduce someone to drug induced dopamine stimulation, and once familiar
with the innovation the individual is more susceptible to using more dangerous
dopamine stimulating drugs such as amphetamines, cocaine, and opiates. The production
of CRF "may lead to a subtle disruption of hedonic systems in the brain that are
then primed for further disruption by other drugs of abuse." (de Fonseca et al,
and colleagues found that an antagonist that blocks opiate receptors also blocked
the cannabinoid effects on the shell of the nucleus accumbens. (Tanda et al, 1997)
While presenting no evidence of a causal relation between marijuana and heroin,
the authors suggest their findings are "consistent with this possibility." (Tanda
et al, 1997) The gateway theory, though, is descriptive not predictive. (Yamaguchi
and Kandel, 1984)
existence of sequential stages of progression, however, does not necessarily imply
causal linkages among different drugs since the observed sequences could simply
reflect the association of each class of drugs with different ages of initiation
and/or individual attributes rather than the specific effect of the use of one
class of drug on the use of another. Furthermore, it is important to keep in mind
that although a clear development sequence in drug involvement has been identified,
use of a drug at a particular stage does not invariably lead to the use of other
drugs higher up in the sequence. Many youths stop at a particular stage and do
not progress further." (Yamaguchi and Kandel, 1984) [pg 671]
It has long been recognized that some individuals' use of marijuana is characterized
by dependence, and that the dependence liability of marijuana is more comparable
to alcohol and tobacco than heroin and cocaine. (Hollister, 1986) Compulsive self-administration
in animal models is a primary attribute of drugs with a serious potential for
abuse. (Cicero, 1992) Animals will not self-administer cannabinoids. (Abood and
Martin, 1992; Herkenham, 1992; Mansbach, 1994) A severe dependence liability is
also characterized as harmful self-administration, excluding such behavior as
heavy caffeine consumption, and subject to influences of set and setting as well
as the pharmacological properties of a drug. (Zinberg, 1984; Cicero, 1992)
The Controlled Substances Act (CSA) regulates access to drugs and substances based
on their relative dependence liability. (U.S. Code Congressional and Administrative
News, 1970; 21 USC 811, 812) Schedule I drugs must have the highest potential
for abuse. (21 USC 812 (b)(1)) Accepted medical use in the United States is not
the primary criteria for scheduling under the CSA, instead Congress placed great
emphasis during the passage of the CSA on abuse potential being the primary factor
that justifies control and the level of regulation. (NORML v. DEA, 1977) In the
context of existing US law and public policy the influence of various drugs on
dopamine justifies regulation and control under the Controlled Substances Act,
but does not by itself indicate the level of control required by law.
The CSA mandates that several factors be considered in determining a substances'
level of regulation, including actual or relative potential for abuse, pharmacological
knowledge, history and current pattern of abuse, scope and significance of abuse,
risk to public health, and psychic or physiological dependence liability. (21
USC 811 (c)) While the similarities of drugs justifies their regulation under
the CSA, their differences determine the level of regulation their distribution
requires, or determines whether they should be prohibited through placement in
findings of Tanda et al and de Fonseca et al add considerably to the scientific
knowledge about marijuana's abuse potential and dependence liability, and should
help scientific evaluations of marijuana abuse potential relative to other known
drugs of abuse. Marijuana's characteristic effects, and its therapeutic applications,
were finally explained by the discovery and mapping of the cannabinoid receptor
system. (Devane, 1988; Herkenham and Lynn, 1990; Howlett et al, 1990) Lack of
deaths by overdose from marijuana is explained by a lack of receptors in areas
of the brain controlling breathing and the heart. (Herkenham and Lynn, 1990) Tolerance
to marijuana is not related to dependence but to a down-regulation of receptor
sites in response to repeated, heavy doses of cannabinoids. (Oviedo, et al, 1993;
de Foncesa, 1994) Mild withdrawal symptoms following cessation of heavy marijuana
use are produced by Corticotropin-Releasing Factor (CRF), a chemical accompanying
withdrawal anxiety associated with other drug. (de Fonseca et al, 1997) Indirect
stimulation of dopamine transmission by cannabinoids may help explain why some
users of marijuana also abuse other drugs. (Gardner and Lowinson, 1991; Tanda
et al, 1997) Cannabinoids may activate some opiod receptor systems in the brain
(Gardner and Lowinson, 1991; Tanda et al, 1997) without the dangers of depressing
heart and lung rate (Herkenham and Lynn, 1992). The relatively low dependence
liability that accompanies marijuana use by many individuals observed by Hollister
(1986) and others is consistent with the failure to establish self-administration
in animal models. (Mansbach, 1994) These and other findings constitute a major
advance in scientific knowledge about marijuana; in retrospect very little was
known before 1988 about the mechanisms behind marijuana's effects on the brain.
