ABSTRACT
Introduction
Tolerance to cannabis
Psychological dependence on cannabis
Physical dependence on cannabis
Physical dependence on cannabis in man
Discussion and conclusion
Acknowledgements
Author: S. KAYMAKÇALAN
Pages: 21 to 31
Creation Date: 1981/01/01
The author reviews the literature on the dependence potential of cannabis. Case studies and experiments of tolerance to cannabis as well as psychological and physical dependence on cannabis are presented in man and in laboratory animals. Some effects common to both species are also recorded. Although the addictive potential of cannabis is often compared with the addictive potential of alcohol and tobacco, the author concludes that the characteristics of cannabis tolerance are similar to those of opiate dependence.
Although cannabis as a psychoactive drug has been used by man for many centuries, its addictive potential has only recently been recognized. Eddy and others in 1965 described the main features of dependence for several drug types and their views on the characteristics of the cannabis-type dependence found general acceptance [ 1] .
However, since 1965, new scientific knowledge has been acquired. The identification of Δ-9-tetrahydrocannabinol (Δ-9-THC) as the main active substance of cannabis and its synthesis [ 2] , [ 3] contributed enormously to knowledge on the pharmacology of cannabis. Moreover, an explosive increase in cannabis consumption has stimulated laboratory, clinical and epidemiological research on cannabis in many countries.
The author of this paper reviewed tolerance to and dependence on cannabis some years ago [ 4] , and this paper presents some additional information.
* This is a revised version of a paper presented at a meeting organized by the Anton Proksch-Institut, Vienna-Kalksburg, 17-18 October 1980. The original paper will be published in German in the proceedings of the meeting.
For a long time it was considered that cannabis did not produce tolerance. Lemberger and others in 1971. after injecting radioactively labelled (C [ 14] )-Δ-9-THC(0.5 mg) intravenously to chronic marijuana smokers and naive subjects, stated that non-smokers did not indicate any all of the long-term marijuana smokers pharmacological effect. In contrast, as 90 minutes [ 5] . They interpreted the reported effects that lasted as long results as chronic marijuana users having "reverse tolerance".
At present it is considered that so-called "reverse tolerance" is a misinterpretation [ 6] . However, there is evidence supporting the view that tolerance develops to many effects of cannabis both in laboratory animals and in man. The diverse effects of cannabis have been described in many species. Ataxia in the dog, ptosis of eyelids in the monkey and tachycardia in man are the most characteristic effects of cannabis use which lose their intensity after repeated administration indicating tolerance development- In most animal and human studies related to tolerance, marijuana (extract or smoke) or Δ-9-THC has generally been used. However, some investigators have also used other pharmacologically active cannabinoids such as DMPH (a dimethylheptyl homologue of Δ-6a(10a)-THC, Δ-8-THC, II-OH-Δ-9-THC) and a few synthetic derivatives- In the following pages the term "cannabis" will, in addition to plant material, include all active cannabinoids.
The indication of psychological dependence to any substance in man is a compulsive need to take the substance, or intensive craving for it. As is the case for many substances of abuse, psychological dependence is the basis of cannabis abuse. The continued self-administration of drugs by animals after evidence of psychological dependence [ 7] . In this context, in 1971, Deneau and Kaymakçalan [ 8] succeeded in producing self-administration of Δ-9-THC in monkeys. In 1972 Kaymakçalan, using cocaine, obtained self-administration of this substance in monkeys [ 9] . The results of these studies have been summarized in an earlier issue of the Bulletin on Narcotics [ 4] .
Pickens and others in 1973 reported intravenous self-administration, of Δ-9-THC in two monkeys which had previously been self-administering phencyclidine (PCP). After the substitution of Δ-9-THC, the animals continued to self-administer this latter drug [ 10] . In addition to intravenous self-injection, the same authors produced self-administration of cannabis smoke by inhalation, training two monkeys to smoke hashish from a tube [ 10] .
