The Cannabis-Psychosis Link

By Marie-Josee Lynch, MD, Rachel A. Rabin, MSc, and Tony P. George, MD, FRCPC | January 12, 2012

Dr Lynch is a PGY-3 Resident in Psychiatry at the University of Toronto; Ms Rabin is a PhD student in the Institute of Medical Sciences at the University of Toronto; Dr George is Professor and Chair in Addiction Psychiatry at the University of Toronto, and Clinical Director of the Schizophrenia Program at the Centre for Addiction and Mental Health in Toronto. Dr George reports that in the past 2 years, he has received grant support from Pfizer; has been a speaker for Astra Zeneca, Eli Lilly, and Pfizer; and served as a consultant to Abbott, Novartis, Pfizer, and Sepracor. Dr Lynch and Ms Rabin have no conflicts of interest concerning the subject matter of this article.
Acknowledgments—This article was supported in part by the Canada Foundation for Innovation (#16014), the Chair in Addiction Psychiatry from the University of Toronto, and by grants from the Canadian Institute for Health Research (MOP#245931, to T.P.G.) and the Ontario Mental Health Foundation to Dr George. Ms Rabin is supported by Studentships from the Canadian Institutes of Health Research and an Ontario Graduate Scholarship.

Marijuana doesn’t count, does it?” Clinicians are familiar with this common reply when screening for drug use. Cannabis—the most common illicit substance—has managed to exempt itself from the hazardous reputation held by other illicit drugs.¹ As mental health practitioners, it is our duty to educate our patients about the potential harms and consequences of cannabis use. This important task is complicated by the disagreement and uncertainty surrounding the nature of the interaction between cannabis and psychotic disorders.

More than 16 million Americans use cannabis on a regular basis, typically beginning in adolescence. Notably, it is estimated that approximately 4% of the population have a diagnosis of either cannabis abuse or dependence.¹ A history of cannabis misuse is even more common in patients who are schizophrenic than in the general population; 25% of patients with schizophrenia have a comorbid cannabis use disorder. Cannabis use disorders are especially common in younger and first-episode patient samples and in samples with high proportions of males.²

Neurobiology

Marijuana contains more than 400 chemical compounds, including over 60 cannabinoids that contribute to its psychopharmacological effects. The primary psychoactive constituent of cannabis is delta-9-tetrahydrocannabinol (THC). Other plant cannabinoids include delta-8-tetrahydrocannabinol; cannabinol; and cannabidiol (CBD); CBD is the second major psychoactive constituent of cannabis.³ The ratios of these and other cannabinoids vary enormously in preparations of cannabis, and little information exists about the concentration of each of the particular cannabinoids in commonly used cannabis products. Concerns have been expressed regarding the large increase in the potency of cannabis and the surrounding health implications. In the 1960s, the THC content was thought to be in the range of 1% to 3%; today it can reach up to 20%.⁴

The endogenous cannabinoid system consists of 2 types of G-protein-coupled receptors: cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors. CB1 receptors are the most abundant in the brain, while CB2 receptors predominate on immune cells. CB1 receptors are highly concentrated in brain regions implicated in the putative neural circuitry of psychosis and cognitive function. These include the hippocampus, prefrontal cortex, anterior cingulate, basal ganglia, cerebellum, and cortex, with lower levels present in the thalamus, hypothalamus, and amygdala. Activation of CB1 receptors mediates the behavioral and physiological effects of both endogenous and exogenous cannabinoids in the brain.⁴

An important role of the CB1 receptor is to modulate neurotransmitter release in a manner that maintains homeostasis by preventing excessive neuronal activity in the CNS.⁵ CB1 receptors are localized on presynaptic neuron terminals on both inhibitory and excitatory neurons, yet they predominate on γ-aminobutyric acid interneurons.⁶ It is the inhibitory neurons that are thought to mediate most of the effects of cannabinoids. In addition, the action of cannabinoids includes interactions, albeit indirectly, with the dopamine(Drug information on dopamine)rgic system.

THC is a partial agonist at the CB1 receptors, where it has modest affinity and low intrinsic activity. In contrast, CBD shows very little affinity for CB1 receptors. Moreover, the precise molecular mechanism of action of CBD remains unclear. The main endocannabinoids are anandamide and 2-arachidonylglycerol. In contrast to classic neurotransmitters, endocannabinoids can function as retrograde synaptic messengers—they are released from postsynaptic neurons and travel backward across synapses, activating CB1 on presynaptic axons and suppressing neurotransmitter release.

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by Francine Eisner | March 08, 2012 9:17 PM EST

I disagree with the previous commentators. It seems that there is a substantial amount of evidence. Furthermore, Dr. Newman should provide a reference for his statement. Just stating, "The DEA says"is unprofessional.
>we must say the risk is low for the movement into schizophrenia as a result of Cannibis [sp].

No, "we must say" nothing of the kind. I'm truly astounded that a medical professional would make such a remark. One can call for additional studies; that would be the appropriate course of action. Psychotropic drugs, whether recreational or prescribed, create risk because they alter brain chemistry. It is clear that this is the case with cannabis; what is not clear is how great the the health risk. Worst of all, those who would use cannabis as a recreational drug use statements employ the comments below as "proof" that they are doing nothing harmful to themselves. Teenagers in particular are still undergoing brain development, and the age group of 15-25 is when schizophrenia is most likely to present. If the DEGREE of risk of cannabis use seems unclear to the two of you, it still should be in the category of "not a good idea."

Francine Eisner, RN

by Lawrence Welkowitz | March 08, 2012 5:11 PM EST

I agree with Dr. Newman's comment that not enough is known to make such definitive statements. The authors call for educating patients about cannabis, but reading their own review makes me think, "educate them by saying what?" With conflicting studies, and little conclusive evidence about harm, I'm not sure what exactly the authors would like clinicians to say.

Just another opinion,

Larry Welkowitz, Ph.D.

by Chevies Newman | February 19, 2012 1:06 AM EST

Interesting conversation, I'm not convinced that telling people that they are at increased risk of schizophrenia by the consumption of Cannibis. According to risk analysis from the DEA, the substance has less risk of health problems than both alcohol and tobacco. Do those who develop schizophrenia have prodromal symptoms relieved by Cannibis at the Gamma benzo receptor? Is there a socioeconomic downward drift allowing these young patients greater access to the drug? Does the rush of dopamine into the Mesolimbic pathway exacerbate a predisposition which pushes some into a diagnosis of severe mental illness that would otherwise not occur.

With widespread use and no conclusive evidence, we must say the risk is low for the movement into schizophrenia as a result of Cannibis. Recurrent bronchitis, underlying depression and self treatment with Cannibis overuse, poor academics among younger starters; these are the best approaches. The scare tactic of a psychotic disorder in a healthy person is so uncommon, even good research must admit weaknesses.

In short, too many confounding variables exist to make a definitive statement. One runs the risk of sounding non credible to the user and making them feel unaccepted as people. I would say treat underlying mood dysfunction, encourage non combustion of plant material via new technology, and use your skills in psychopharmacology to have them use less. It's not Crack or Meth, most can improve use if desired.

Just an opinion,

Chevies Newman, M.D.

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