All of these findings
provide explanations for previously observed phenomena. They put to rest claims
that marijuana has no dependence liability and is somehow different in this respect
from other recreational drugs, and also they should put to rest the notion that
when scientists finally figure out what marijuana does in the brain they will
prove the worst fears of the last generation. Instead marijuana is just as it
was perceived in 1970 when the Controlled Substances Act was passed, producing
mild dependence in some heavy users, but otherwise producing less symptoms of
dependency than alcohol or tobacco. (See U.S. Code Congressional and Administrative
1973 the National Commission on Marihuana and Drug Abuse suggested that the country
apply the same standards to all drugs, licit and illicit, on the premise that
all drugs affect individuals according to similar principles:
drugs act according to the same general principles. Their effects vary with dose.
For each drug there is an effective dose (in terms of the desired effect), a toxic
dose and a lethal dose. All drugs have multiple effects. The lower the dose, the
more important non-drug factors become in determining drug effect. At high dose
levels, and for some individuals at much lower dose levels, all drugs may be dangerous.
The individual and social consequences of drug use escalate with frequency and
duration of use. American drug policy will never be coherent until it is founded
on uniform principles such as these, which apply to all drugs." (Shafer, 1973)
These recent findings
on marijuana have revolutionized understanding of marijuana and the risks associated
with marijuana use. They add to the evidence that supports the case for a new
assessment of marijuana's abuse potential by the federal government and a reconsideration
whether marijuana satisfies the criteria for prohibited schedule I status. A fair
reconsideration in accordance with the existing legal and scientific standards
could greatly improve the coherency of existing drug policy, which rests on the
premise that marijuana has a similarly high potential for abuse as heroin and
Abood, M.E., and
Martin, B.R. (1992), "Neurobiology of Marijuana Abuse," Trends in Pharmacological
E., Moss, D.E., et al.,, "THC Does Not Affect Striatal Dopamine Release: Microdialysis
in Freely Moving Rats" Pharmacology, Biochemistry & Behavior. 40,:587-591, 1991
Chen, J., Paredes,
W., Lowinson, J.H., and Gardner, E.L. "[Delta-9] Tetrahydrocannibinol enhances
presynaptic dopamine efflux in medial prefontal cortex." European Journal of Pharmacology
J., Paredes, W., Li, J., Smith, D., Lowinson, J., and Gardner, E.L. "[Delta-9]
Tetrahydrocannibinol produces naloxone-blockable enhancement of presynaptic basal
dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured
by intracerebral microdialysis." Psychopharmacology (1990) 102: 156-162.
J. "Dopaminergic mechanisms and brain reward." Seminars in The Neurosciences,
Vol 5, 1993: pp 315-320.
J., Marmur, R., Pulles,A., Paredes, W., Gardner, E.L. "Ventral tegmental microinjection
of [Delta-9] tetrahydrocannabinol enhances ventral tegmental somatdendritic dopamine
levels but not forebrain dopamine levels: evidence for local neural action by
marijuana's psychoactive ingredient." Brain Research, 621 (1993) 65-70.
T., Assessment of Dependence Liability of Psychotropic Substances: Nature of the
Problem and the Role of the College on Problems on Drug Dependence. Contractor
Document for the Office of Technology Assessment. (Springfield, VA: National Technical
Information Service,) 1992. (NTIS Doc. #PB94-175643)
W.A., Dysarz, F.A., et al., "Determination and Characterization of a Cannabinoid
Receptor in Rat Brain." Molecular Pharmacology 34:605-613. 1988.
Chiara, G. and Imperto, A. "Drugs abused by humans preferentially increase synaptic
dopamine concentrations in the mesolimbic system of freely moving rats." Proc.
Natl. Acad. Sci. USA Vol 85. pp 5274-5278, July 1988.
Chiara, Gaetano. "The role of dopamine in drug abuse viewed from the perspective
of its role in motivation." Drug and Alcohol Dependence 38 (1995) 95-137.
Foncesa, F.R., Gorriti, M., et al., "Downregulation of Rat Brain Cannabinoid Binding
Sites After Chronic D9-Tetrahydrocannabinol Treatment." Pharmacology, Biochemistry,
and Behavior. 47:33-40, 1994.
Fonseca, F.R. et al "Activation of Corticotropin-Releasing Factor in the Limbic
System During Cannabinoid Withdrawal" Science. Vol 276 June 27, 1997 pg 2050 -
Parades, W., Smith, D., Seeger, T., Donner, A., Milling, C., Cohen, D., and Morrison,
D. "Strain-Specific Sensitization of Brain Stimulation Reward by [Delta-9] Tetrahydrocannabinol
in Laboratory Rats." Abstract published in Psychopharmacology, 96 Suppl:365. (1988a)
Gardner, E.L., Parades,
W., Smith, D., Seeger, T., Donner, A., Milling, C., Cohen, D., and Morrison, D.
"Facilitation of brain stimulation reward by [delta-9]-tetrahydrocannabinol."
Psychopharmacology (1988b) 96:142-144.
E.L. and Lowinson, Joyce "Marijuana's Interaction With Brain Reward Systems: Update
1991" Pharmacology, Biochemistry, & Behavior. vol 40. pp 571-580. 1991.
