Management of substance abuse

The health and social effects of nonmedical cannabis use

New WHO publication on cannabis


Chapter 2. Cannabis substance profile and its health impact

2.1 What do we know?

2.1.1 Cannabis, cannabinoids, cannabis-use disorders

Cannabis. A generic term used to denote the several psychoactive preparations of the cannabis plant. Cannabis is the preferred designation of the plant Cannabis sativa, Cannabis indica and, of minor significance, Cannabis ruderalis (Gloss, 2015). Cannabis resin means “separated resin”, whether crude or purified, obtained from the cannabis plant.

In this report the term “cannabis” will be used instead of marijuana or other names indigenous to local cultures. The discussion of the health and social consequences of cannabis use is limited to the nonmedical use of the cannabis plant.

Cannabinoids: Cannabinoids are a class of diverse chemical compounds that act on cannabinoid receptors in cells that modulate neurotransmitter release in the brain. The composition, bioavailability, pharmacokinetics and pharmacodynamics of botanical cannabis differ from those of extracts of purified individual cannabinoids. Cannabinoids are basically derived from three sources: (a) phytocannabinoids are cannabinoid compounds produced by plants Cannabis sativa or Cannabis indica; (b) endocannabinoids are neurotransmitters produced in the brain or in peripheral tissues, and act on cannabinoid receptors; and (c) synthetic cannabinoids, synthesized in the laboratory, are structurally analogous to phytocannabinoids or endocannabinoids and act by similar biological mechanisms. Cannabinoids are sometimes used therapeutically (e.g. for management of spasticity in multiple sclerosis or nausea in the process of cancer chemotherapy). Discussion of the health impact of the illicit use of synthetic cannabinoids is beyond the scope of this document.

Cannabis-use disorders: Cannabis-use disorders refer to a spectrum of clinically relevant conditions and are defined via psychological, social and physiological criteria to document adverse consequences, loss of control over use, and withdrawal symptoms. Cannabis-use disorders are defined in the Diagnostic and statistical manual of mental disorders (DSM-5; APA, 2013) and in the International statistical classification of diseases and related health problems (ICD-10; WHO, 1992). ICD-10 distinguishes between harmful and dependent use of cannabis, while in DSM-5 cannabis-use disorders are classified by the severity of health impairments into mild, moderate and severe disorders. Both classifications also describe a specific cannabis withdrawal syndrome which can occur within 24 hours of consumption. For cannabis withdrawal syndrome to be diagnosed, the person must report at least two mental symptoms (e.g. irritability, restlessness, anxiety, depression, aggressiveness, loss of appetite, sleep disturbances) and at least one physical symptom (e.g. pain, shivering, sweating, elevated body temperature, chills). These symptoms are most intense in the first week of abstinence but can persist for as long as a month (Hoch et al., 2015; Budney & Hughes, 2006).

2.1.2 Cannabis preparations and mode of administration.

Cannabis preparations are usually obtained from the female Cannabis sativa plant. The plant contains at least 750 chemicals and some 104 different cannabinoids (Radwan et al., 2015; Izzo et al., 2009). The principal cannabinoids in the cannabis plant include delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN). THC is the primary psychoactive compound, with CBD, a non-psychoactive compound, ranking as the second cannabinoid. Generally, THC is found at higher concentrations than CBD. The known chemical composition of Cannabis sativa is constantly changing. New non-cannabinoid and cannabinoid constituents in the plant are discovered frequently. From 2005 to 2015, the number of cannabinoids identified in the whole plant increased from 70 to 104 and other known compounds in the plant increased from some 400 to around 650 (Izzo et al., 2009; ElSohly & Slade, 2005; Ahmed et al., 2008).

The cannabinoid that is primarily responsible for the psychoactive effects sought by cannabis users is THC (Gaoni & Mechoulam, 1964; Martin & Cone, 1999; Iversen, 2007). THC is found in a resin that covers the flowering tops and upper leaves of the female plant. Most of the other cannabinoids are either inactive or only weakly active, although some, such as CBD, may modify the psychoactive effects of THC (Mechoulam & Hanus, 2012).

