Chapter 7 - Cannabis: Effects and Consequences

Tolerance and dependence

 

When we think drugs we think drug addiction since, as F. Caballero states, a drug is [translation] “any substance likely to lead to addiction”.[1][70] In France and Europe, monitoring groups created in recent years are called monitoring centres for drugs and drug addiction. In Quebec, the advisory body created by the government is called the “Comité permanent de lutte à la toxicomanie” [standing committee on the fight against drug addiction]. The expression “drug addiction” is found everywhere: in legislation, in information documents, and in everyday language. However, since 1963, the WHO has recommended that we abandon this expression because it is imprecise and refer instead to states of physical and psychic dependence, defined as follows:

Psychic dependence is a “condition in which a drug produces a feeling of satisfaction and a psychic drive that requires periodic or continuous administration of the drug to produce pleasure or to avoid discomfort. Physical dependence is an “adaptive state that manifests itself by intense physical disturbance when the administration of the drug is suspended or its action is opposed by a specific antagonist. These disturbances, that is the abstinence or withdrawal symptoms, consist of physical and psychic symptoms and signs that are characteristic for each drug. [2][71][translation]

 

Furthermore, with the extension of the notion of drugs to other substances (pharmaceutical products, tobacco, alcohol), and with the extension of international control of substances to psychotropic drugs, in 1969 the WHO created a new definition for the term drug dependence that, though its application was initially limited to medication only, has come to be more widely accepted over time:

 

Drug dependence. A state, psychic and sometimes also physical, resulting from the interaction between a living organism and a drug, characterized by behavioural and other responses that always include a compulsion to take the drug on a continuous or periodic basis in order to experience its psychic effects, and sometimes to avoid the discomfort of its absence. Tolerance may or may not be present. A person may be dependent on more than one drug. [3][72]

 

But it is even more interesting for our purposes to quote even older definitions from the WHO dealing with habituation and addiction:

 

Drug habituation (habit) is a condition resulting from the repeated consumption of a drug. Its characteristics include:

1.1.      A desire (but not a compulsion) to continue taking the drug for the sense of improved well-being which it engenders;

2.2.      Little or no tendency to increase the dose;

3.3.      Some degree of psychic dependence on the effect of the drug, but absence of physical dependence and hence of an abstinence syndrome;

4.4.      Detrimental effects, if any, primarily on the individual.

 

Drug addiction is a state of periodic or chronic intoxication produced by the repeated consumption of a drug (natural or synthetic). Its characteristics include:

1.1.      An overpowering desire or need (compulsion) to continue taking the drug and to obtain it by any means;

2.2.      A tendency to increase the dose;

3.3.      A psychic (psychological) and generally a physical dependence on the effects of the drug;

4.4.      Detrimental effect on the individual and on society. [4][73]

This definition is important because, more than the previous two, it allows us to better distinguish between drugs that create primarily a habit and those that create an addiction, that is, the overwhelming need to use them. Now, as we will see in this chapter, cannabis corresponds much more to the criteria of a substance likely to create some degree of habituation and not an addiction.

In addition to drug addiction, thinking about drugs means also thinking about illicit substances. Now, as a wide range of works and an increasing number of practices have established, for practical purposes, the actual distinction is made on the combined levels of the substance’s toxicity (its dangers) and the uses (use, abuse, heavy use) that characterize it, not on the level of its legal and symbolic status.

 

Cannabis dependence

Let us first establish that animal studies on dependence and withdrawal are not very pertinent since most of them use doses that have nothing in common with the doses used by humans, even chronic users. Moreover, we note that studies on naïve animals (no experience with other drugs) have not been able to establish self‑administering behaviour and that is the only technique that allows for the direct assessment of the reinforcing properties of a molecule. One of the probable explanations stems from the long plasma half-life of D⁹THC, which we know is eliminated slowly by an organism (up to 25 days as we saw in the Chapter 5).[5][74] We also note that even after administration of very high doses of D⁹THC, somatic signs of spontaneous withdrawal were not observed in rodents, pigeons, dogs or monkeys.[6][75] Lastly, we note that all in all, we know little about the biophysiological and psychological mechanisms of dependence.

The idea of cannabis dependence has been the subject of criticism due to its overly medical aspect (having little regard for the differences in social context of the ways and situations in which it is used) and circular reasoning (for example, the fact that drugs are illegal means that their use is necessarily illegal, yet this is one of the criteria for dependence).[7][76] Nevertheless, when measured in accordance with the criteria of the DSM, a cannabis dependence syndrome presents no differences from an alcohol or heroin dependence syndrome. Furthermore, establishing the relative dangers of cannabis is not contrary to the objectives of public health.

