Pharmacokinetics

Cannabis can be consumed via smoking (e.g., hand-rolled cigarettes, water pipes, nonwater pipes, vaporizers), ingestion (e.g., mixed into foods or used in the process of brewing tea), transdermally, or rectally. Cannabis shares some qualities with tobacco in that it is composed principally of plant material, often is used via smoking routes (e.g., pipes, joints), and contains a myriad of chemical compounds. Unlike tobacco, however, the active agents in cannabis are cannabinoids (unique to the marijuana plant). There are at least 100 different cannabinoids in marijuana, although the pharmacokinetics of most of these compounds is largely unknown. Of these, the most abundant cannabinoid is tetrahydrocannabinol (THC), which is considered responsible for the main psychotropic effects of cannabis. The THC content of plants from a range of sources and strains varies dramatically. With a focus on improved plant breeding and improved growing techniques, the THC content of cannabis has increased dramatically in a short period of time. As one illustrative example, THC content from a typical cannabis cigarette (joint) in the 1960s was 10 mg, whereas estimates suggest that it currently is around 1 g (or 150–200 mg). Cannabidiol (CBD) is another constituent in cannabis that lacks the same psychoactive effects as THC, and instead appears to act as an antagonist of some of the negative psychoactive effects of THC. Data indicate that CBD has a range of therapeutic effects including anticonvulsant, antipsychotic, analgesic, and neuroprotective properties. In addition, there is growing prevalence in the use of synthetic cannabis compounds, which include oral formulations (pill, capsules) of cannabis that are available for prescription (e.g., nabilone, dronabinol), and other nonmedical synthetic cannabinoids products (e.g., K2, spice).

Since the discovery of a cannabinoid receptor within the brain in the late 1980s, researchers have been able to explicate the process by which THC acts on the brain. Currently, there is evidence of three potential cannabinoid receptors, only one of which is located within the brain (the cannabinoid-1 receptor). When THC is inhaled into the body via cannabis smoking, it passes from the lungs into the bloodstream. Once in the blood, THC attaches to cannabinoid receptors, such as the cannabinoid-1 receptor, adding to or reducing the naturally occurring endogenous ligands for these receptors (e.g., anandamide). The cannabinoid-1 receptor, in particular, has been found to mediate both neurochemical and behavioral properties of these cannabinoids, including tolerance. It also is noteworthy that THC and other cannabinoids move rapidly into fat and other bodily tissues but are released relatively slowly from these tissues back into the bloodstream. Eventually, cannabinoids are cleared from the body via urine and fecal matter, although elimination is relatively slow. The detection window in urine depends upon various factors, including drug dose, form of administration, duration/frequency of use, and individual differences in absorption, metabolism, and excretion. Specifically, urinary detection windows (via 11-nor-9-carboxy-THC [THCOOH] metabolite) ranges from several days in infrequent users to months in frequent users.

Acute Intoxication Features

THC can produce a range of acute psychosensory experiences including perceptual distortions (e.g., hallucinogenic properties), relaxation, anxiety, acute paranoia, inhibition, and so on. Periods of intoxication depend on use patterns and potency but tend to last for at least a few hours. The acute effects of THC also impair executive functioning, including working memory, attentional and information processing, and impulsivity, as well as psychomotor performance on complex, demanding tasks. There is a dose-dependent relation between THC and psychomotor and cognitive impairment, with higher doses being associated with more impairment for more demanding tasks. Although cognitive impairment for hours after exposure to THC is a well-replicated phenomenon in laboratory studies, there has been consistent debate about the permanent cognitive effects of THC. Data are mixed as to whether there are long-term effects of THC on impulsivity; however, attention and working memory appear to be largely unaffected. Although decision-making and risk-taking behavior are not consistently affected by acute intoxication, one study found that heavy cannabis users who abstained from cannabis use had impaired decision-making capacities and great risk-taking tendencies. The observed deficits appear to be more clearly documented among chronic, heavy cannabis users, relative to occasional or light users.

