Editor’s Note: The following article is very dense in technical information. I have tried my best to simplify it for a layman’s understanding, but if you just want to read the conclusion, skip to the end.

Americans are using Cannabis with increasing frequency to treat a wide variety of medical disorders. Despite the growth of medical Cannabis use in the United States, many still have concerns about certain issues of Cannabis safety. Cannabis has been scientifically shown to be less dangerous than alcohol and pharmaceutical drugs. This is largely due to the fact that Cannabis has significantly lower physical toxicity than other drugs, and does not promote harmful psychological effects such as destructive behavior and addictive tendencies that other common drugs might promote.

However, there is one area of safety when it comes to Cannabis that scientific study has not revealed to be safer than traditional drugs: risk of psychosis. Although very rare, some people have experienced prolonged psychotic episodes after Cannabis use. In a majority of these cases, the patients affected are typically adolescents with a family history of schizophrenia. The evidence seems to suggest that the psychoactive component of Cannabis, THC, can trigger psychosis in certain individuals, but another component of Cannabis, CBD, can reverse psychosis.

So, without further ado, here is our detailed and annotated examination of the evidence relevant to the relationship between Cannabis and psychosis:

Large et al. performed a meta-data analysis on many studies in 2011, and found an inverse correlation between adolescent use of Cannabis and the age at onset of psychotic disorders (mainly schizophrenia). In other words, in adolescents prone to psychosis, Cannabis seemed to accelerate the onset of said psychosis.

The authors noted that much of the raw scientific data was derived from various studies that did not indicate whether Cannabis use predated the onset of psychosis, making the link correlational rather than causal. This means that the authors cannot be sure if the psychosis increases the likelihood of Cannabis use, or if the Cannabis increases the likelihood of psychosis, which is an important distinction.

Large M, Sharma S, Compton MT, Slade T, Nielssen 0 (June 2011). "Cannabis use and earlier onset of psychosis: a systematic meta-analysis". Arch. Gen. Psychiatry 68 (6): 555-61. doi:10.1001/archgenpsychiatry2011.5. PMID 21300939

According to Arseneault’s 2004 study, although Cannabis use is correlated with an earlier onset of psychosis in adolescents, they hypothesized that this phenomenon tends to occur in already at-risk groups, such as individuals with a family history of psychosis, or symptoms of psychosis predating Cannabis use.

Unfortunately, our knowledge of how psychosis develops in the brain is limited. Additionally, our knowledge of how cannabinoid receptors develop and the role they play in psychosis is even more limited. This makes Arseneault’s hypothesis difficult to prove. Despite how difficult it is to prove this hypothesis, the literature indicates a pervasive acceptance of the idea that Cannabis use can exacerbate at-risk (of psychosis) youths.

The authors’ language best describes the exact nature of the relationship: “Cannabis use appears to be neither a sufficient nor a necessary cause for psychosis. It is a component cause, part of a complex constellation of factors leading to psychosis.”

Arseneault L, Cannon M, Witton J, Murray RM (2004). "Causal association between Cannabis and psychosis: examination of the evidence. The British Journal of Psychiatry 184(2): 110-117. doi:10.1192/bjp.184.2.110. PMID 14754822

Caspi et al’s 2005 study correlated the early onset of psychosis in Cannabis users with a specific polymorphism in the catecholamine o-methyltransferase gene, specifically the Valine-158 allele was the most likely to correlated with psychotic symptoms.

Editor’s Note: For those not familiar with genetics lingo, a polymorphism is a change in a part of a gene that differs from the general population. Single nucleotide polymorphisms (abbreviated as SNPs) are changes in a single base-pair (A-T, or G-C), and are some of the most common examples of polymorphisms.

This indicates that those who are at risk of psychosis may potentially learn about it through genetic testing. The paper even goes so far as to state that Cannabis users with a homozygous Methionine-158 genotype (in other words, a normal genotype) will have no adverse effects from Cannabis consumption.

A later study conducted by Zammit et al in 2007 concluded that Cannabis use had no modulatory effects on psychotic symptoms nor did it interplay with either valine or methionine allele catecholamine o- methyltransferase, so the evidence is a little mixed on this one.

Caspi A, Moffitt TE, Cannon M, McClayJ, Murray R, Harrington H, Taylor A, Arseneault L, Williams B, Braithwaite A, Poulton R, Craig IW (2005). "Moderation of the Effect of Adolescent-Onset Cannabis Use on Adult Psychosis by a Functional Polymorphism in the Catechol-O-Methyltransferase Gene: Longitudinal Evidence of a Gene X Environment Interaction". Biological Psychiatry 57 (10): 1117-27. doi:10.1016/j.biopsych.2005.01.026.PMID 15866551

The debate over whether Cannabis has a causal connection to schizophrenic onset in adolescents has been going on in the scientific community for some time, and has produced a wealth of literature. More importantly, the debate has resulted in empirical evidence on the subject. For example, Henquet’s 2005 study concludes that, “Cannabis use moderately increases the risk of psychotic symptoms in young people but has a much stronger effect in those with evidence of [a] predisposition for psychosis.”

Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Wittchen HU, van OsJ (2005)."Prospective cohort study of Cannabis use, predisposition for psychosis, and psychotic symptoms in young people". BMJ 330 (7481): 11-0. doi:10.1136/ bmj.38267.664086.63.PMC 539839. PMID 15574485

Conversely, Moore’s 2007 longitudinal study concluded with a very different tone: “The evidence is consistent with the view that Cannabis increases risk of psychotic outcomes independently of confounding and transient intoxication effects, although evidence for affective outcomes is less strong. The uncertainty about whether Cannabis causes psychosis is unlikely to be resolved by further longitudinal studies such as those reviewed here. However, we conclude that there is now sufficient evidence to warn young people that using Cannabis could increase their risk of developing psychotic illness later in life”

Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, Lewis G (2007). "Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review". The Lancet 370 (9584): 319-28. doi:10.1016lSOl40-6736 (07)61162-3. PMID 17662880

Zuardi et al’s 2006 study investigated CBD’s anti-psychotic nature, and found that its effects are broadly anxiolytic and antipsychotic. While it might seem that CBD serves only as an antagonist to THC’s psychosis-inducing effects, CBD is able to reverse anxiety in subjects who have not used cannabinoids before. This strongly suggests that CBD’s antipsychotic effects are independent of THC.

In an experiment, mice were induced into psychosis by amphetamines and ketamines, which affect the dopaminergic neurons (D2) and glutaminergic neurons (NMDA), respectively. The psychoses triggered by both drugs were reversed by CBD administration. This indicates that CBD’s antipsychotic effects may have a broader pharmacological basis than just a few receptors. This is consistent with Campos et al’s 2012 theory that the TRVP1 receptor (of which CBD is an agonist) is responsible for contributing to CBD’s antipsychotic effects. Additionally, Zuardi’s team found that CBD was both a safe and efficient alternative treatment for schizophrenia.

Editor’s Note: TRVP1 is colloquially referred to as the “capsaicin receptor” and is associated with the sensation of heat from spicy foods. Recently, I also learned that capsaicin can be used to reduce the effects cannabis hyperemesis syndrome, suggesting that this receptor can play multiple roles in regards to cannabis.

Zuardi AW, Crippa JA, HallakJE, Moreira FA, Guimaraes FS (April 2006)."Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug". Braz. J. Med. Biol. Res. (Review) 39 (4): 421-9. doi:10.1590/SOl00-879X2006000400001.PMID 16612464

Long et al’s 2005 study investigated CBD’s ability to reverse Dizocilpine-induced psychotic symptoms in mice. Dizocilpine, also known as MK-801, is an NMDA agonist, and can be used in animals to experimentally induce the symptoms of schizophrenia.

CBD did reverse the effects of Dizocilpine, but when it was co-administered with capsazepine, a TRVP1 antagonist, CBD’s effects disappeared. This evidence strongly suggests TRVP1’s role in CBD-treatable psychosis, and potentially its interrelation to several other neural systems.

Long, L. E.; Malone, D. T.; Taylor, D. A. (2005). "Cannabidiol Reverses MK-801-lnduced Disruption of Prepulse Inhibition in Mice". Neuropsychopharmacology 31 (4): 795-803.doi:10.1038/sj.npp.1300838. PMID 16052245

Leweke et al’s 2012 study performed a clinical trial with schizophrenic patients comparing the efficacy of CBD against amisulpride. The study found that CBD was equally effective as amisulpride at treating psychotic symptoms of schizophrenia, but with a much reduced profile of side-effects. These findings indicate that proper use or drug-assisted optimization of the transmission of endocannabinoids can preclude harsher dopamine antagonist drug therapy.

With THC’s rare but significant tendency to induce psychosis in adolescents, the question arises: Why does THC triggering the CB1 receptor cause psychosis, while anandamide triggering the same CBl receptor seem to reverse psychosis?

One factor to consider is that the body’s natural endocannabinoid system. When THC is ingested and enters the brain, the CB1 receptors are triggered randomly and uniformly. This is not a normal, organized stimulus from the brain, and causes a degree of chaos and interference. CBD, on the other hand, inhibits the breakdown of endocannabinoids, which assists the body in transmitting normal signals. The natural feedback loop in the endocannabinoid system can prevent overstimulation of CB receptors, something that does not occur when ingesting THC. THC flows through the blood and cerebrospinal fluid, and will not target specific synapses, but rather target them all. These factors may reconcile the seemingly paradoxical relation between psychosis, CB1 receptors, and THC and CBD’s apparently opposite effects on the same receptor.

Leweke, FM; Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, KlosterkotterJ, Hellmich M and Koethe D. (2012). "Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia". Translational Psychiatry 2 (3): e94-.doi:10.1038ltp.2012.15. PMC 3316151. PMID 22832859

Due to the complex relationship between Cannabis and psychosis, we have provided a brief summary of our research below:

A summary of the findings relating THC and psychosis: Large’s study indicates a correlation between psychosis and adolescent Cannabis use. Arseneault’s study found a correlation as well, but described Cannabis use as neither necessary nor sufficient to cause psychosis, merely a component cause. Caspi’s study found a strong correlation between adolescents with Cannabis-induced psychosis and a specific genetic mutation, and postulates that genetic testing may indicate who is susceptible to Cannabis-induced psychosis in the general population. Henquet’s study found that most of the ability of Cannabis to induce psychosis was found in patients with a predisposition to psychosis. Moore performed longitudinal studies and found that adolescent Cannabis use correlated with higher probability of psychosis later in life.

A summary of the findings relating CBD and psychosis: Zuardi’s study found that CBD was able to reverse psychosis caused by amphetamines and ketamines. Long’s study found that CBD reversed psychosis brought on by dissociative drug MK-801. Leweke’s study found found that CBD was as effective at treating schizophrenia as the FDA-approved drug amisulpride with a much reduced profile of side-effects.

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