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Reefer Madness? The Truth Behind Medical Marijuana

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Adverse Medical Effects of Cannabis and THC

The extant scientific literature by and large reflects the harmful effects of inhaled cannabis smoke.  In what follows we review some of these reports.

Respiratory

Many of the same mutagens and carcinogens found in tobacco smoke are found in marijuana smoke as well.11 Marijuana smoking has been shown to decrease pulmonary function, produce chronic cough, airway inflammation and abnormal cell growth that may antecede the onset of cancer.12 However, the International Agency for Research on Cancer found the epidemiologic data inconclusive as to the increased risk of cancer from cannabis use versus that of tobacco smokers.13 In contrast to tobacco, marijuana-smoking lung injury is not reversed on abstinence.14

Immunologic

In humans, an increase in mortality of HIV-positive cannabis users has been observed.15

Cardiovascular

Direct stimulation of the cardiac pacemaker by marijuana leads to an increase in heart rate making THC unsafe in cardiac patients.14

Liver

 Daily cannabis use is a risk factor for fibrosis progression via steatogenic effects, thus, daily cannabis use in patients with liver disease is contraindicated.16 Cannabis users metabolize and activate or inactivate drugs more slowly than normal17,  potentiating the deleterious effects of the drugs.

Endocrine and reproductive systems

In preclinical studies, cannabinoids have shown inhibitory effects on pituitary luteinizing hormone, prolactin, growth hormone, and thyroid stimulating hormone with little effect on follicle-stimulating hormone.18, 19 Marijuana can disrupt female reproductive health.20 Women who smoke marijuana during pregnancy are more likely to have low birth weight infants possibly from a shorter gestation.21 The effects of maternal marijuana use on infant development have not been systematically studied. However, the lipid solubility of THC allows for rapid transit in breast milk, where it has been shown to accumulate and eventually pass to the newborn.22

Carcinogenesis

Cannabis use increases the incidence of testicular germ cell tumors – TGCT.23 Theauthors observed a 70% increased risk of TGCT associated with current marijuana use, and the risk was particularly elevated for current use that was at least weekly or that began in adolescence. These associations were independent of known TGCT risk factors.

 

Effects of Smoked Cannabis on Mental Health

Smoking cannabis has a number of acute and chronic pathogenic effects on human mental health. 3, 24 Direct causal effects of chronic use are difficult to scientifically establish because the condition cannot be randomly assigned or manipulated experimentally for ethical reasons.  Nevertheless, prospective population studies indicate that early cannabis use frequently serves as a prelude (or “gateway”) to other illicit drug use. Despite occasional non-confirmatory results, the “gateway sequence” is the most common pattern in the sequential progression in drug use25, where marijuana use often is the initial step leading towards more powerful and more harmful drugs.

The mental effects of smoked cannabis include mental slowness, “relaxation”, tiredness, euphoria, and some users report anxiety and paranoia. Acute negative effects on cognition and performance, limited to periods of intoxication, have been all well-documented.26,27 Long-term effects of cannabis use on cognitive performance involve subtle and selective impairments of specific higher cognitive functions 27, 28 including an impaired ability to focus attention and filter out irrelevant information, which is progressive with the cumulative duration of exposure to cannabis. 29 These effects of chronic use recover only partially in ex-cannabis users, but the past duration of cannabis use continued to have an adverse effect on the ability to effectively reject complex irrelevant information. 30

Remodeling of brain reward circuits (cannabis addiction)

Active ingredients in cannabis, THC in particular, affect neurophysiological and behavioral systems in ways similar to addictive drugs.31 Cannabis use is associated with reinforcing pleasurable feelings of reward and euphoria either through direct effects on CB1 receptors expressed in  N. Accumbens or through collateral circuits (including endogenous opiate receptors) with similar effects on the reward pathway in the brain.31 In most cases, addictive drugs “reset” the threshold for stimulation of the  reward pathway at a higher level, where only supraphysiological stimulation by drugs can generate the desired feeling of reward. This “hijacking” of the reward pathway reduces the motivational power of natural rewards (e.g. food, opportunity to mate, relationships, etc) and thus reshapes normal motivational priorities. With repeated stimulation of this pathway, cannabis use induces neural plasticity and alters reward-based learning32, all leading to phenomenological and behavioral features typical of addiction. Suggestive of its high addictiveness, cannabis is the most commonly used illicit drug in the US and rate of its use continues to rise. 4, 5, 6

Cannabis use and well-being

  Proponents of cannabis use argue that smoking cannabis provides relaxation and pleasure, enhances the sense of well being, contributes to stress-relief, and helps to deal with hard reality. Of course, any enhancement of well being of a mentally healthy person through use of a psychoactive substance is some sense an oxymoron. Furthermore, cannabis use decreases cortical dopamine33 which plays a major role in higher cognitive functions, working memory, executive function, etc.  Hence, the “relaxed” feeling most cannabis users report as a desirable acute effect, in all likelihood reflects cognitive dulling (“amotivational syndrome”) caused by decreases in cortical dopamine.  In other words, the weight of evidence indicates  that cannabis creates cognitive dulling rather than reduction in anxiety, indifference rather than relaxation,  and amotivation rather than inner peace, all closer to psychopathology than to well being.

