Meet the Experts is a series of interviews conducted by experts from the field of Cannabis to world leaders in research and clinical practice of Cannabis as medicine.
Ryan McLaughlin received his Ph.D. in Psychology in 2012 at the University of British Columbia (UBC), where he studied the interaction between stress hormones and endocannabinoids to produce dysfunctional mood states, under the supervision of Dr. Boris Gorzalka. Ryan then continued his postdoctoral training at McGill University, where he examined the role of endocannabinoid signaling on the neonatal stress response.
Then, he joined the Department of Integrative Physiology and Neuroscience at Washington State university (WSU) as an Assistant Professor. He has held fellowships from the Michael Smith Foundation for Health Research, Canadian Institutes of Health Research, and Fonds de Recherche en Santé du Québec.
He is also a recipient of a Healthy Minds Canada Prize in Children's Mental Health. Current research in the McLaughlin Laboratory is funded by the National Institute on Drug Abuse, and examines how developmental cannabinoid exposure and alterations in the endogenous cannabinoid system contribute to stress responsivity, emotional behavior, reward learning, cognitive functioning, and mesocorticolimbic neurotransmission in adulthood.
Fundación CANNA: Dear Ryan, thank you so much for agreeing to participate in this series of interviews. Can you tell us how did you first got involved with cannabinoid research? What aspects of endocannabinoid physiology interest you more?
Ryan McLaughlin: I became interested in cannabinoid research as a graduate student at the University of British Columbia in Vancouver, BC. I grew up in a relatively small town in eastern Canada, so moving out to the West Coast for graduate school really exposed me to a different cultural attitude towards cannabis. It was much more common for me to see friends get together to "smoke and chill" rather than "drink and party". When I would ask people why they prefer cannabis, the most common answer was that it helped to relax, relieve stress, and promote relaxation in the face of anxiety. I became fascinated with learning how cannabis affects the brain to produce these stress-alleviating effects, and why some individuals seem to see greater benefits than others. This interest became a primary research question of my PhD studies; namely, what are the neurobiological mechanisms subserving individual differences in stress coping strategies, and is there a role for the endogenous cannabinoid system in these effects? I later became interested in the impact of chronic stress on the endocannabinoid system, as more and more studies were indicating that chronic stress causes perturbation in this system in several brain areas known to be implicated in stress-related illnesses such as major depression. We are now interested in whether deficits in endocannabinoid signaling are important for the development of these stress-related illnesses, and whether the therapeutic potential of the endocannabinoid system could be harnessed to develop novel treatment strategies to help individuals cope with stress and hopefully avoid these debilitating disorders. So, with that said, the aspects of endocannabinoid physiology that interest me most are with respect to interactions with the neuroendocrine stress response, and this gives rise to complex stress-related behaviors.
FC: Your research is focused on the role of the endogenous cannabinoid system in emotional and neurobiological responses to stress and in the etiology and treatment of stress-related mental illnesses. There is growing concern regarding the use of cannabis (particularly in the youth) and the incidence of mental illness. What can you tell us about that?
RM: I think that the concern is valid when it comes to cannabis use among adolescents or exposure during other sensitive developmental stages. The endocannabinoid system is fundamentally involved in many neurodevelopmental processes, and as such, interfering with the activity of this system with exogenous agonists could have long-term consequences. I think that the research is a bit more tenuous when it comes to cannabis use among healthy adults. Often individuals use cannabis to self-medicate symptoms of stress and pain, improve sleep, etc., and acutely, cannabis does seem to produce positive outcomes in those individuals. However, when casual use turns into dependence, I think there is a question about whether using cannabis is the best coping strategy, and whether cannabis use could cause other coping strategies to deteriorate, thereby causing increased reliance on cannabis for future stressful episodes. It can lead to a vicious cycle, and in fact, our group has recently shown that although human cannabis users indicate significant reductions in symptoms of stress, anxiety, and depression at the time of use, their baseline symptoms of depression actually appear to worsen over time (Cuttler et al., 2018, Journal of Affective Disorders). I think there is a need for more controlled research into the long-term consequences of chronic cannabis use, in both adolescent and adult users.
FC: Translational value of data arising from animal models is often received by clinicians with skepticism, in particular, behavioral models. You are making significant efforts to come up with a translationally relevant preclinical model of cannabis use. How would that work?
