This is the first report to our knowledge comparing the behavioral, subjective, cognitive, physiological and endocrine effects of intravenous Δ-9-THC in frequent users of cannabis and controls.
In summary, frequent users showed blunted perceptual alterations (CADSS), psychotomimetic effects (PANSS), “anxiety” (VAS), recall impairments, distractibility and increases in plasma cortisol induced by Δ-9-THC. Frequent users also had lower baseline prolactin levels. Overall, the magnitude of the group differences in Δ-9-THC effects ranged in effect sizes of 0.38 for psychotomimetic effects (PANSS) to 0.78 for anxiety (VAS). These group differences cannot be explained by pharmacokinetic differences since there were no group differences in plasma Δ-9-THC or Δ-9-THCCOOH levels. In contrast to the above, frequent users were no different from controls in their response to Δ-9-THC induced feeling states of “high” and “calm and relaxed” (VAS). Similarly, there were no group differences in the tachycardiac effects of Δ-9-THC.
Feeling “high”, “calm and relaxed”, mellow, and creative are characterized as “desirable” or positive effects of cannabis while paranoia, hallucinations, anxiety, perceptual alterations and memory impairments are characterized as “undesirable” or “negative” effects. Taken collectively, frequent users showed blunted responses to some of the “undesirable” effects of Δ-9-THC but not to its “desirable” effects. These group differences in Δ-9-THC effects raise the possibilities that frequent users develop tolerance to the negative effects of Δ-9-THC and/or are “protected” from these effects.
There is considerable preclinical evidence demonstrating tolerance to most of the pharmacological effects of cannabinoids reviewed in
(Gonzalez et al. 2005
; Lichtman & Martin 2005
). However, the evidence supporting tolerance in humans is limited. Self-report (Anthony & Trinkoff 1989
), experimental (Jones et al. 1976
; Jones et al. 1981
) and direct observational (Haney et al. 1999a
; Haney et al. 1999b
) studies in humans suggest that with heavy and prolonged exposure to cannabis tolerance develops to some of its subjective and physiological effects reviewed in
(Lichtman & Martin 2005
). But whether tolerance develops to the psychotomimetic and amnestic effects of cannabinoids has not been systematically studied. In light of the current focus on the association between cannabis and psychosis, this would be important. One interpretation of the current results is that frequent cannabis use is associated with the development of tolerance to the psychotomimetic effects of Δ-9-THC.
Animal studies have shed light on the mechanisms of cannabinoid tolerance with increasing detail. For example, behavioral tolerance has been correlated with changes in brain glucose utilization before and after repeated dosing with cannabinoids (Freedland et al. 2002
), with normalization i.e. tolerance, of cerebral glucose utilization following chronic exposure (Whitlow et al. 2003
). The mechanisms underlying tolerance to cannabinoids include the downregulation and desensitization of receptors. Down regulation is believed to be due to receptor internalization (Romero et al. 1997
), the rate and magnitude of which has been shown to vary by region (Breivogel et al. 1999
; Romero et al. 1998
). In the current study, frequent users showed blunted responses to the amnestic but not to the euphoric effects of Δ-9-THC, which are believed to be mediated by different regions: the hippocampus and basal ganglia, respectively. Region specific differences in CB1 receptor density are believed to determine the magnitude of receptor downregulation (Martin et al. 2004
; Romero et al. 1998
; Sim-Selley 2003
). For example, the basal ganglia has a higher density of CB1 receptors relative to the hippocampus or cerebellum, yet down regulation occurs more rapidly in the hippocampus and cerebellum compared to basal ganglia. This may provide a possible explanation for the differential blunting of Δ-9-THC effects observed in this study. Similarly, the desensitization of receptors due to changes in downstream second messenger cascade including G protein coupling may also vary by region (Martin et al. 2004
The group differences in Δ-9-THC-induced subjective, behavioral and cognitive effects were complemented by endocrine group differences. This is the first report that we are aware of demonstrating Δ-9-THC induced blunted cortisol release and lower prolactin levels in frequent cannabis users as compared to healthy controls. Cannabinoids increase ACTH and cortisol release via CB-1R activation in the hypothalamus pituitary (HPA) axis (Pagotto et al. 2006
). The blunted Δ-9-THC induced cortisol release in frequent users of cannabis is consistent with the animal literature (Murphy et al. 1998a
). The latter is thought to reflect tolerance secondary to a downregulation of CB-1R in the HPA axis. The absence of group differences in baseline cortisol levels may be explained by the lack of very early morning (< 6 a.m.) sampling.
Cannabinoids produce a predominantly late inhibitory effect on prolactin release (Harclerode 1984
; Murphy et al. 1998b
; Pagotto et al. 2006
) which is mediated by CB-1R activation of tuberoinfundibular DA neurons (Rodriguez De Fonseca et al. 1992
). Δ-9-THC failed to reduce prolactin release; this may be explained by the short sampling duration. However, consistent with preclinical evidence that chronic exposure to cannabinoids leads to a long lasting suppression of prolactin release (de Miguel et al. 1998
) frequent users of cannabis had significantly lower prolactin levels compared to controls.