The nosologic criteria of the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) of the American Psychiatric Association undoubtedly remain the most widely used in studies on dependence, especially since the majority of drug research is conducted in the United States and Commonwealth countries (England, Australia, Canada…) that use this instrument.

The DSM-IV distinguishes between criteria for substance abuse and criteria for dependence. We have reprinted them here in accordance with the INSERM report.

 

 

Diagnostic Criteria for Substance Abuse according to the DSM-IV

A.A.     A maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by one (or more) of the following, occurring within a 12-month period: 1.1.       Recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home; 2.2.       Recurrent substance use in situations in which it is physically hazardous; 3.3.       Recurrent substance-related legal problems; 4.4.       Continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance. B.B.     The symptoms have never met the criteria for Substance Dependence for this class of substance.

 

 

Diagnostic Criteria for Substance Dependence according to the DSM-IV

A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by three (or more) of the following, occurring at any time in the same 12-month period: 1.1.       Tolerance, as defined by either of the following: a.a.       A need for markedly increased amounts of the substance to achieve intoxication or desired effect; b.b.      Markedly diminished effect with continued use of the same amount of the substance. 2.2.       Withdrawal, as manifested by either of the following: a.a.       The characteristic withdrawal syndrome for the substance; b.b.      The same (or a closely related) substance is taken to relieve or avoid withdrawal symptoms. 3.3.       The substance is often taken in larger amounts or over a longer period than was intended; 4.4.       There is a persistent desire or unsuccessful efforts to cut down or control substance use; 5.5.       A great deal of time is spent in activities necessary to obtain the substance, use the substance, or recover from its effects;   6.6.       Important social, occupational, or recreational activities are given up or reduced because of substance use;  7.7.       The substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance.

 

The existence of a cannabis dependence syndrome in humans can be inferred using various methods: epidemiological investigations and clinical studies (which usually use DSM criteria), and requests for treatment.

 

Epidemiological investigations

Some epidemiological studies show that cannabis use can lead to psychological dependence. In some cases, they estimate that half of chronic users would develop this kind of dependence.[8][77] People who use cannabis on a daily basis for several months would be at greater risk of becoming dependent.[9][78] Interpretation and intercomparison of the various studies is difficult because the denominator is not always common, or even specified (in some cases, it is the general population while in others it is cannabis users and in the latter case, there is not always a distinction among life-long, recent and regular users). The authors also do not always specify if the dependence is recent or life-long.

In the United States, several investigations were conducted into the frequency of use of various psychoactive substances and dependence. Through the Epidemiological Catchment Area study, close to 20 000 people were interviewed in five years during the 1980s. The prevalence (in the general population) of cannabis dependence was 4.4%.[10][79] The National Comorbidity Survey, an investigation to estimate the comorbidity between substance abuse and other mental disorders, undertaken between 1990 and 1992 and involving more than 8,000 subjects from the general population between the ages of 15 and 55, also estimated the prevalence of dependence. For the purposes of the investigation, DSM criteria were used and dependence was observed when respondents presented at least three of the nine criteria. According to this study, 4.2% of the 15‑54 year olds presented cannabis dependence (14% were dependent on alcohol and 24% on tobacco). Of those who had used cannabis at least once during their life (46%), 9% were considered dependent, compared to 32% for tobacco and 15% for alcohol. Cannabis dependence was more common in men than women (12% versus 5.5% of users), and in those 15-24 than in the others (15% versus 8%).[11][80] Combining the results of three large investigations into the use of psychoactive substances conducted on households (nearly 88,000 respondents aged 12 and up) Kandel et al.[12][81] observed that 8% of those who had used cannabis in the previous year (0.7% of the sample) were considered dependent.

