The marijuana minefield: medical use also poses complications

Of the marijuana-derived cannabinoids, delta 9-tetrahydrocannabinol (THC) and cannabidiol seem to be the most important. In response to consumer demand, selective plant breeding has resulted in an increase in THC content, both in absolute terms and relative to cannabidiol, Donald Goff (Nathan Kline Institute, New York University School of Medicine, USA) told the meeting.

These developments may be contributing to the increased harm associated with use of the drug: the cannabis of today is not the same as that of twenty years ago.

The cannabis of today is not the same as twenty years ago.

We have also seen the development of synthetic cannabinoids with high affinity for the cannabis-1 (CB-1) receptor which are typically sprayed onto herbal material and sold on the street under names such as “Spice” and “K2”. In contrast to plant derived cannabinoids, synthetic CB-1 compounds act as full rather than partial agonists and have long half lives, resulting in the potential for both rapid desensitization and longer exposures.

The misuse of synthetic cannabinoids  is resulting in a large increase in toxicity-related presentations to the emergency departments of major US cities. Professor Goff cited figures of 20-30 cases a day at one New York Hospital.

As became clear in later presentations, this does not mean synthetic cannabinoids have no therapeutic potential. But the evidence to support their use – outside the indications of spasticity related to multiple sclerosis and neuropathic pain – is weak.

Cannabis and psychosis

The association between cannabis use and psychosis is clear. Any history of use results in a 40% increase in lifetime risk of schizophrenia, and risk is doubled with heavy consumption. In healthy subjects, THC produces symptoms which mimic both the positive and negative effects of schizophrenia. In people with schizophrenia, continued cannabis use worsens the course of the illness; and abstinence from cannabis improves functional outcomes in the disease.

But, while THC increases anxiety and psychotic symptoms in healthy subjects, cannabidiol does not. In fact, cannabidiol increases levels of the endogenous cannabinoid anandamide and there is evidence that anandamide may act as an endogenous antipsychotic, attenuating the effects of THC on the CB-1 receptor. CNS levels of anandamide are raised in medication-naive first episode psychosis, and higher levels are associated with less severe symptoms -- though not in heavy users of cannabis.

Might anandamide be an endogenous antipsychotic?

All in the balance

The evidence is preliminary, but promising results from two controlled randomized trials suggest that cannabidiol may improve symptoms of psychosis in patients already on standard antipsychotic treatment. The results of two other ongoing trials are awaited. That said, Professor Goff takes seriously the idea that we may be able to take clinical advantage of endogenous cannabinoid systems that seem designed to maintain brain equilibrium and modulate response to stress.

Light marijuana use might have consequences

Can even one or two uses of cannabis affect the structure of the developing adolescent brain? It is a provocative idea, but one that Hugh Garavan (University of Vermont, Burlington, USA) thinks plausible.

Firstly, the number of CB-1 receptors increases substantially during puberty. Secondly, we know from rodent models that a single exposure to THC disrupts brain plasticity. But the new evidence is from a neuroimaging study comparing 46 adolescents who had used cannabis once or twice with 46 matched controls who had never used it. Significant differences were found in grey matter volume in brain areas rich in CB-1 receptors.

There are of course many caveats. The number of subjects in the study is relatively small; and, although attempts were made to control for correlated factors such as alcohol and nicotine use, these may not have been completely successful. Finally, since this is not a longitudinal study, we do not know if these differences in brain structure preceded rather than followed cannabis exposure.

And what of medicinal use?

Deepak Cyril D’Souza (Yale University School of Medicine, West Haven, Connecticut, USA) was generally sceptical about the strength of evidence for medicinal uses of cannabis and cannabinoids.

Despite some suggestion of improved sleep and reduced nightmares, a paper in press will conclude that the overall level of evidence for benefit in post traumatic stress disorder is low. That is also true in Tourette’s syndrome, despite some evidence of reduction in tics.

The strongest data are in multiple sclerosis, especially in relation to spasticity, and in neuropathic pain. However, even in neuropathic pain, studies have methodological challenges. These include large expectancy effects, difficulties in blinding, and failure to demonstrate effects on objective measures such as need for opiates.

Professor D’Souza regards evidence of efficacy in chemotherapy-induced nausea and vomiting as moderate, with the same being true of HIV/AIDS cachexia.

He sees one of the difficulties as being the rapid development of tolerance. Exposure to cannabinoids results in a prompt reduction in CB-1 receptor availability. This is evident over a period of days. Although the recovery of response to cannabinoids is also fast, initial induction of tolerance raises questions about maintaining therapeutic efficacy during long term treatment without the need for dose escalation.

Concern was expressed about the need to maintain the requirement for two positive randomized controlled trials before acceptance of a treatment for a new indication. Although some may want to relax this requirement in some circumstances, the risks associated with cannabinoid use should preclude this. 

A speaker from the floor agreed: medicinal use was, in his mind, simply part of the pressure towards decriminalization.

Want to get our APA2016 congress report directly in your mailbox? Sign-up to our newsletter 

SIGN ME UP