The most common cannabis preparations are marijuana, hashish and hash oil. Marijuana is a herbal form of cannabis prepared from the dried flowering tops and leaves of the plant. Its potency depends on the growing conditions, the genetic characteristics of the plant, the ratio of THC to other cannabinoids, and the part of the plant that is used (Clarke & Watson, 2002). Cannabis plants may be grown to maximize their THC production by the “sinsemilla” method by which only female plants are grown together (Clarke & Watson, 2002).

Cannabis is typically smoked as marijuana in a hand-rolled cigarette or “joint”, which may include tobacco to assist burning. A water pipe or “bong” is also a popular means of using all cannabis preparations (Hall & Degenhardt, 2009). Cannabis smokers typically inhale deeply and hold their breath to ensure maximum absorption of THC by the lungs.

One increasingly popular way of administrating cannabis is the use of vaporizers. Lower temperature vaporization of cannabis has been postulated as safer than smoking, as it may deliver fewer components of high molecular weight than smoked cannabis (Bloor et al., 2008). Whether vaporizing cannabis is a safer alternative to smoking remains uncertain, as the reduction in toxic smoke components needs to be weighed against the hazards of acute intoxication and long-term consequences to the brain (Wilsey et al., 2013; Eisenberg et al., 2014).

Inhalation by smoking or vaporization releases maximal levels of THC into the blood within minutes, peaking at 15-30 minutes and decreasing within 2-3 hours. Even with a fixed dose of THC in a cannabis cigarette, THC pharmacokinetics and effects vary as a function of the weight of the cannabis cigarette, the THC potency in the cigarette, its preparation, the concentration of other cannabinoids, the rate of inhalation, the depth and duration of puffs, the volume inhaled, the extent of breath-holding, the vital capacity and the escaped smoke and dose titration (Azorlosa, Greenwald & Stitzer, 1995; Azorlosa et al., 1992).

Hashish, once a general term for cannabis in the Eastern Mediterranean Region, now is being used to define cannabis resin (WHO, 1994). Hashish (derived from the resin of the flowering heads of the cannabis plant) may be mixed with tobacco and smoked as a joint or (typically in South Asia) it may be smoked in a clay pipe or chillum with or without tobacco, Hashish may also be cooked in foods and eaten. In India and other parts of South Asia, cannabis preparations from stalks and leaves, called bhang, is traditionally used as a drink or chewed and is part of religious and ritual use.

Survey data on patterns of cannabis use in most high- and middle-income countries indicates that most cannabis users smoke cannabis (Hall & Degenhardt, 2009). The chemistry and pharmacology of cannabis make it easiest to control doses when it is smoked (Iversen, 2007; Martin & Cone, 1999). Given the preponderance of smoking as the route of cannabis administration in developed countries, readers should assume throughout the remainder of this report that smoking is the method used unless otherwise stated.

2.1.3 Changes in cannabis potency

There has been an upward trend in the mean THC content of all confiscated cannabis preparations in the USA and in some European countries. The breeding of different strains has yielded plants and resins with dramatic increases in THC content over the past decade, from around 3% to 12-16% or higher (% of THC weight per dry weight of cannabis) with differences in different countries (Radwan et al., 2008; Niesink et al., 2015; Swift, et al., 2013; Zamengo, et al., 2014; Bruci, et al., 2012)

In the USA the THC content of cannabis increased from less than 2% in 1980 to 4.5% in 1997 and 8.5% in 2006 (ElSohly et al., 2000; ONDCP, 2007) to 8.8% in 2008 (Mehmedic et al., 2010). The increase in cannabis potency in the USA was mainly due to the increased potency of imported rather than domestically-produced cannabis (Mehmedic et al., 2010). In 2015, according to a number of USA laboratories, some retail cannabis seized by the US Drug Enforcement Administration (DEA) was found to contain 20% THC or more.

