Etiology and Pathophysiology
Cannabis dependence develops as a result of repeated use of the drug, and frequency of use is one of the most important predictors of developing dependence (Chen and Kandel, 1998; Kandel and Chen, 2000). Like most other dependence-producing drugs, cannabis produces its reinforcing effects by activating the mesolimbic dopaminergic “reward” pathway, which consists of dopaminergic neurons in the ventral tegmental area (VTA) that project to the nucleus accumbens, increasing dopamine levels in the shell of the nucleus accumbens (Diana et al., 1998a; Gardner, 1999; Tanda et al., 1997). Naloxone, an opiate antagonist at the μ1 opioid receptor in the VTA, blocks this increase in dopamine, which suggests that ∆-9-THC and opiates share the same mecha-nism of activating this pathway (Tanda et al., 1997). Studies have shown that people choose higher-potency cannabis preparations over lower-potency preparations, a finding which suggests that increased potency may result in an increased risk of progression to addiction and dependence (Chait and Burke, 1994; Harder and Reitbrock, 1997).
Regular use of cannabis for periods as short as 1 to 3 weeks can produce tolerance to many of its acute physiological and psychological effects (Jones et al., 1976, 1981; Jones, 1983). Such tolerance may cause some individuals to increase their use in order to continue to experience desired effects. As with other addictive drugs, discontinuation of cannabis use increases cor-ticotropin-releasing factor (CRF) in the central amygdala and decreases dopaminergic transmission in the limbic system, re-sulting in withdrawal symptoms (Diana et al., 1998b; Rodriguez et al., 1997).
The core symptoms of cannabis withdrawal are irritability, anxiety, physical tension, and decreases in mood and appetite. Restlessness, tremors, sweating, insomnia, increased aggres-siveness and very vivid dreams have also been reported (Budney et al., 1999; Haney et al., 1999; Kouri et al., 1999; Kouri and Pope, 2000; Kaymakcalan, 1973, 1981; Tennant, 1986; Comp-ton et al., 1990; Jones et al., 1976, 1981; Jones, 1983; Wiesbeck et al., 1996). The symptoms of cannabis withdrawal are similar to those of opiate withdrawal, except that their intensity is milder and their course is delayed and prolonged due to the fact that can-nabis is cleared from the body gradually as it is released slowly from storage in adipose tissue. Symptoms typically begin the day after last use, do not reach maximal intensity until the third day, and then resolve over the following week. The severity of the withdrawal syndrome varies considerably among individu-als. In a recent study of 108 chronic, long-term cannabis users, the authors observed a number of individuals who experienced severe withdrawal symptoms which precluded their completion of the month-long abstinence period required by the study proto-col, suggesting that, for at least some individuals, the withdrawal syndrome is an important factor in the development and persist-ence of dependence (Pope et al., 2001a; Gruber et al., in press).
Environment appears to play a major role in determining whether an individual will initiate cannabis use, but only a minor role in determining whether an individual will go on to develop cannabis dependence. Genetic factors, on the other hand, appear to play only a moderate role in determining whether an individual will initiate cannabis use, but a major role in determining whether an individual who initiates use will subsequently develop canna-bis dependence. A study of female twins reported that genetic factors accounted for 60 to 80% of the variance in liability for cannabis dependence (Kendler and Prescott, 1998). A study of male twins reported that genetic factors contributed significantly to progression from first exposure or opportunity to use cannabis to initial use of cannabis, from initial use to use more than five times, and from use more than five times to regular use (Tsuang et al., 1999). A second study of male twins reported that genetic factors were responsible for 44% and common environmental factors for only 21% of the variance in risk of developing can-nabis dependence (True et al., 1990)
In addition to the addictive properties of cannabis and the genetic predisposition of individuals, another possible etiology for cannabis dependence is that some individuals may be “self-medicating” themselves for underlying psychiatric symptoms. Some patients with depression, anxiety, or negative symptoms of schizophrenia report that marijuana use alleviates their symp-toms (Peralta and Cuesta, 1992; Dixon et al., 1991; Estroff and Gold, 1986; Warner et al., 1994; Gruber et al., 1996). In addition, a large portion of adolescents and young adults with cannabis dependence have reported using marijuana to self-treat anger, boredom, or lack of direction (Chen and Kandel, 1998; Gruber et al., in press; Johnston et al. 2001; Newcombe and Bentler, 1988). An interesting finding of a longitudinal study of chronic cannabis users is that prescriptions for psychoactive medications increased as cannabis use decreased when the subjects were in their late twenties and early thirties, raising the possibility that for some individuals the prescription medications were serving the same purpose as the cannabis (Chen and Kandel, 1995, 1998). We have observed this apparent self-medication phenomenon in a number of patients with underlying depressive illness or bipolar disorder.
However, contrary to the beliefs of the users, cannabis may also contribute to the symptoms enumerated above (Miller et al., 1989; Lex et al., 1989; Mirin et al., 1971; Chen and Kandel, 1998; Baigent et al., 1995, Green and Ritter, 2000).
The mechanism causing the euphoria experienced during can-nabis intoxication is activation of the mesolimbic dopaminergic “reward” pathway, and is described in detail in the botany and pharmacology section (Diana et al., 1998a; Gardner, 1999; Tanda et al., 1997). The mechanisms causing the physiological signs and symptoms associated with cannabis intoxication are thought to result from the action of the cannabinoid system on other major neurotransmitter systems including the noradrenergic, choliner-gic, serotonin and opioid systems (Ameri, 1999).
There are no adequate data regarding the mechanism by which cannabis intoxication delirium, cannabis-induced psy-chotic disorder, or cannabis-induced anxiety disorder can occur de novo in individuals without preexisting medical or psychiat-ric disorders. In a review of studies of patients with cannabis-induced psychotic disorder, it was found that most of the studies had not excluded individuals with a preexisting Axis I disorder, such as schizophrenia or a major mood disorder, which would render the individual vulnerable to psychotic symptoms even in the absence of cannabis use. At present, therefore, it seems pos-sible that the majority of cannabis-induced psychotic or anxiety disorders represent exacerbations of preexisting DSM-IV Axis I psychiatric disorders in individuals who become intoxicated with the drug (Gruber and Pope, 1994).