Psychoactive drugs are often widely used before tolerance and dependence is fully appreciated. Tolerance to cannabis‐induced cardiovascular and autonomic changes, decreased intraocular pressure, sleep and sleep EEG, mood and behavioral changes is acquired and, to a great degree, lost rapidly with optimal conditions. Mechanisms appear more functional than metabolic. Acquisition rate depends on dose and dose schedule. Dependence, manifested by withdrawal symptoms after as little as 7 days of THC administration, is characterized by irritability, restlessness, insomnia, anorexia, nausea, sweating, salivation, increased body temperature, altered sleep and waking EEG, tremor, and weight loss. Mild and transient in the 120 subjects studied, the syndrome was similar to sedative drug withdrawal. Tolerance to drug side effects can be useful. Tolerance to therapeutic effects or target symptoms poses problems. Clinical significance of dependence is difficult to assess since drug‐seeking behavior has many determinants. Cannabis‐induced super sensitivity should be considered wherever chronic drug administration is anticipated in conditions like epilepsy, glaucoma or chronic pain. Cannabis pharmacology suggests ways of minimizing tolerance and dependence problems.

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AIMS-To quantify blood Δ 9 -tetrahydrocannabinol (THC) concentrations in chronic cannabis users over seven days of continuous monitored abstinence.PARTICIPANTS-Twenty-five frequent, long-term cannabis users resided on a secure clinical research unit at the U.S. National Institute on Drug Abuse under continuous medical surveillance to prevent cannabis self-administration.MEASUREMENTS-Whole blood cannabinoid concentrations were determined by twodimensional gas chromatography-mass spectrometry.FINDINGS-Nine chronic users (36%) had no measurable THC during seven days of cannabis abstinence; 16 had at least one positive THC ≥0.25 ng/mL, but not necessarily on the first day. On day 7, six full days after entering the unit, six participants still displayed detectable THC concentrations (mean ± SD, 0.3 ± 0.7 ng/mL) and all 25 had measurable carboxy-metabolite (6.2 ± 8.8 ng/mL). The highest observed THC concentrations on admission (day 1) and day 7 were 7.0 and 3.0 ng/mL, respectively. Interestingly, five participants, all female, had THC positive whole blood specimens all seven days. Body mass index did not correlate with time until last THC positive specimen (N = 16; R = −0.2; p = 0.445).CONCLUSIONS-Substantial whole blood THC concentrations persist multiple days after drug discontinuation in heavy chronic cannabis users. It is currently unknown whether neurocognitive impairment occurs with low blood THC concentrations, and whether return to normal performance, as previously documented following extended cannabis abstinence, is accompanied by removal of residual THC in brain. These findings also may impact the implementation of per se limits in driving under the influence of drugs legislation.

We examined the effects of cocaine hydrochloride (40 mg intravenously) on regional cerebral metabolic rates for glucose and on subjective self-reports of eight polydrug abusers in a double-blind, placebo-controlled, crossover study. The regional cerebral metabolic rate for glucose was measured by the [fluorine 18]-fluorodeoxyglucose method, using positron emission tomography. With eyes covered, subjects listened to a tape that presented white noise, "beep" prompts, and questions about subjective effects of cocaine or saline. Cocaine produced euphoria and reduced glucose utilization globally (mean reduction, 14%). Twenty-six of 29 brain regions (all neocortical areas, basal ganglia, portions of the hippocampal formation, thalamus, and midbrain) showed significant decrements (5% to 26%) in the regional cerebral metabolic rate for glucose. No significant effects of cocaine were observed in the pons, the cerebellar cortex, or the vermis. Right-greater-than-left hemispheric asymmetry of regional cerebral metabolic rates for glucose occurred in the lateral thalamus. The findings demonstrate that reduced cerebral metabolism is associated with cocaine-induced euphoria.