In 2011, cannabis resin at retail level in Europe was reported to have an average THC content that varied from 4% (Hungary) to 16% (Netherlands). According to the 2015 report of the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), 3-14% THC is the range of the THC content in herbal cannabis in Europe (2015a). Herbal cannabis produced by intensive indoor growing methods may have an average potency that is 2-3 times greater than that of imported herbal cannabis (EMCDDA, 2004). More recently in the European Union (EU), imported resin appears to be increasing in potency – possibly because resin producers are responding to the increased availability of high-potency domestically-produced herbal cannabis in the EU (EMCDDA, 2015b).

Hashish oil, a solvent-extracted liquid, is consumed by smoking, use of vaporization, or as a food additive. Users report more addictive behaviours and withdrawal symptoms with the high THC levels in hashish oil. In the USA hashish potencies did not increase consistently, with the mean annual potency varying from 2.5–9.2% in 1993–2003 to 12.0–29.3% in 2004–2008 (Mehmedic et al., 2010). Hashish oil potencies also varied considerably during this period, from a mean of 11.6 % in 1994 to a mean of 28.6% in 2000 to a mean of 19.4% the following year (Mehmedic et al., 2010).

2.1.4 Risk and protective factors

The terms “risk factors” and “protective factors” are widely used in public health. The term “risk factor” is used to describe individual or social factors that predict an increased risk of a disease or undesirable health condition. It is important to note that risk factors do not necessarily cause, but are associated with, the initiation of cannabis use, transitioning to frequent high-risk cannabis use and to the development of cannabis-use disorders.

Most of the studies on risk and protective factors for nonmedical use of cannabis and other drugs have been conducted in a small number of high-income countries such as Australia, Germany, Netherlands, New Zealand and the USA (Hawkins, Catalano &Miller, 1992; Stone et al., 2012; EMCDDA, 2015b). The limited studies in developing countries suggest that some of the same risk and protective factors also apply in these countries (Hall & Degenhardt, 2007). More research is needed to confirm that this is the case.

In developed countries the major social and contextual factors that increase the likelihood of initiation of cannabis use are drug availability, the use of tobacco and alcohol at an early age, and social norms that are tolerant of alcohol and drug use (Lascala, Friesthler & Gruenwald, 2005; Hawkins et al., 1992; Stone et al., 2012, EMCDDA, 2015). Overall, people from socially disadvantaged backgrounds are more likely to use illicit drugs (Daniel et al., 2009), although illicit drugs can also be commonly used in specific subgroups and party settings.

Family factors that are found to increase the risk of illicit drug use during adolescence include the poor quality of parentchild interaction and parentchild relationships, parental conflict, and parental and sibling drug use (Degenhardt et al., 2010; Fergusson, Boden & Horwood, 2015). However, there is no absolute relationship and not all adolescents growing up in families with these risk factors become illicit drug users.

Individual risk factors that increase the risk include: male gender (Ferguson, Horwood & Lynskey, 1994; Korhonen, et al., 2008); the personality traits of novelty (Cannon et al., 1993) and sensation seeking (Lipkus et al., 1994; Pinchevsky et al., 2012), peer early oppositional behaviour and conduct disorders in childhood (Lynskey, Fergusson & Horwood, 1994; Lynskey & Fergusson, 1995; Wymbs et al., 2012; Collins et al., 2011), poor school performance, low commitment to education and early school leaving (Townsend, Flisher & King, 2007; Lynskey & Hall, 2000; Tu, Ratner & Johnson, 2008) and inadequate sleep (Mednick, Christakis & Fowler, 2010). Associating with antisocial and drug-using peers is a strong predictor of adolescent alcohol and drug use (Fergusson, Boden & Horwood, 2008; Kandel & Andrews, 1987), independent of individual and family risk factors (Lynskey & Hall, 2000; Hawkins, Catalano & Miller, 1992). Figure 2.1 lists risk factors favourable to drug use.

In developed countries protective factors in childhood and adolescence are found to be positive family environments. Young adults who experienced strong parental support during adolescence are less likely to develop drug-use problems (King & Chassin, 2004; Stone et al., 2012). Perceptions of parental care play a key role in predicting cannabis use (Gerra et al., 2004). Good family management – encompassing effective monitoring, discipline, reward systems, reinforcement, etc. – is associated with lower rates of substance use among young adults (Stone et al., 2012). Religious involvement is associated with lower cannabis use and higher rates of abstinence in adolescents in most countries (Schulenberg et al., 2005). The same study (Schulenberg et al., 2005) also found that high scholastic achievement was associated with higher rates of abstinence from cannabis use.

