CLINICAL STUDIES OF CANNABIS TOLERANCE

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Annals New York Academy of Sciences
by those investigators as withdrawal symptoms or evidence of physical dependence.3% Some of the inconsistency in the preceding reports might be explained by considering what we know about other more well-studied drugs. In a general review of the determinants of tolerance and dependence, Seevers and Deneau make a simple but important point often overlooked or forgotten when discussing cannabis tolerance and dependence.15 They point out that conditions for optimal development of dependence require “continual neuronal exposure” to the drug without interruption. Failure to recognize this requirement has led to “erroneous conclusions from poorly designed experiments.” They were mainly discussing opiates, but the same might be said about cannabis. Other general reviews indicate that with a variety of sedative-hypnotic drugs and opiates continued “around the clock,” chronic intoxication is necessary to most clearly demonstrate abstinence phenomena.1, 15-1‘J Even with opiates, ordinary conditions of clinical or illicit administration are rarely adequate to produce maximal dependence.15 For example, the standard stabilization dose of morphine in the Lexington studies was 200-400 mg per day in four equal doses.’, lB Nowadays, this dose sounds like a rather large one, but in the Lexington studies, it yielded only a midgrade intensity of dependence.’ There appears to be a “safe interval” between doses of opiates and other psychoactive drugs at which tolerance and dependence are not exhibited. This interval may vary from hours to days, depending on the drug, its disposition, and kinetics.’. With any psychoactive drug, there appears to be a certain dose level below which measurable physical dependence does not develop, even after prolonged and repeated administration, and below which tolerance, if evident at all, is minimal. On the other hand, there is virtually no psychoactive drug that has been experimentally tested in what Seevers and Deneau would term “adequate experiments” that does not produce dependence and show tolerance.’, We designed cannabis experiments with optimal conditions for the development of tolerance and dependence. The dosage range was selected to produce a level of intoxication similar to that experienced t the same time, and in contrast to previous research, the dosage schedule maintained this level of intoxication for prolonged periods of time. Other studies reported at this Conference used equivalent cannabis doses.’* For example, the smoked dose consumed by Mendelson et al.’s subjects was in some cases in excess of equivalent oral doses given to our subjects. Though Mendelson et al.’s study used an adequate dose for a well-designed experiment on tolerance and dependence, they used an inappropriate dose schedule.‘5 The subjects in that study tended to distribute their self-selected dosage, so that for fairly long periods of time each day, the “continual neuronal exposure to the drug” was probabty lacking. With proper attention to the factors that produce optimal conditions for the l6 it should not be development of tolerance and dependence to cannabis,’, surprising that both occur quite predictably in man.
* Supported by Grants DA00033 and DA4RG012 and Contract HSM-42-73-181 from the National Institute on Drug Abuse and National Institute of Mental Health Career Scientist Award K02MH32904 to R.T.J.
CLINICAL STUDIES OF CANNABIS TOLERANCE AND DEPENDENCE *
Reese T. Jones, Neal Benowitz, and John Bachman
Department of Psychiatry University of California, San Francisco San Francisco, California 941 43
INTRODUCTION
Statements like cannabis-related “tolerance and physical dependence do not occur” are commonly made in standard pharmacology texts.l The summary report of the National Commission on Marihuana and Drug Abuse, when discussing the “addiction potential” of marijuana concluded that “fact and fancy have become irrationally mixed regarding marijuana’s physiological and psychological properties. Marijuana clearly is not in the same category as heroin insofar as its physiologic and psychological effects are concerned. In a word, cannabis does not lead to physical dependence.” A recent book that describes extensive chronic marijuana studies in man does not even mention the possibility of dependence.3 Yet, after a comprehensive review of various aspects of cannabis tolerance and dependence, Wikler thinks the evidence indicates that both tolerance and dependence can develop in man.4 For some years, we and others have noted, in outpatient studies, that very frequent cannabis users show diminished drug effects when compared to less frequent users,5- though not all investigators agree.? Such indirect evidence of tolerance, of course, could be explained by several alternate hypotheses : personality or genetic differences, other drug use, and so on. Clinical reports of an abstinence syndrome associated with cannabis use are rare. Occasionally, very frequent cannabis users tested in our laboratories have reported the sudden onset of irritability, restlessness, insomnia, and perspiration after cessation of regular use.s Other investigators have reported similar signs and symptoms in small groups of cannabis users and in primates after prolonged high doses of c a n n a b i ~ . ~ - l ~ reports from outpatients should Such be viewed with some skepticism because of the possibility that these symptoms represent withdrawal from other drugs or concurrent illness. Possible species differences in drug response make the animal data open to question. Williams et al. reported several years ago that experimental subjects given frequent doses of cannabis or synhexyl compound reported a jittery feeling, insomnia, decreased appetite, weight loss, and autonomic symptoms when the experimental drug administration was suddenly st0pped.1~ In more recent studies of chronic marijuana smoking, Mendelson et d ’ s experimental subjects experienced rapid weight loss, decreased appetite, tremor, increased urine specific gravity, and irritability after a 21-day period of frequent marijuana smoking. However, the signs and symptoms were not interpreted