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The cannabis conundrum: Thinking outside the THC box

Despite nationwide movements to legalize and regulate cannabis, our understanding of its effects on human health is tenuous at best. Developing a solid evidence base regarding the health effects of cannabis is imperative given the momentum for legalization and the demand for sound regulatory practices. This present commentary will identify limitations with respect to previous research on cannabis, discuss the genesis and implications of these limitations, and offer suggestions for future research. Over the past 40 years, cannabis research has largely oversimplified the effects of both acute and chronic use. Cannabis is an immensely complex plant that includes more than 60 cannabinoids and can be bred to yield hundreds of strains, each with a unique cannabinoid profile. Thus, the cannabis that consumers use can vary greatly from plant to plant and strain to strain. Despite this complexity, “marijuana” continues to be represented within the research community, media, and society as a homogenous compound that is often conflated with the effects of THC. In truth, however, the effects of cannabis use likely depend on many factors, including the concentration and ratio of a number of different cannabinoids. For example, recent research suggests that D-tetrahydrocannabinol (THC) and cannabidiol (CBD) are 2 cannabinoids that account for differences across plant varieties. A more nuanced understanding of the effects of these different cannabinoids is critical for informing public health policy and regulatory mechanisms. One particularly compelling example of the complexity of cannabis applies to schizophrenia. The widely held belief in the clinical community is that cannabis use is a risk factor for triggering psychosis and developing schizophrenia, especially among at-risk individuals. However, other major studies have reported no relationship or minimal effects. Although issues relating to design, sampling, quantifying usage, and definition of psychosis likely play a role in contributing to betweenstudy differences, there clearly are other factors at play here. For example, a recent meta-analysis found that those with schizophrenia reporting lifetime cannabis use appear to show superior cognitive function when compared with nonusing schizophrenia patients, and there are currently 7 officially registered clinical trials of CBD used to treat schizophrenia and psychotic symptoms (see clinicaltrials. gov). In support of this trend, 1 study found that pretreatment with CBD prevented the acute triggering of psychotic symptoms by THC. That is, results suggested that THC modulated striatal amygdala activation, which might underlie acute induction of psychotic and anxiety symptoms, whereas CBD had opposite effects on neural activation and subjective response ratings. These results lend support to the therapeutic potential of CBD to mitigate the detrimental and psychotogenic effects of THC. These data also raise the question about whether all strains of cannabis increase the risk for psychosis or whether strains with significant levels of CBD might not be associated with that risk. In additional, some literature suggests that CBD and THCmoderate anxiety differently. One study in particular administered oral capsules of THC and CBD and found that the 2 cannabinoids demonstrated distinct neural and symptomatic response patterns to an anxiety-provoking The Journal of Clinical Pharmacology 2015, 55(8) 839–841 © 2015, The American College of Clinical Pharmacology DOI: 10.1002/jcph.511