 

In New Zealand, a longitudinal study involving a cohort of 1,265 children born in 1977 in an urban setting and followed since birth revealed that at age 21, not less than 70% had used cannabis. Of those, 13% had had a problem with dependence measured in accordance with the DSM-IV during their lifetime.[13][82] Another New Zealand study involving a cohort of 1,000 people found similar results: at age 21, 62% had used cannabis and at age 26, 70% had. The prevalence of dependence using DSM III-R criteria went from 3.6% at age 18 to 9.6% at age 21 (or nearly 15% of users).[14][83]

In Australia, an investigation involving more than 10,000 people from the general population who were over 18 years of age showed that approximately 1.5% of users during the previous year and 20% of current users showed signs of dependence based on the DSM-IV.[15][84]

In the Netherlands, a study involving a sample of the national population aged 18 to 65 (7,000 subjects) showed that 10% of users had had signs of dependence during their lifetime.[16][85]

 

Clinical studies

It is difficult to generalize based on the results of clinical studies, but it is interesting to see to what extent their results are similar to those of epidemiologic studies. Kosten examined the validity of DSM-III R criteria to identify syndromes of dependence on various psychoactive substances including cannabis. He observed that the criteria for syndromes of alcohol, cocaine and opioid dependence were strongly consistent. The results were more ambiguous for cannabis. A criterion-referenced analysis revealed that there were three dimensions to the cannabis dependence syndrome: (1) compulsion – indicated by a change in social activities attributable to the drug; (2) difficulty stopping – revealed by the inability to reduce use, a return to previous levels after stopping temporarily and a degree of tolerance of the effects; and (3) withdrawal signs – revealed by their disappearance with re-use and continuing use despite recognized difficulties.[17][86]

 

Studies on long-term users

In Canada, Hathaway conducted a study between October 2000 and April 2001 to identify problem use and dependence in long-term users based on the DSM-IV criteria.[18][87] The sample was made of 104 individuals (64 men and 40 women) aged 18 to 55 (mean age 34). 80% had used cannabis on a weekly basis, 51% on a daily basis during the preceding 12 months, and close to half (49%) had used one ounce (28 grams) or more per month. Reasons to use included: to relax (89%), to feel good (81%), to enjoy music or films (72%), because they are bored (64%) or as a source of inspiration (60%).

Respondents were asked if they had ever engaged in deviant activity related to cannabis use. The most frequent answer was to have been in an uncomfortable situation in order to get cannabis. Other activities included borrowing money, selling cannabis to support their own drug use, and taking on extra work to buy cannabis. Only 6% ever had recurring legal problems due to their use of cannabis. With respect to dependence, 30% reported a lifetime prevalence of three or more of the criteria, 15% during the 12 months prior to the interview.

 

In light of this finding, the most frequently encountered problems with cannabis have more to do with self‑perceptions of excessive use levels than with the drug’s perceived impact on health, social obligations and relationships, or other activities. Lending support to the highly subjective nature of his evaluative process, no significant correlations were found between amounts nor frequency of use and the number of reported DSM-IC items. For those whom cannabis dependency problems progress to the point of seeking out or considering formal help, however, the substantive significance of perceived excessive use levels cannot be overlooked. [19][88]

 

The comparative study by Cohen and Kaal presented in the previous chapter also included data on dependency symptoms. Between 21% and 24% of the subjects presented 3 or more DSM-IV criteria in their lifetime as the following table shows.

 

Number of positive DSM IV answers

Amsterdam, San Francisco, Bremen [20][89]

	Ever experienced		Last twelve months
Number of criteria	Amsterdam    N               %	San Francisco    N                %	San Francisco    N                 %	Bremen    N               %
0 1 2 3 4 5 6 Total Average incl. 0 Average excl. 0	85              39    37              17    43              20    19                9    15                7      9                4      8                4   216            100            1,5            2,5	129              49     53              20     30              11     28              11     15                6       7                3       3                1   265             100               1,2               2,3	233               88     17                 6       9                 3       3                 1 33                               1     265265                            100            0,2            1,8	43              78      5                9      4                7      2                4 11                              2     5555                          100           0,4           1,9

 

 

The authors observe a significant correlation between amount of cannabis use (in grams) during top period of use and the number of DSM-IV items ever experienced. However, no correlation was found between the amount of cannabis use during top period of use and number of criteria experiences in the last twelve months.

 

Requests for treatment

Lastly, we can examine dependence indirectly through requests for treatment. Obviously, this is a very indirect and definitely very imperfect means for several reasons. The very great majority of cannabis users use it irregularly and stop when they reach their twenties. Of those who continue and become regular users, we have just seen that between 10% and 20% will present the criteria for dependence. Most users do not think they need help, which their ability to stop without outside assistance would confirm. Lastly, those who ask for help could be influenced simultaneously by the availability of services as well as the interaction of other problem substances, alcohol, medication or other drugs, or other mental disorders. In fact, it seems that in a significant proportion of cases, requests for treatment related to cannabis come from people with multiple disorders.

Nevertheless, we have heard testimony to the effect that requests for treatment for problems with cannabis dependence are on the rise and that this increase could be related to the THC content.

