Update - Dopamine and the Dependence Liability of Marijuana, July 1997

by Jon Gettman

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)

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 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, 1992)

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 , 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 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 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 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 News, 1970).

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 high potential for abuse as heroin and cocaine.


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