The addictive potential of cannabis 23
Van Ree and others, as well as Takahashi and Singer, were able to induce self-administration of Δ-9-THC in the rat [ 11] , [ 12] . The former authors produced this effect by intravenous injection following a four-day forced injection period. At the highest dose level (0.3 mg/kg/injection) only 40 per cent of animals initiated self-administration of Δ-9-THC [ 11] . This percentage and the drug intake were low in comparison with self-administration of amphetamine and narcotics in the rat.
Although there are reports of CNS hyper-excitability [ 13] , [ 14] or increased aggressiveness in mice after abrupt withdrawal of Δ-9-THC [ 15] , the most conclusive evidence on the physical dependence of animals to cannabis is obtained from studies of rats and monkeys.
Deneau and Kaymakçalan [ 8] and Kaymakçalan [ 9] in experiments in self-administration of Δ-9-THC in monkeys observed a typical abstinence syndrome which was not dissimilar from the opiate abstinence syndrome.
Other investigators also observed withdrawal changes in monkeys receiving either Δ-9-THC or cannabis smoke. Stadnicki and others reported the effects on behaviour and EEG in three rhesus monkeys following chronic oral administration of marijuana extract. The two monkeys that became tolerant after 50 days' treatment with Δ-9-THC (37.5 mg/kg) responded to termination of treatment with withdrawal signs manifested by increased aggressiveness. One of the two exhibited hallucinations and a period of increased EEG desynchronization [ 16] . Heath studied the effects of cannabis smoke on the EEG patterns taken from electrodes implanted in different parts of the brain of monkeys. After three months' exposure to cannabis there were some EEG changes which ameliorated following administration of an increased amount of cannabis [ 17] . Snyder and others have trained three monkeys to press a lever on a special schedule for liquid reinforcement. Following a stable baseline performance, two monkeys received 2 mg/kg of Δ-9-THC orally every third day for 90 days, with a placebo administered on intervening days. The third animal received a placebo throughout testing. When the drug was discontinued there was an abstinence effect in the drug-monkeys characterized by a change in performance [ 18] ,
Recent studies indicate that the abstinence syndrome of THC-treated rats consists of many signs and symptoms. However, some earlier works suggested the presence of some cannabis abstinence signs in rats. For example, Davis and others injected rats daily with 25 mg/kg Δ-9-THC subcutaneously for 20 days. During the immediate post-drug period a slight but statistically significant elevation of activity occurred on the second day [ 19] . Similarly, Pirch and others recorded electrocorticograms of rats by implanted electrodes. During the period of chronic oral administration of marijuana extract distillate to the rats, animals were given 20 mg/kg or 40 mg/kg Δ-9-THC for 9 - 13 days. Upon termination of chronic treatment, a "rebound" increase in integrated ECoG voltage was observed. This rebound" was maximal on the second and third day following the last dose [ 20] . The same group of investigators confirmed their earlier reports to a subsequent study increasing the dose of Δ-9-THC to 100 mg/kg in two animals [ 21] . Another cannabis withdrawal sign in the rat was an increase in grooming which was reported by Sjoden. This author studied the effects of long-term administration and withdrawal of THC (5 mg/kg Δ-8-THC or 2.5 mg/kg Δ-9-THC) on open-field behaviour in rats. During the two-week injection period a depressant effect of both isomers was noted on ambulation, rearing, groomingand latency. At drug withdrawal most open-field measures slowly returned to control levels, whereas the rate of grooming showed a definite increase [ 22] .