 

In Europe, requests for treatment where the main problem is cannabis-related vary widely from country to country, ranging from 6% in Spain (one of the countries where use is most widespread and most tolerated) to 25% in Belgium. Sweden, which however has a relatively low rate of use, is at 14%, comparable to France (16%) which, however, has a much higher rate of use. In the United States, demand is just as variable depending on the state, from 5% to 30%.[21][90]

 

Severity of dependence

Severity of dependence has been evaluated in different ways. In the United States, a study examined approximately 1,100 subjects who had used cannabis more than six times and evaluated the severity of their dependence based on DSM-IV criteria. The level of dependence (low, intermediate or high) corresponded to the number of criteria met.[22][91] The following results were obtained:

 

 

Severity of cannabis dependence based on use[23][92]
	Distribution of subjects based on type of use
	Low	Intermediate	Heavy	Total
Dependence (number of criteria)	T          A          C	T          A          C	T          A          C	T          A          C
Nil (0-2) Low (3-4) Moderate (5-6) Severe (7-9)	18         88         85 28           8         11 34           3          2 19           1          3	14         45         53 30         22         21 39         15         14 17         17         12	5           8         35 22         12         34 51         19         23 23         61         17	13         47         59 27         14         18 40         12         13 20         27         10

T = tobacco; A = alcohol; C = cannabis

 

 

We see a consistent situation in which the link between heavy use and dependence is lower for cannabis than for tobacco and alcohol, and in which, over all, dependence on cannabis is the lowest of the three substances.

For his part, professor Roques proposes three classes of products based on their dangers. The first includes heroin, cocaine and alcohol; the second psychostimulants, hallucinogens, tobacco and benzodiazepines; and cannabis is set apart in a separate class. He classifies the dangerousness of drugs using a diverse set of criteria. We have reprinted his table of the dangerousness of drugs on the following page.

 

Danger Factors of “drugs” (reprinted from Roques, B. (1999), page: 296
	Heroin	Cocaine	MDNA	Psycho-stimulants	Alcohol	Benzo-diazepines	Cannabi-noids	Tobacco
Dopamine Overactivation     Hypersensi-tivity to Dopamine   Activation of Opioid System   Physical Dependence   Psychic Dependence   Neurotoxicity     General Toxicity   Danger to Society   Replacement Therapy	+++       ++     ++++       very high     very high     low     high     very high     yes	++++       +++     ++       low     high but intermittent   high     high     very high     yes	+++       ?     ?       very low     ?     very high ( ?)     possibly very high   low ( ?)     no	++++       +++     +       low     average     high     high     low (exceptions)   no	+       ±     ++       very high     very high     high     high     high     yes	±       ?     +       average     high     0     very low     low     not researched	+       ±     ±       low     low     0     very low     low     not researched	+       ?     ±       high     very high     0     very high (cancer)   0     yes

In closing, we note that there is no known physical dependence on cannabis, even though in the most severe cases, withdrawal is sometimes accompanied by physical signs such as trembling, insomnia, irritability, etc.

 Tolerance

From a technical standpoint, tolerance is defined as follows:

 

the property of the human organism to endure the administration of usually effective doses of a given substance without displaying a reaction. With respect to drugs, this tolerance can lead to increased doses in order to achieve the desired effect. [24][93] [translation]

 

Development of tolerance is associated with pharmacodynamic changes. In some animal studies, chronic administration of THC reduced the density of receptors in some regions of the brain[25][94] and increased it in others; these effects were reversible.[26][95]

In man as in animals, studies have observed the phenomenon of cannabis tolerance. However, the data must be interpreted with care insofar as some studies and clinical cases have also found that regular users needed less cannabis to achieve the desired effect.[27][96] Nevertheless, a study by Wiesbeck et al. involving 5,611 subjects reported that 16% of frequent cannabis users had a history of a withdrawal syndrome.[28][97]

It is tolerance of a substance that leads to withdrawal symptoms. In recent years, clinical data has been accumulated on withdrawal symptoms in heavy cannabis users (several doses per day in an ongoing manner for several years). The symptoms observed include agitation, loss of appetite, nausea, disturbed sleep, irritability or hyperactivity and an increased body temperature.[29][98] These symptoms appeared after 24 hours of abstinence, peaked after two to four days and diminished within seven days. The symptoms were markedly less severe and of shorter duration than with other psychoactive substances. Furthermore, clinical studies showed that most subjects continued to perform their daily activities in a normal fashion.