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
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)
Di 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
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,
Lewis rats 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, 1990]"
George Koob 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
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 liability.
The authors 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, 1997)
Di Chiara 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)
"The 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
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 Schedule I.
The 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
In 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:
"All 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
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