Hirschhorn and Rosecrans in 1977 reported that Naloxone precipitated a narcotic-like withdrawal syndrome in rats treated for five weeks with increasing doses of Δ-9-THC, the highest dose being 32 mg/kg given during the last three weeks. The main withdrawal symptoms were diarrhoea, teeth chattering, wet-dog shakes, salivation and ptosis [ 23] . Kaymakçalan and others in 1977 confirmed the above and showed that abrupt withdrawal of chronic injections of Δ-9-THC can cause an abstinence syndrome. They injected 10 rats subcutaneously with Δ-9-THC daily for five weeks in increasing doses. During the last three weeks the rats received 40 mg/kg Δ-9-THC at each administration. Ten control rats received the same amount of the vehicle by the same route for the same period. The administration of Naloxone on the 22nd and 31st days and the termination of drug administration on the 35th day caused an opiate-like abstinence syndrome [ 24] . The most common signs of abstinence in THC-treated animals were ptosis, teeth chattering, piloerection, defecation, urination, complete pal-pebral closure, dyspnea and grooming. Other signs observed in less than 50 per cent of the animals were chewing, tremors on the face, rearing, abnormal posture, yawning, escape behaviour, ear blanching, eating of objects, wet-dog shakes, jumping, biting of fingers and sniffing. During abstinence, increasing locomotor activity was recorded in THC-treated animals by an activity-meter. Both abstinence scores and increased motility exhibited a peak at the 48th hour of withdrawal [ 24] .
Taylor and Fennessy reported a chlorimipramine-induced withdrawal syndrome in the rat after chronic treatment with Δ-9-THC [ 25] . Chlorimipramine, which is a potent inhibitor of serotonin uptake, may antagonize some effects of Δ-9-THC in the rat. Therefore, precipitation of an abstinence syndrome with this chemical in Δ-9-THC-treated rats is considered somewhat similar to the action of Naloxone in opiate-dependent animals. The rats received increasing doses of intravenous Δ-9-THC twice daily for 10 days. The highest dose was 120 mg/kg, twice a day administered on days 6 - 10. On day 11, some of the rats were injected intraperitoneally with 5 mg/kg chlorimipramine. Quantifiable changes in behaviour consisted of writhing, wet-dog shakes, jumping and backward kicking of the hind legs. Other symptoms included front paw tremor, ptosis, chewing movements, excessive grooming, yawning, squealing, ataxia, unsteadiness in gait and sitting up on the posterior for long periods. Reporting these findings, on another occasion, the authors stated that "Δ-9-THC is capable of inducing a state of physical dependence" [ 26] .
A close survey of the literature reveals that several authors have described cannabis withdrawal symptoms in man. Most publications on this subject, with a few exceptions [ 27] , [ 28] , [ 29] , appeared after 1970.
Observations on abstinence symptoms in man refer mainly to those countries where potent forms of cannabis (ganja, dagga, hashish) are available. However, even in the United States of America where until recently weak preparations of cannabis were being used, a detailed description of marijuana withdrawal symptoms was reported by Marcovitz and Myers in 1944 based on 35 "confirmed marihuana addicts" who were admitted to a military hospital [ 27] . In the same decade, Fraser in India reported on soldiers who had been ganja smokers for some years and after joining the army exhibited severe withdrawal symptoms due to difficulty in obtaining cannabis [ 29] . Some recent studies from India also confirmed the dependence liability of cannabis, Chopra and Jandu, in their investigation of 275 chronic cannabis users, found that a large percentage of heavy users developed physical dependence [ 30] . In a research project sponsored by the World Health Organization (WHO) and carried out by the Department of Forensic Medicine of Banaras Hindu University in 1976, the long-term effects of cannabis were studied in 50 cannabis users, and a comparison was made with the data obtained from 25 non-user controls. It was found that the majority of users (98 per cent) felt uncomfortable if they were unable to obtain their daily supply or dose of cannabis and in addition to a strong craving for the drug (86 per cent), the majority also showed mental irritability and feelings of anxiety (74 per cent), as well as profound lethargy and physical weakness (60 per cent). As many as 70 per cent of the users reported some kind of physical discomfort in the absence of the drug [ 31] .