L, Hoebel, BG. "Food reward and cocaine increase extracellular dopamine in the
nucleus accumbens as measured by microdialysis. Life Sci 2:1705-1712. [cited in
L. et al, Neuroscience 41, 89-125 (1991) [cited in Tanda, et al 1997].
M., Lynn, A.B., et al., "Cannabinoid Receptor Localization in Brain," Proceedings
of the National Academy of Sciences, 87:1932-1936, 1990.
M. (1992), "Cannabinoid Receptor Localization in Brain: Relationship to Motor
and Reward Systems," P.W. Kalivas and H.H. Samson (eds.), The Neurobiology of
Drug and Alcohol Addiction, Annals of the American Academy of Sciences. 654:19-32,
1992. pg. 29.
L.E. "Health Aspects of Cannabis", Pharmacological Reviews, 38(1):1-20, 1986.
Howlett, A.C., Bidaut-Russell,
M, Devane, W., Melvin, L., Johnsons, M., & Herkenham, M., "The Cannabinoid Receptor:
Biochemical, Anatomical, and Behavioral Characterization." Trends in Neuroscience
13:10, 420-423, 1990.
M.K. and Melvin, L.S. "The Discovery of Nonclassical Cannabinoids" in Cannabinoids
as Therapeutic Agents, Mechoulam, R., ed., CRC Press, Boca Raton, FL, 1987 Chapter
7. pg 121 - 145.
G. "Drug Addiction: The Yin and Yang of Hedonic Homeostasis" Neuron. Vol 16. 893-896.
R. S. et al "Failure of Delta-9-tetrahydrocannabinol and CP 55,940 to maintain
intravenous self-administration under a fixed-interval schedule in rhesus monkeys."
Behavioral Pharmacology 5, 219-225. (1994)
Eric J. Molecular mechanisms of drug addiction. J Neurosci 12:2439-2450. cited
in Nestler, 1993.
Eric J. Molecular mechanisms of drug addiction in the mesolimbic dopamine pathway.
Seminars in The Neurosciences, Vol 5, 1993: pp 369-376.
Eric J. "Under Siege: The Brain on Opiates". Neuron, Vol 16, 897-900, May, 1996.
NORML v. DEA, 559
F.2d 735 (1977)
A., Glowa, J, and Herkenham, M., "Chronic cannabinoid administration alters cannabinoid
receptor binding in rat brain: a quantitative autoradiographic study." Brain Research,
F.E., Tanda, G., and Di Chiara, G., "Intravenous cocaine, morphine, and amphetamine
preferentially increase extracellular dopamine in the "shell" as compared with
the "core" of the rat nucleus accumbens." Proc. Natl. Acad. Sci. USA Vol 92, pp.
12304-12308, December 1995.
F.W., Tanda, G., Orzi, F., and Di Chiara, G. "Effects of nicotine on the nucleus
accumbens and similarity to those of addictive drugs" Nature Vol 382. 18 July
J.G., Damsma, G., Nomikos GG, Wenkstern, D.G., Blaha C.D., Phillips, A.G., Fibiger,
H.C. (1990) "Sexual behavior enhances central dopamine transmission in the male
rat." Brain Res. 530:345-348. [cited in Chen, 1993]
Mark. "Cannabinoids and Analgesia" in Cannabinoids as Therapeutic Agents, Mechoulam,
R., ed., CRC Press, Boca Raton, FL, 1987 Chapter 8. pg 105 - 120.
R., Commission on Marihuana and Drug Abuse, (1973) Drug Use In America: Problem
In Perspective, second report of the National Commission on Marihuana and Drug
Abuse, Vol. I. March 1973. (Washington, D.C.: U.S. Govt. Print. Off.,) 1973.
G. et al "Cannabinoid and Heroin Activation of Mesolimbic Dopamine Transmission
by a Common Opiod Receptor Mechanism" Science. Vol 276 June 27, 1997 pg 2048 -
U.S. Code Congressional
and Administrative News. 91st Congress -- Second Session, 1970. Vol. 3. Legislative
History. Comprehensive Drug Abuse Prevention and Control Act of 1970 [P.L. 91-513].
pg. 4566 - 4657.
Congress Office of Technology Assessment Biological Components of Substance Abuse
and Addiction, OTAA-BP-BBS-117 (Washington, D.C.: U.S. Government Printing Office)
of Health and Human Services, Public Health Service, Substance Abuse and Mental
Health Services Administration (1994) "Advanced Report number 7, Preliminary Estimates
From the 1993 National Household Survey on Drug Abuse." (Rockville, MD: Office
of Applied Studies,) July 1994.
Ingrid. "Marijuana: Harder Than Thought?" Science, Vol. 276, 1967-1968, June 27,
K., Kandel, D., "Patterns of Drug Use From Adolescence to Young Adulthood Predictors
of Progression." American Journal of Public Health. 74:7, July, 1984.
N. Drug, Set, and Setting. (New Haven: Yale University Press) 1984.