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Cannabis is one of the most widely used illicit substances and there is growing interest in the association between cannabis use and psychosis. Delta-9-Tetrahydrocannabinol (Δ-9-THC) the principal active ingredient of cannabis has been shown to induce psychotomimetic and amnestic effects in healthy individuals. Whether people who frequently use cannabis are either protected from or are tolerant to these effects of Δ-9-THC has not been established. In a 3-day, double-blind, randomized, placebo-controlled study, the dose-related effects of 0, 2.5, and 5 mg intravenous Δ-9-THC were studied in 30 frequent users of cannabis and compared to 22 healthy controls. Δ-9-THC (1) produced transient psychotomimetic effects and perceptual alterations; (2) impaired memory and attention; (3) increased subjective effects of ‘high’; (4) produced tachycardia; and (5) increased serum cortisol in both groups. However, relative to controls, frequent users showed blunted responses to the psychotomimetic, perceptual altering, cognitive impairing, anxiogenic, and cortisol increasing effects of Δ-9-THC but not to its euphoric effects. Frequent users also had lower prolactin levels. These data suggest that frequent users of cannabis are either inherently blunted in their response to, and/or develop tolerance to the psychotomimetic, perceptual altering, amnestic, endocrine, and other effects of cannabinoids.Neuropsychopharmacology (2008) 33, 2505–2516; doi:10.1038/sj.npp.1301643; published online 9 January 2008 [ABSTRACT FROM AUTHOR]

Recent advances in the understanding of brain cannabinoid receptor function have renewed interest in the association between cannabinoid compounds and psychosis. In a 3-day, double-blind, randomized, and counterbalanced study, the behavioral, cognitive, and endocrine effects of 0, 2.5, and 5 mg intravenous delta-9-tetrahydrocannabinol (Δ-9-THC) were characterized in 22 healthy individuals, who had been exposed to cannabis but had never been diagnosed with a cannabis abuse disorder. Prospective safety data at 1, 3, and 6 months poststudy was also collected. Δ-9-THC (1) produced schizophrenia-like positive and negative symptoms; (2) altered perception; (3) increased anxiety; (4) produced euphoria; (5) disrupted immediate and delayed word recall, sparing recognition recall; (6) impaired performance on tests of distractibility, verbal fluency, and working memory (7) did not impair orientation; (8) increased plasma cortisol. These data indicate that Δ-9-THC produces a broad range of transient symptoms, behaviors, and cognitive deficits in healthy individuals that resemble some aspects of endogenous psychoses. These data warrant further study of whether brain cannabinoid receptor function contributes to the pathophysiology of psychotic disorders. [ABSTRACT FROM AUTHOR]

Some of the most compelling evidence supporting an association between cannabinoid agonists and psychosis comes from controlled laboratory studies in humans. Randomized, double-blind, placebo-controlled, crossover laboratory studies demonstrate that cannabinoid agonists, including phytocannabinoids and synthetic cannabinoids, produce a wide range of positive, negative, and cognitive symptoms and psychophysiologic deficits in healthy human subjects that resemble the phenomenology of schizophrenia. These effects are time locked to drug administration, are dose related, and are transient and rarely necessitate intervention. The magnitude of effects is similar to the effects of ketamine but qualitatively distinct from other psychotomimetic drugs, including ketamine, amphetamine, and salvinorin A. Cannabinoid agonists have also been shown to transiently exacerbate symptoms in individuals with schizophrenia in laboratory studies. Patients with schizophrenia are more vulnerable than healthy control subjects to the acute behavioral and cognitive effects of cannabinoid agonists and experience transient exacerbation of symptoms despite treatment with antipsychotic medications. Furthermore, laboratory studies have failed to demonstrate any “beneficial” effects of cannabinoid agonists in individuals with schizophrenia—challenging the cannabis self-medication hypothesis. Emerging evidence suggests that polymorphisms of several genes related to dopamine metabolism (e.g., COMT , DAT1 , and AKT1 ) may moderate the effects of cannabinoid agonists in laboratory studies. Cannabinoid agonists induce dopamine release, although the magnitude of release does not appear to be commensurate to the magnitude and spectrum of their acute psychotomimetic effects. Interactions between the endocannabinoid, gamma-aminobutyric acid, and glutamate systems and their individual and interactive effects on neural oscillations provide a plausible mechanism underlying the psychotomimetic effects of cannabinoids. [ABSTRACT FROM AUTHOR]

Background Drugs that induce psychosis may do so by increasing the level of task-irrelevant random neural activity or neural noise. Increased levels of neural noise have been demonstrated in psychotic disorders. We tested the hypothesis that neural noise could also be involved in the psychotomimetic effects of delta-9-tetrahydrocannabinol (Δ 9 -THC), the principal active constituent of cannabis. Methods Neural noise was indexed by measuring the level of randomness in the electroencephalogram during the prestimulus baseline period of an oddball task using Lempel-Ziv complexity, a nonlinear measure of signal randomness. The acute, dose-related effects of Δ 9 -THC on Lempel-Ziv complexity and signal power were studied in humans ( n = 24) who completed 3 test days during which they received intravenous Δ 9 -THC (placebo, .015 and .03 mg/kg) in a double-blind, randomized, crossover, and counterbalanced design. Results Δ 9 -THC increased neural noise in a dose-related manner. Furthermore, there was a strong positive relationship between neural noise and the psychosis-like positive and disorganization symptoms induced by Δ 9 -THC, which was independent of total signal power. Instead, there was no relationship between noise and negative-like symptoms. In addition, Δ 9 -THC reduced total signal power during both active drug conditions compared with placebo, but no relationship was detected between signal power and psychosis-like symptoms. Conclusions At doses that produced psychosis-like effects, Δ 9 -THC increased neural noise in humans in a dose-dependent manner. Furthermore, increases in neural noise were related with increases in Δ 9 -THC-induced psychosis-like symptoms but not negative-like symptoms. These findings suggest that increases in neural noise may contribute to the psychotomimetic effects of Δ 9 -THC. [ABSTRACT FROM AUTHOR]