Health-Related Problems

One of the foremost negative effects of cannabis use is long-term cognitive impairment. A wealth of research indicates that long-term and heavy cannabis use may cause neuropsychological impairment, which may last even after abstinence. For example, one large study of 1037 individuals followed from birth until age 38 examined the longitudinal association between intelligent quotient (IQ) and cannabis use. Data indicated that (a) individuals who persistently met criteria for regular cannabis use and/or cannabis dependence had significant declines in global IQ a loss of approximately 6 IQ points). These effects were significant after adjusting for other drug dependence, tobacco use, alcohol dependence, schizophrenia, and number of years of education. It is notable that early onset of cannabis use was linked to greater IQ decline (initiation of cannabis use in adolescence vs. adulthood). Persistent cannabis dependence was also associated with decreased likelihood of pursuing education after high school and greater attention/memory problems identified by a collateral informant. Moreover, the effects of cannabis cessation did not fully restore neuropsychological functioning among individuals who initiated cannabis use in adolescence.

There have been a series of important large-scale prospective studies documenting the negative effects of cannabis over time on pulmonary functioning (e.g., Sherrill et al. and Tashkin et al. ). Although the results across investigations are not fully consistent, they converge on the observation that greater duration of cannabis use is related to increased bronchitis symptoms (e.g., coughing, wheezing). Some data also indicate that the combination of smoking tobacco and cannabis relative to tobacco alone is associated with greater odds of respiratory symptoms and increased odds of having chronic obstructive pulmonary disease if more than 50 cannabis cigarettes were used in lifetime. Some data indicate that among certain subpopulations of users (e.g., those using cannabis more frequently), the negative medical effects of this drug are, perhaps, even more clinically noteworthy. For example, frequent cannabis use is associated with an increased risk of severe respiratory illnesses, especially chronic bronchitis ; however, pulmonary effects are not similarly observed among lighter/occasional lifetime users. In addition, there are studies of the relation between cannabis use and cancer. Epidemiological data indicate that heavy cannabis use (smoking at least 50 cannabis cigarettes in lifetime) is associated with a twofold increased risk of developing lung cancer ; however, controlled studies of these cancer-related negative effects of cannabis use are underrepresented in the literature. Overall, more research is needed to understand the effects of inhaled cannabis on the effects of pulmonary health.

It is also noteworthy that some research suggests that cannabis use may be related to poor cardiovascular health, especially following acute cannabis use and among those with coronary artery disease, although the mechanism underlying this risk is not well understood. Cannabis use is also associated with impaired immune system functioning, but these investigations, again, have not been consistently replicated. Upon close inspection of these studies, it becomes clear that some of the inconsistencies of these investigations may be related to problems in the measurement of cannabis use, individual differences in use, or confounded by other health risk behaviors (e.g., tobacco smoking). A similar set of issues is evident for linkages between cannabis use and impaired reproductive effects. Here, nonhuman research suggests that heavier cannabis use is related to impaired reproductive capacity, but controlled evidence among humans is currently lacking.

It should be noted that although most research has focused on elucidating putative negative health consequences or correlates of cannabis use, there has been scientific and clinical interest in possible health benefits of the drug. Namely, cannabis use has been suggested to improve certain disease symptoms (e.g., by decreasing eye pressure, involuntary movement, and perceived pain) and stimulate appetite. Although this body of work is complicated, the strongest evidence of possible health benefits for cannabis use appears to be focused on increasing appetite, decreasing nausea and vomiting, preventing systemic weight loss, and possibly improving pain tolerance.