Frequent users had equivalent “high,” “calm and relaxed” feelings and tachycardia induced by Δ-9-THC. Perhaps, as discussed earlier, tolerance to the various effects of Δ-9-THC develops at different rates. Alternatively, frequent users of cannabis may be innately “protected” from some of the negative effects of cannabis.
Several recent studies provide examples of how innate differences may account for some of the variance in the response to cannabis and also the risk for cannabis use disorders. Higher concordance in the subjective response to cannabis in monozygotic vs. dizygotic twins (Lyons et al. 1997
), identification of specific CB1 receptor haplotypes that contribute to the risk of developing cannabis dependence symptoms (Hopfer et al. 2006b
), and recent evidence of linkage for cannabis dependence on chromosome 3q21 and 9q34 (Hopfer et al. 2006a
) suggest genetic influences on the cannabis response. Finally, recent evidence suggests that a single nucleotide polymorphism of the Catechol-methyl-transferase (COMT) gene may influence vulnerability to the psychotomimetic effects of cannabis (Caspi et al. 2005
; Henquet et al. 2006b
). While admittedly speculative, innate differences may contribute to the blunted “negative” effects of Δ-9-THC in frequent users.
Another interpretation to the study results is that frequent users who arguably are more experienced with the “negative” effects of cannabis may discount these effects more than infrequent users i.e., the controls in this study. Several findings in this study would not support the above hypothesis. First, the group differences were selective; there were no group differences on other self-report measures (e.g., VAS “high” and “calm & relaxed”). Second, as discussed in the results section, frequent users reported greater baseline (preΔ-9-THC) perceptual alterations. Finally, there were group differences in Δ-9-THC effects on performance based (e.g., memory) and endocrine measures which are less likely to be influenced by subjective effects.
Group Differences in Baseline and Δ-9-THC induced recall deficits
Relative to controls, frequent users had significantly worse baseline (placebo condition) immediate, delayed and cued recall (). Whether these baseline differences reflect long term or residual effects of cannabis, or innate differences is unclear. Importantly however, despite having lower I.Q. scores and worse recall at baseline (placebo condition), frequent users had blunted Δ-9-THC induced immediate recall impairment relative to controls. Another intriguing finding of this study is that frequent users had better
delayed recall under the influence of 2.5 mg Δ-9-THC, relative to the placebo condition (). This pattern of effects is consistent with unpublished observations in ongoing studies at our center (D’Souza et al., in review) and may represent a distinct response of frequent users to low doses of Δ-9-THC. Perhaps state (Δ-9-THC)-dependent learning or the reversal of withdrawal might explain the better performance under 2.5 mg Δ-9-THC dose in frequent users. The latter is unlikely given the absence of any baseline symptoms suggestive of withdrawal e.g., nervousness, anxiety, irritability, restlessness reviewed in
(Budney et al. 2004
) and the exclusion of cannabis dependence.
Implications for cannabis related psychosis
Individuals without any psychotic disorder, family history of psychosis or other Axis 1 disorder who frequently use cannabis may be innately protected and/or develop tolerance to the psychotomimetic and amnestic effects of Δ-9-THC. However, these data may not be relevant to individuals who have a risk for psychosis or have an established psychotic disorder.
The findings are relevant to a growing literature suggesting an association between cannabis exposure and the risk of developing a psychotic disorder. Thus, studies of individuals with significant cannabis exposure may find a lower risk for psychotic disorders since as our data suggest these individuals either develop tolerance to or are inherently less vulnerable to the psychotomimetic effects of cannabis. Further, in association studies it may be possible that beyond a certain, albeit unspecified, magnitude of cannabis exposure, the likelihood of finding an increased risk of psychosis may actually decrease.
Implications for cannabis addiction
Perhaps a more balanced battery of assessments that included more measures of “positive” effects may not have shown this profile of group differences predominantly in “undesirable” effects of cannabinoids. Further, since expectancy to drug effects was not measured or manipulated it is unknown whether expectancy may have contributed to the results. However, given that participation was voluntary and that both groups had experience with cannabis, albeit to different degrees, it is unlikely that subjects had strong negative expectancy to drug effects. Finally, as discussed elsewhere (D’Souza et al. 2004
), the intravenous route, the speed of drug administration and the subjects not being able to “titrate” the dose or rate of administration is different from recreational cannabis use or the substantial literature on studies with smoked and oral Δ-9-THC administration. Nevertheless, the experimental controls in the current study address some of the confounding factors associated with naturalistic studies or studies with oral/smoked THC (D’Souza et al. 2004
). Finally, this study was not designed to discriminate the contributions of tolerance and innate differences to the group differences observed.
In summary, there are differences in the psychotomimetic, amnestic, endocrine and subjective effects of Δ-9-THC between frequent users of cannabis and healthy controls. These differences may have implications for cannabis related psychosis and addiction. The precise neurobiology of these differences remains unclear and warrants further investigation.