Middle Eastern and east Mediterranean countries are historically known to have a relative high hashish consumption. Kielholz and Ladewig observed withdrawal symptoms which lasted three to seven days in three young chronic hashish smokers who came to Switzerland from the Middle East [ 32] . According to Miras, writing on chronic hashish smokers in Greece, "there is definitely a dependence risk, although much less serious than with opiates" [ 33] .
In South Africa also, cannabis dependence has been reported. In five young South Africans, Bensusan reported marijuana withdrawal symptoms which persisted for one to three days. The disappearance of withdrawal symptoms coincided with the possibility of obtaining cannabis [ 34] . The same author observed two other similar cases of acute withdrawal symptoms from cannabis smoking. Morley and others collected information on the subjective effects of cannabis from 150 individuals who had used it on at least five occasions. Fourteen reported withdrawal symptoms [ 35] . Levin, in a paper delivered at the First South African International Conference on Alcoholism and Drug Dependence, reported that cannabis use elicited psychiatric complications in 33 per cent of 137 cannabis users. In 5 per cent o f the total group, these complications were related to drug withdrawal [ 36] . Again, in South Africa, Schweitzer and Levin described a case of acute brain syndrome due to cannabis withdrawal in a patient who had been hospitalized for multiple fractures [ 37] .
Current epidemics of marijuana use among young persons have redirected the attention of psychiatrists, family physicians and paediatricians to the possibility of physical dependence on marijuana. Teitel (1977) reported three cases of manic-depressive illness which followed withdrawal of marijuana after prolonged use [ 38] . Manatt indicated that heavy users of cannabis experienced a mild flu-like withdrawal syndrome [ 39] . Lantner reported that marijuana develops tolerance rapidly, is physically addictive and many smokers report withdrawal symptoms [ 40] .
In addition to the withdrawal symptoms in cannabis users described above, some experiments have been carried out using cannabinoids on volunteers. Williams and others in 1946 applied Parahexyl (a synthetic cannabinoid having marijuana-like effects and also known as Synhexyl) to six patients between the ages of 26 and 33 who were former marijuana smokers. The drug was given in self-chosen doses at self-chosen intervals for a period of 26 to 31 days. The daily dose ranged from 60 to 2,400 mg and was taken orally in one to eight individual doses. On the third day, after abrupt discontinuation of the drug, most patients exhibited some symptoms of withdrawal [ 28] .
In other experimental studies the main active component of cannabis, Δ-9-THC, has been used. Some investigators were interested in the withdrawal changes in sleep patterns and in the EEG of volunteers after Δ-9-THC administration. Freeman, using all-night polygraphic recordings, studied the effect of cannabis on the sleep patterns of two young women. At night they took 20 mg/kg Δ-9-THC in fruit juice. It was noticed that physiologic withdrawal effects occurred after only four nights of Δ-9-THC use, and the author concluded that these findings support the view that marijuana does cause physical dependence [ 41] . In a subsequent study, Freeman administered 20 mg Δ-9-THC orally at bedtime to five volunteers, who slept for 8-15 consecutive nights in the laboratory. He monitored EEG, chin EMG and eye movements, and noted that Δ-9-THC decreased the REM phase of sleep. As in the first study, abrupt withdrawal of the drug after four to six consecutive nights of use produced mild insomnia [ 42] . In another study, Freeman and A1-Marashi (1977) followed the EEG patterns in sleep of two volunteers who spent 30 consecutive nights in the laboratory. The patients received 20 mg Δ-9-THC orally for 12 nights on days 7 to 18. During the first five withdrawal nights sleep latency increased more than twofold. Also, during the withdrawal period, there were a greater number of eye move-meats during REM sleep and a large decrease in slow wave sleep. Many changes in polygraphic sleep patterns persisted for at least 12 days following discontinuation of Δ-9-THC [ 43] . Feinberg and others studied the influence of orally administered Δ-9-THC on the sleep patterns of seven male volunteers. During withdrawal, total sleep time was significantly reduced, and this change was entirely due to increase in sleep latency. In addition, both REM sleep and eye movements increased; the rebound effect being greater for eye movement [ 44] .