Cannabis use and work performance

There is an ongoing debate whether cannabis use interferes with people’s ability to work, relate to others, and/or live a normal life. Recent research clearly shows that any work that requires cognitive involvement and decision making is affected by cannabis use. 27,28,29,34  In a study of young, otherwise mentally and physically healthy cannabis users, Wadsworth et al28 report an association between cannabis use and impairment in cognitive function and mood but not with workplace errors (although there was an association with lower alertness and slower response organization). Users experienced working memory problems at the start, and psychomotor slowing and poorer episodic recall at the end of the work week.  This highlights the importance of the timing of testing within the context and routine of everyday life.  In a separate study of the same sample, cannabis use had a significant negative impact on safety at work (such as self-reported accidents), road traffic accidents, and minor injuries.34 Those who had higher levels of other risk factors associated with accidents and who also used cannabis were more likely to report an accident in the previous year. Thus, it is possible that cannabis-related effects were linked to an amplification of other risk factors associated with accidents and injuries.34

Cannabis use and motor vehicle accidents

In a recent state-of-the art meta analysis involving 9 independent studies and close to 50000 people, researchers have found that drivers who had used marijuana within three hours of beginning to drive had nearly double the risk of  causing a collision, especially those that were fatal, in comparison to sober drivers35.  Given its impeccable methodology,  this study is close to being a final answer to the issue of (un) safe driving under the influence of  cannabis.

Cannabis use and mental health in the general population

According to the study36 of 18500 cannabis smokers published by Statistics Netherlands in October of 2010, cannabis users suffer mental health problems twice as often as nonusers. The relative risk of mental problems was doubled in male and female cannabis users (20% and 28%, respectively) compared to male and female nonusers (10% and 14%, respectively). Most common mental health issues reported by cannabis users were anxiety, melancholy, sadness, and impatience. In contrast, physical health of users and nonusers barely differed.  Though technically illegal, the Netherlands decriminalized the consumption and possession of less than 5 grams (0.18 ounces) of cannabis in 1976 under an official "tolerance" policy.

CNS effects of chronic cannabis use

Recently, specific pathogenic effects of cannabis on human brain tissue have been documented. Using high-resolution (3-T) structural magnetic resonance imaging (MRI), Yucel et al37 determined long-term heavy cannabis use is associated with gross anatomical abnormalities in 2 cannabinoid receptor–rich regions of the brain, the hippocampus and the amygdala. Subects were healthy males with long-term (more than 10 years) and heavy (more than 5 joints daily) cannabis use with no history of poly-drug use or neurologic/ mental disorders. Cannabis users had bilaterally and significantly reduced hippocampal and amygdala volumes, with changes greater in the hippocampus.  In fact, left hemisphere hippocampal volume was inversely associated with cumulative exposure to cannabis during the previous 10 years as well as with subthreshold positive psychotic symptoms. Positive psychosis symptom scores were also associated with cumulative exposure to cannabis. 

 

Cannabis Use and the Risk of Schizophrenia, Psychosis, and Affective Disorders

Cannabis use is among the environmental factors associated with increased risk and worsened prognosis of schizophrenia and some data suggest a causal effect.3 Cannabis use also is associated with more prevalent expressions of a wider psychosis phenotype. Isolated psychotic symptoms have reported prevalences of 5–15% among chronic cannabis users.2,3 Although causality remains difficult to infer from observational studies, the weight of the evidence appears to favor a causal contribution from cannabis use for the development of Schizophrenia and psychosis.2

Recent meta-analyses lend further support to the hypothesis that cannabis use causally contributes to the increased risk of development of schizophrenia.  In a comprehensive and systematic meta-analysis, Moore et al38 determined whether cannabis use contributes causally to the development of nonsubstance psychiatric illness, such as schizophrenia and affective disorders. The study was designed to address as much as possible two of the most important methodological problems in studying the relation between cannabis use and psychosis: i) the potential for reverse causality (where psychosis causes cannabis use and not vice versa) and ii) the transitory intoxication effects (that is misinterpreted as psychosis as the false positive error). The results indicated that the risk of psychosis is increased by roughly 40% (pooled adjusted OR: 1.41) in cannabis users.  The results were not as impressive for affective disorders. Within the users, a dose-response effect was observed with the risk more than doubled (OR =2.1) in the most frequent users. For cannabis and psychosis, there was evidence of confounding effects, but the associations persisted in almost all studies, even after adjustment for comprehensive lists of variables. The authors concluded that “there is now sufficient evidence to warn young people that using cannabis could increase their risk of developing a psychotic illness later in life” (page  319).  Since the publication of this study, British government has reversed its stance on the issue from initially not supporting the connection.