Some factors are specifically associated with progression to dependence. These are found to be intensive or risky patterns of cannabis use, persistent use and early onset. Individuals who experienced positive effects of their early cannabis use (at age 14–16 years) had an increased risk of cannabis dependence later in life (Fergusson, Horwood & Beautrais, 2003). Also associated with the progression to dependence are various psychological and mental health factors (including low self-esteem, low self-control and low coping skills) and socioeconomic factors (including low socioeconomic status and a difficult financial situation) (Coffey et al., 2003; Fergusson, Horwood & Swain-Campbell, 2003; von Sydow et al., 2002).

Rates of cannabis dependence are higher among individuals reporting any lifetime psychiatric disorder, mood disorder, anxiety disorder, conduct disorder, personality disorder or attention deficit hyperactivity disorder (ADHD). Having a history of a substance use disorder (SUD) predicts development of an additional SUD. The transition to cannabis (or cocaine) dependence occurs considerably more quickly than the transition to nicotine or alcohol dependence (Lopez-Quintero et al., 2011).

Figure 2.1. Risk factors for drug use

Source: UNODC, 2015, World Drug Report

2.1.5 Short-term health effects of cannabis use

The short-term effects of cannabis use are those that can occur shortly after a single occasion of use. These short-term effects depend on the dose received, the mode of administration, the user’s prior experience with cannabis, any concurrent drug use, and the “set and setting” – i.e. the user’s expectations, attitudes towards the effects of cannabis, mood state, and the social setting in which it is used (Fehr & Kalant, 1983).

 

In terms of short-term effects, it is implied that cannabis use precedes the effect, and that cannabis use and the effect occur closely together in time. When it is ethical to do so, these effects can be reproduced by administering cannabis under controlled conditions – for instance, in studies of the effects of cannabis use on cognitive performance and driving skills. These conditions apply to the short-term euphoric and relaxing effects sought by cannabis users and to some of its dysphoric effects (e.g. anxiety symptoms that are experienced by some users).

The most obvious short-term health effect of cannabis is intoxication marked by disturbances in the level of consciousness, cognition, perception, affect or behaviour, and other psychophysiological functions and responses. The magnitude of these effects will depend on the dose used, the route of administration, the setting and the mindset of the user (Brands et al., 1998). In this report, evidence is evaluated as to whether the short-term intoxicating effects of cannabis are possible causes of injuries, psychoses, suicidal behaviour and adverse physical health effects, such as stroke or acute coronary syndrome (See Box 2.1).

 

BOX 2.1. Acute cannabis intoxication

ICD–10 definition (WHO, 1993).

F12.0 Acute intoxication due to use of cannabinoids. A. The general criteria for acute intoxication (F1x.0) must be met.

B. There must be dysfunctional behaviour or perceptual abnormalities, including at least one of the following:

(1) euphoria and disinhibition;

(2) anxiety or agitation;

(3) suspiciousness or paranoid ideation;

(4) temporal showing (a sense that time is passing very slowly, and/or the person is experiencing a rapid flow of ideas;

(5) impaired judgement;

(6) impaired attention;

(7) impaired reaction time;

(8) auditory, visual, or tactile illusions;

(9) hallucinations with preserved orientation;

(10) depersonalization;

(11) derealization;

(12) interference with personal functioning.

 

C. At least one of the following signs must be present:

(1) increased appetite;

(2) dry mouth;

(3) conjunctival injection;

(4) tachycardia.

 

DSM-5 definition (APA, 2013)

Cannabis intoxication, a cannabis-related disorder coded as 292.89, is defined by DSM-5, as the following:

·       Recent use of cannabis

·       Clinically significant problematic behavioural or psychological changes (i.e. impaired motor coordination, euphoria, anxiety, sensation of slowed time, impaired judgment, social withdrawal) that developed during, or shortly after, cannabis use.