Social Problems

In addition to the potential risk of a number of negative physical consequences, adverse social consequences related to certain types of cannabis use have been reported (e.g., frequent users, such as those who use on a daily or weekly basis). Lynskey and Hall, for example, reviewed evidence suggesting that cannabis use was a contributing factor to impaired educational attainment, and others have found that cannabis use leads to reduced workplace productivity, as well as impaired judgment within hours after cannabis use (e.g., among airline pilots). It is possible that (1) cannabis use causes poor educational attainment, (2) cannabis use is a consequence of poor educational attainment, (3) both are true, or (4) shared risk factors increase the likelihood of both cannabis use and poor educational performance (e.g., cognitive impairment, attention-deficit/hyperactivity disorder). Although the direct patterning of effects is unknown, a consistent pattern emerges: the greater the amount of use (measured in frequency of use or severity of use), the greater the impairment. The specific mechanism(s) underlying these use-related effects are as yet theoretically and empirically unspecified.

As another example, cannabis use has been linked to fatal traffic accidents and general driving impairment. Cannabis is the most common illicit drug detected among drivers who were tested for drugs. ^, The prevalence of positive cannabis results among drivers who died in a motor vehicle crash have increased from 4.2% in 1999 to 12.2% in 2010 ; this increase was not observed for positive alcohol results. Driving-simulation and on-road studies indicate that reaction time, road tracking, speed, divided attention, and visual processing speed are impaired by THC, although these results have not been consistently documented, perhaps due to variability in methodological approaches. In addition, data convincingly indicate that performance is increasingly impaired as blood concentrations of THC increase, and that the risk associated with cannabis is incrementally increased when considered used with alcohol.

Other work suggests that frequent or more severe cannabis use may lead to using more severe forms of other drugs (e.g., widely publicized, but sometimes controversial, gateway theories of the developmental nature of substance use patterns). One overarching limitation to the vast majority of work linking certain types of cannabis use to social and interpersonal functioning, and even future use of other substances, is that there is a dearth of (controlled) prospective evaluations. Thus conclusions drawn from extant work should be viewed conservatively.

Psychological Problems

There have been a variety of psychological problems associated with cannabis use and its disorder. Perhaps the most well-known psychological problem(s) associated with cannabis use has been psychotic-spectrum disorders. There are numerous lines of empirical evidence that have provided robust evidence of an association between cannabis use and psychotic-spectrum disorders. Indeed, case reports of cannabis use have documented that such drug use can precede the onset of certain psychotic-spectrum disorders such as schizophrenia at higher rates than expected by chance of psychosis among regular cannabis users. Although the directional nature of the cannabis-psychotic-spectrum problem association has been the subject of consistent intellectual debate (e.g., Hambrecht et al. ), one position has been that the use of cannabis may actually increase the risk of psychotic-spectrum disorders. Consistent with this cannabis-to-psychotic symptoms/disorders perspective, the acute effects of cannabis use have been found to contribute to the elicitation of psychotic episodes and exacerbations of such symptoms among previously afflicted persons (e.g., the recurrence of psychotic symptoms ). Other research has found that intravenous THC administered to antipsychotic-treated patients with schizophrenia and nonpsychiatric controls exacerbated positive schizophrenic symptoms in the patient sample and induced positive symptoms in controls. Neuroimaging studies have also found similarities between neural networks impaired by cannabis use and those known to be implicated in the etiology of schizophrenia (see Loeber et al. for a review). Finally, in a meta-analytic review of the existing empirical literature, Semple and colleagues concluded that the early use of cannabis increased the risk of schizophrenia or a schizophrenia-like psychotic illness by approximately threefold. Although a model indicating that cannabis may lead to psychotic-spectrum disorders provides only one possible way in which these factors may be related, it documents the importance of understanding cannabis in the context of severe mental illness. It is worth noting that the scientific literature also indicates that cannabidiol (CBD) may attenuate the effects of THC on psychosis symptoms ^; in turn CBD may have beneficial antipsychotic effects. This area of study requires further attention.