The work of Jones and others, carried out by oral administration of Δ-9-THC to volunteers, is the most convincing evidence that cannabis can produce physical dependence in man. The volunteers, after a gradual increase in dose, received a fixed dose of 180 - 210mg Δ-9-THC per day for 11 to 21 days, and were then abruptly switched to a placebo for 5 - 9 days. During this period all subjects showed a variety of abstinence signs and symptoms [ 45] . The main objection to this work was the amount of the drug given daily to the volunteers. The term "elephant doses" has been used for this regimen [ 46] . However, considering that in some parts of the world daily doses of 240 - 360mg of Δ-9-THC are not unusual, daily amounts of 180 - 210 mg may represent a human dose [ 47] .
Some symptoms of cannabis withdrawal syndromes common to man and animals
|
Signs and symptoms |
Man |
Monkey |
Rat |
|---|---|---|---|
|
Hyperactivity
|
+
|
+
|
+
|
|
Increased excitability
|
+
|
+
|
-
|
|
Aggressiveness
|
+
|
+
|
-
|
|
Tremors
|
+
|
+
|
+
|
|
EEG changes
|
+
|
+
|
+
|
|
Hallucinations
|
+
|
+
|
?
|
|
Photophobia or palpebral closure
|
+
|
+
|
+
|
|
Yawning
|
+
|
+
|
+
|
|
Salivation
|
+
|
-
|
+
|
|
Anorexia
|
+
|
+
|
-
|
|
Diarrhoea
|
+
|
-
|
+
|
|
Piloerection
|
-
|
+
|
+
|
|
Abnormal posture
|
-
|
+
|
+
|
|
Licking or biting of fingers
|
-
|
+
|
+
|
|
Eating unusual things
|
-
|
+
|
+
|
|
Masturbation
|
+
|
+
|
?
|
|
Craving for cannabis
|
+
|
+
|
?
|
+ = present; - = absent or not checked; ? = difficult to assess.
Nevertheless, the wealth of findings leaves little doubt about the existence of a cannabis withdrawal syndrome, confirming the possibility of physical dependence in man. The most frequently observed cannabis abstinence symptoms in man are excitation, irritability, agitation, restlessness, tremors or tremulousness, anxiety, depression or suicidal tendency, insomnia or sleep disturbances, sweating, abdominal distress, nausea, anorexia or decreased appetite, general malaise and muscular aches.
It is interesting to note that some of the cannabis withdrawal symptoms in man are also observed in laboratory animals (see table).
The demonstration of tolerance and of the dependence-producing properties of cannabis may have important academic and practical implications. In experimental animals the initiation, degree and duration of cannabis tolerance show great similarities to the characteristics of opiate dependence. There are also similarities between cannabis and opiate withdrawal symptoms in the monkey and the rat. Cannabis can potentiate some of the effects of morphine and there is cross-tolerance between the two substances. Furthermore, several common pharmacologic actions are induced by cannabis and opiates [48,49]. The addictive potential of cannabis is often compared with the addictive potential of alcohol and tobacco, It seems that the development of dependence to any of these three most widely abused substances is related to such factors as dose (potency), frequency, duration of use as well as some possible individual factors. However, the pharmacokinetic and pharmacologic properties of the three substances are very different. Whereas alcohol and nicotine are easily destroyed or eliminated from the body, active cannabinoids remain in the tissues for a long time. In addition, the spectrum of pharmacologic effects of cannabis is so large that they cannot be compared with the effects of alcohol or nicotine.
In the future, if the availability of potent forms of cannabis becomes widespread, dependence on cannabis may create more serious problems to society.
The author would tike to express his gratitude to the National Institute on Drug Abuse (USA), Rockvillie, Maryland, and especially to Dr. Monique Braude for the generous supply of Δ-9-THC. The typing of the manuscript by Miss Yüksel Kurucu is also highly appreciated.
The addictive potential of connabis 29
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