 

At least 2 of the following signs, developing within 2 hours of cannabis use:

·       Conjunctival injection

·       Increased appetite

·       Dry mouth

·       Tachycardia
Symptoms not due to a general medical condition and not better accounted for by another mental disorder.

 

2.1.6 Long-term health effects of cannabis use

Long-term health effects are those that arise from regular cannabis use – especially daily use – over periods of months, years or decades. The time interval between the initiation of regular cannabis use and the development of long-term health effects may vary from several years to decades.

This report evaluates the evidence on whether long-term cannabis use is a contributory cause of the following health outcomes: dependence, cognitive impairment, mental disorders (psychoses, depression, anxiety and suicidal behaviour), and adverse physical health effects such as cardiovascular disease (CVD), chronic obstructive pulmonary disease and respiratory and other cancers. More information can be found in chapters 6 and 7 of this report.

2.1.7 Approach to making causal inferences

For this report, when judging the evidence on the adverse health effects of cannabis use, the criteria set out in Box 2.2 (Hall & Pacula, 2010) were used. The important contribution of Hill (1965) in his article The environment and disease: association or causation? is acknowledged.

The first criterion requires evidence of an association between cannabis use and the health outcome. This evidence can come from animal studies, human laboratory studies, case-control studies and prospective longitudinal epidemiological studies. As the consistency of the evidence of an association increases in various types of research studies, so does confidence in the existence of such an association.

The second requirement is evidence that makes reverse causation an implausible explanation of the association. We need to rule out the possibility that cannabis use is a consequence of the health outcome rather than a cause of it. The latter could be the case, for instance, if persons with clinical depression were more likely than non-depressed persons to use cannabis as a form of self-medication. This requirement can be satisfied by evidence from experiments (when they are ethically acceptable) and from prospective studies (when experiments are not ethically acceptable). Either type of study can show whether cannabis was used before the health outcome developed.

The third requirement is the most difficult to satisfy. This requires evidence that the association is not explained by other uncontrolled and unmeasured factors that increase the likelihood of persons both using cannabis and developing the health outcome that cannabis use is assumed to cause. This challenge arises because cannabis users (especially regular users) differ from non-users in various ways (apart from using cannabis) and these differences increase cannabis users’ risks of experiencing adverse health and social outcomes independently of their cannabis use. Cannabis users are, for instance, more likely to use alcohol, tobacco and other illicit drugs than people who do not use cannabis (Kandel, 1993). They also differ from non-users in risk-taking, impulsivity, cognitive ability and other ways that increase their risk of adverse health outcomes such as accidents, using other illicit drugs or performing poorly in school (Fergusson, Boden & Horwood, 2015). These differences can make it difficult to be sure that adverse health outcomes that occur more often in regular cannabis users are caused by their cannabis use (Hall, 2015).

The most common method of addressing these inferential challenges has been by the statistical analysis of data from prospective studies to control for the effects of potentially confounding variables, such as other drug use and personal characteristics on which cannabis users differ from non-users (Hall, 2015). The major limitations of this approach are that not all studies have measured all plausible confounders and, when they have done so, these variables are measured with error, which prevents analyses from fully controlling for the effects of these variables. There may also be unmeasured factors that we do not know about and so do not measure in these studies (Costello & Angold, 2011; Richmond et al., 2014).

Mendelian randomization has been proposed as an approach to overcome this limitation of observational epidemiological studies (Davy Smith, 2011). This method uses genotypic information to approximate the design of a randomized control trial of the effects of the exposure via cannabis use (Richmond et al., 2014). This approach has not been applied to studying the health effects of cannabis because genetic studies have not yet identified common genotypes that are associated with cannabis use but not associated with the health outcomes under study (Kendler et al., 2012). The fourth requirement for making a causal inference is evidence that a causal relationship between cannabis use and the health outcome is biologically plausible (Hall & Pacula, 2010). This may come from animal or human experiments on the biological effects of cannabis use on brain and bodily functions and from detailed understandings of the neurobiology of the cannabinoid system and the pathophysiology of the health outcomes in question. Other factors that may support a causal interpretation include strength of the association, dose–response relationships, specificity of the association and reversibility of the effect after removal of the drug.