The cannabis conundrum: Thinking outside the THC box.

Abstract

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 cannabinoids1 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 Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are 2 cannabinoids that account for differences across plant varieties.2 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.3 However, other major studies have reported no relationship or minimal effects.4 Although issues relating to design, sampling, quantifying usage, and definition of psychosis likely play a role in contributing to between-study 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,5 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.6 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 THC moderate 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 task, such that THC had anxiogenic effects and CBD reduced subjective anxiety.7 Another study investigated the effects of CBD during a stressful public speaking task, which involved subjects who suffered from social anxiety disorder (SAD). Results suggest that pretreatment with CBD significantly reduced anxiety, cognitive impairment, and discomfort during speech performance among suffers of SAD.8 These results again indicate that the interaction of different cannabinoids is key to understanding the harmful and beneficial effects of cannabis with respect to anxiety. However, recognition of the complex effects of cannabis is often lacking in clinical and epidemiological research on the effects of cannabis use. These studies often oversimplify the effects of cannabis and perpetuate the false notion that all forms of cannabis represent the action of only 1 compound (eg, THC). For example, most studies have investigated the consequences of chronic cannabis use with a simple assessment of whether individuals use cannabis and a rough estimation of the quantity used. Moreover, many of these studies lack biological verification of exposure to THC and other cannabinoids. Many of these studies draw wide-sweeping conclusions about the effects of “cannabis use” without identifying the specific compounds that underlie the observed effects. This methodological approach perpetuates the idea that all cannabis has uniform effects and that all users share the same set of consequences. Despite oversimplified epidemiological and clinical research to date, the pharmacological research community has long recognized the complexity of compounds within cannabis, having identified and conducted pharmacokinetic research on individual cannabinoids more than 60 years ago. The fact that we have long known about the complexities of cannabis calls into question why published research continues to perpetuate the notion that the effects of cannabis are uniformly a function of THC content. This misrepresentation may be due, in part, to regulatory practices related to the Controlled Substances Act. Specifically, the preclinical literature has exclusively relied on synthetic cannabinoids to examine the effects of “cannabis” in vitro and in animal models (eg, see reference 9). Likewise, a number of the human laboratory studies designed to examine the effects of CBD and THC have used synthetic cannabinoids.10 In fact, it is very difficult to find a single animal or human study that examines CBD derived from Cannabis sativa or human studies on the effects of CBD or other cannabinoids derived from plant material. These results are difficult to generalize to the real world, in which people actually use cannabis strains that contain far more compounds than just THC and CBD. To compound the problem, epidemiological and clinical studies on cannabis users often interpret findings on the effects of cannabis in the context of the preclinical studies that were conducted with THC and/or CBD in isolation, without any data to suggest that the effects of synthetic cannabinoids generalize to the effects of cannabis as it is used in the real world. Clearly, conducting human and animal studies that use cannabinoids extracted from the plant itself would generalize much better to the everyday human condition. In short, the legal status of cannabis, and cannabinoids such as CBD, as a federal Schedule I drug makes it nearly impossible to conduct tightly controlled laboratory studies using strains and forms of plant extract that are typically consumed in the real world. Although government-grown cannabis can be administered in a university setting in accordance with certain regulations, the generalizability of findings drawn from these studies is questionable given that government-grown plants represent a very limited range of what is available to the public. For example, there are currently hundreds of strains being sold in Colorado dispensaries alone, some of which vary 40-fold in terms of the ratio of THC to CBD. In contrast, the government has historically been unable to provide cannabis with substantial levels of CBD. Limitations of the current research implore several key suggestions for future research improvements. First, clinical studies should report as much specific information about the variety or varieties of cannabis being used by individuals in their sample. Ideally, these studies should report the concentration of cannabinoids in the plant material being used as well as the concentrations of major cannabinoids (THC and CBD) in participants' blood after consumption. Second, scientists should avoid equating the effects of cannabis in human samples with the effects of synthetic THC and CBD observed in preclinical studies, given that the plant form represents a complex set of interactions of many cannabinoids and terpenes. A more nuanced methodological approach to the study of cannabis use is likely to lead to an enriched understanding of the mechanisms that underlie different effects of use in humans (eg, the cognitive effects versus the anxiolytic or anxiogenic effects). Finally, scientists must be allowed to conduct research on the strains of cannabis that are actually being used in the real world, rather than being restricted to only those strains that are provided by the government. In conclusion, legalization of cannabis continues to gain momentum. In the most recent election, in November 2014, Oregon, Alaska, and Washington, DC, joined Colorado and Washington state among the list of places where recreational marijuana has been legalized, and projections suggest that a growing number of states will follow suit in the 2016 election. Despite the national movement toward recreational legalization, our understanding of the harmful and beneficial effects of cannabis use and, more importantly, the interaction of cannabinoids is extremely limited. Without conducting research in naturalistic settings involving the types of cannabis that people actually use, it is not possible to understand the harmful and beneficial effects of cannabinoids. As a result, there is no solid scientific foundation for new policies and regulatory practices, which will be essential as more states legalize the use of cannabis and make policy suggestions that are based in science. Clearly, more sophisticated approaches to the study of cannabis are needed to inform both the public and policy makers about the public health effects of cannabis use. This research received no specific grant from any funding agency, commercial or not-for-profit sectors. None.