            In a meta analysis of  peer-reviewed publications in English reporting age at onset of psychotic illness in substance using and non–substance using groups Large et al39 found an association between cannabis use and earlier onset of psychosis (the effect was not seen with alcohol). The authors suggest the need for renewed warnings about the potentially harmful effects of cannabis. Similar findings are reported by other authors.40

Genetic Moderation of Cannabis Effect on Psychosis

One of the most puzzling aspects of cannabis-associated psychosis is that schizophrenia is not rising in incidence to reflect prevalent cannabis use. The likely answer is that there is variation in individual sensitivity to the psychosis-inducing effects of cannabis. In other words, individuals who have a greater biological vulnerability to psychosis are more likely to develop psychotic experiences when exposed to cannabis.  As an example, the COMT Val/Val genotype is a risk factor for schizophrenia in the general population41 presumably by providing a pathological substrate, such as low dopamine in the frontal cortex 41 and high mesolimbic dopamine.42 Both conditions are believed to contribute to schizophrenia symptoms. Carriers of the COMT Val/Val genotype have low cortical dopamine but do not automatically develop schizophrenia. Rather, this genotype is considered to be a matter of individual variability in the level of cortical dopamine. Hovever, carriers of this genotype, who were also chronic cannabis users as adolescents, have a dramatically (up to 10 times) higher risk of psychosis43 compared to adult-onset cannabis users with the same genotype.  Cannabis use is reported to further decrease cortical33 and increase mesolimbic dopamine44 possibly amplifying the preexisting genetic dopamine dysfunction. If occurring during the sensitive developmental period of adolescence, such augmentation may synergistically facilitate the onset of psychosis.  Similar interactive synergism was recently described for the AKT1 gene and cannabis45 possibly through a mechanism of cannabinoid-regulated AKT1/GSK-3 signaling downstream of the dopamine D2 receptor.

Finally, recent study by Welch et al46 was the first  longitudinal study to demonstrate an association between thalamic volume loss and exposure to cannabis in people currently unaffected by Schizophrenia but with increased  risk for the illness due to positive family history. As Welch et al46 conclude,  this finding may be important in understanding the link between cannabis exposure and the subsequent development of Schizophrenia.

 

Conclusion

Empirical and clinical studies reviewed here clearly demonstrate pathological effects of cannabis smoking on physical and especially mental health as well as its interference with social and occupational functioning. We did not find a single methodologically sound study to suggest that the benefits of smoking cannabis outweigh the associated risks.  These negative data far outweigh documented benefits for a limited set of medical indications for which safe and effective alternative treatments are readily available. However, advocacy groups are pursuing legalization or medical use of smoked cannabis, largely ignoring pills containing extracted THC and other cannabinoids.  It appears therefore that it is not the benefit of active cannabis ingredients, but the route of administration, a wider set of indications, and the ritual of use that’s being advocated.  Based on the empirical and clinical evidence reviewed here, it seems safe to conclude that, if there is any medical role for cannabinoid drugs, it lies with chemically modified extracts, not with unprocessed cannabis plant.

We agree that public health policies should be driven primarily by medical issues, while legal policies take into account not only medical issues but a number of other issues as well (e.g., crime, revenue, resources, etc).  Accordingly, some argue that societal policies for MJ use should be health related, not legal.  This would mean education of users to increase their awareness of the risks associated with use, including addiction.  Recall, however, that  health policies implemented for tobacco (such as health “warnings” on cigarette packages) were largely ineffective until legal policies were implemented (such as banning of smoking in public places, etc).  Most people first use MJ at the age 12-14 years.   “Hazard to health” labels on legalized cannabis products  are unlikely to deter adolescents from using it – as at this age health concerns are not their priority (“invincible youth”).  Once addicted, however, no “hazard to health” labels would be effective for adult users, as shown in the case of tobacco and cigarette smoking. 

Recent push to promote legalization of MJ seems archaic in the context of current (successful) campaign by the society to eradicate tobacco smoking.  Would medical cannabis users be allowed to administer their  medicine (i.e., smoke cannabis)  in restaurants, movie theaters, public places, hospitals?  Banning medical MJ use in public places would impinge on the basic right for medical treatments.  Second hand cannabis smoke may be the reason for banning its use in public places. However, as anxiety is one of the indications for medical MJ,  and no one can predict anxiety attacks,  this provides excuse to users to smoke cannabis anywhere they want.

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