In another area of research, scientific activity has been focused on addressing the relationship between cannabis and depressive symptoms or problems. The interest in this line of inquiry appears to have been historically fueled by the clinical observation that regular (i.e., on a daily or weekly basis) cannabis users often reported a lack of motivation for completing day-to-day activities (e.g., going to school). The depression-cannabis literature has sometimes identified statistically significant relations between cannabis use and depressive symptoms and disorders. However, the most recent work in this domain has indicated that the strength of such cannabis-depressive associations may be relatively weak, and markedly attenuated, or even nonexistent, after adjusting for common variables such as gender. As one illustrative example, Brook and colleagues completed a study that involved a two-time (1- to 2-year interval) prospective study of Colombian adolescents ( n = 2226; 48.2% female) who were 12- to 17-years-old. Findings indicated that cannabis use in early adolescence did not significantly predict later depressive symptoms (time 2) after controlling for distress and interpersonal functioning in earlier adolescence (time 1). However, among a large sample of Australian adolescents ages 14–15 ( n = 1601) who were followed for 7 years, the prevalence of depression and anxiety increased as the frequency of cannabis use increased. This effect was observed particularly in females, relative to males. This work, when considered in the context of the psychotic-spectrum research, highlights that cannabis should not be considered to have the same types of linkages with all forms of mental illness.

Another area of research has begun to address the relations between cannabis use and anxiety symptoms and disorders. This work was initially stimulated by the observation that cannabis use may acutely promote heightened levels of anxiety symptoms and elicit panic attacks under certain conditions or in certain individuals. For example, when a person is intoxicated from using cannabis, they may experience acute paranoia, escalating anxiety symptoms, and perhaps a panic attack. This type of experience makes intuitive sense in that cannabis can elicit a wide range of acute sensory-oriented experiences and distortions that may be perceived as out of the person’s control and could be interpreted as threatening by some persons who are fearful of such internal stimuli and experiences. Some evidence appears consistent with this perspective. For example, Hathaway found that among weekly users of cannabis ( n = 104), approximately 40% reported having had at least one panic attack related to such use. These prevalence rates are noteworthy in light of lifetime rates of panic attacks among the general population of approximately 5%–8%. Another study found that, after covarying cigarettes per day, alcohol use, and negative affectivity, the interaction between cannabis use and anxiety sensitivity (fear of anxiety and related internal sensations) is related to increased levels of anxiety symptoms among cannabis users who also use tobacco. Thus, certain individual differences such as anxiety sensitivity may be important to consider in understanding the linkages between cannabis use and anxiety states and disorders.

Another study involving a representative sample ( n = 4745) found that a lifetime history of marijuana dependence, but not use or abuse, was related to an increased risk of panic attacks after covarying the effects of polysubstance use, alcohol abuse, and demographic variables. In a more recent investigation, Zvolensky and colleagues prospectively evaluated marijuana use, abuse, and dependence in relation to the onset of panic attacks and panic disorder. Participants at the start of the study were adolescents ( n = 1709) with a mean age of 16.6 years (SD = 1.2; time 1) and were reassessed 1 year later (time 2) and then again as young adults (time 3; mean age = 24.2 years, SD = 0.6). Results indicated that adolescent-onset marijuana use and dependence were significantly prospectively associated with increased odds for the development of panic attacks and panic disorder. However, marijuana use or dependence was not incrementally associated with the development of panic after controlling for daily cigarette smoking. There is also growing research in the area of cannabis and posttraumatic stress disorder (PTSD). For example, nationally representative data indicate that PTSD is associated with increased likelihood of using cannabis in the past year, which was significant after adjusting for cooccurring anxiety and depressive disorders. In addition, among a sample of military veterans exposed to combat who were enrolled in a residential treatment program for PTSD, those who had a cannabis use disorder relative to those without had less change in PTSD symptom severity posttreatment. Collectively, these recent findings underscore the importance of considering the role of cannabis use with regard to understanding anxiety vulnerability.

It is worth noting that the anxiety-cannabis link may be driven by the effects of THC relative to CBD. Indeed, a review of preclinical and clinical studies indicated that CBD is associated with anxiolytic effects relevant to various psychological disorders (PTSD, generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, social anxiety disorder). This effect was consistently observed in 29 of 33 pretrials and 7 of 10 clinical trials.