RM: Clinicians are right to be skeptical of the translational value of data arising from animal models. This is supported by the fact that very few drugs that show efficacy in preclinical models actually lead to better treatment outcomes in human populations. We as a field are being led astray in the pursuit of unifying models for diseases that are incredibly complex and heterogeneous in nature. For instance, we will likely never be able to model "major depression" in a rodent, so clinicians may automatically assume that since there is no such thing as a depressed rat (in the human sense of the term), we will never be able to learn anything about depression or how to treat it. However, I think the issue is with the interpretation of the data. Rather than modeling depression per se, researchers are actually modeling individual symptoms that are more objective in nature. By harnessing the potential of animal models, this can lead to a better understanding of the neurobiological mechanisms that give rise to various symptoms, which can then be used to develop treatment strategies designed to help with these symptoms, rather than a disease as a whole. But it all starts with the development of translationally relevant models, and in the case of cannabis, this couldn't be more true.
FC: What are the issues with the animal models available until these days?
RM: I would argue that the limitations of current preclinical models of cannabis use have limited our understanding of the causes and effects of cannabis use in human populations. Very few groups are administering pure cannabis to rodents, instead opting for isolated cannabis constituents like THC or CBD, or synthetic CB1R agonists which we know do not activate the CB1R in the same way as those constituents. Moreover, the route of administration is very important to consider when attempting to model cannabis use in rodents. The vast majority of researchers employ forced injections or intravenous delivery of cannabinoids, despite the fact the intrapulmonary inhalation is by far the most common route of administration in human users. This is important because the pharmacokinetics and pharmacodynamics of cannabinoids vary greatly depending on the route of administration. We are working towards a more translationally relevant model by employing response-contingent delivery of vaporized cannabis extracts that retain concentrations of other phytocannabinoids besides simply THC. I think that this approach is an important advancement in the field because it will offer insight into how actual cannabis affects the brain and behavior, which is something that has been sorely lacking to date. Establishing this more translationally relevant model will afford empirical evaluation of mainstream beliefs regarding the effects of cannabis (i.e., more deleterious effects following early-onset cannabis use or the use of high THC preparations), permit finer interrogation of the effects of cannabis on the brain, and help to identify genetic or environmental factors that may increase vulnerability for developing cannabis-related problems.
FC: After many years of pharmaceutical development, phytocannabinoids still remain the tools we have to target the ECS clinically. Do you think there is therapeutic potential on cannabis and cannabinoids to treat stress- or drug- related illnesses? What about mental health or dual pathologies?
RM: I definitely feel that there is therapeutic potential for cannabinoid-based compounds in treating stress-related illnesses, but I think that the most viable approach will be to augment the endocannabinoid system (through the use of ECB hydrolysis inhibitors or allosteric modulators), rather than by administering cannabis. Our research has indicated an important role for the endocannabinoid system in the emergence of stress-related symptoms and preclinical studies have further shown that endocannabinoid enhancers are capable to mitigating deleterious effects of chronic stress. However, until results from large-scale clinical trials are released, we will not know how well the knowledge generated from these preclinical studies translates to human populations. As I mentioned above, most compounds that demonstrate efficacy at the preclinical level fail to translate to human populations, so it remains to be seen whether the optimism is warranted.
FC: Do you think there are inherent risks for public health in allowing legal access to cannabis worldwide?
RM: As with most things, I think that there are inherent risks associated with allowing legal cannabis worldwide, but the bigger question is whether the harms associated with cannabis legalization outweigh the potential benefits. Eliminating stigma and perceived harms of cannabis use may encourage those at risk to consume cannabis under the assumption that it is less harmful than X, Y, or Z. But until we have research on the long-term ramifications of cannabis use in at-risk users, we won't know to what extent such reform would have on public health.
FC: In your talk at 2018 ICRS you presented data on a rat model of pre-natal exposure to cannabis vapor. Can you describe briefly how the model works? What are the conclusions of the study?
RM: In these studies, we were interested in exploring whether prenatal cannabis exposure alters cognitive flexibility in exposed offspring at adulthood. We used the cannabis vapor delivery approach to expose pregnant dams to a high or low dose of cannabis vapor (28.4% THC, 1% CBD) twice daily throughout the mating and gestation period. We also included control groups receiving vehicle vapor (containing propylene glycol and vegetable glycerol, which is the standard vehicle used in commercially available e-cigarettes), and another control group that did not receive any vapor at all. Dams assigned to vapor exposure groups received 10 second puffs of vapor every 2 minutes for 60 minutes. The chambers have circulating air at all times via vacuum pumps, and work via standard e-cigarette technology. Our cannabis extracts are mixed at different concentrations inside commercially available tanks equipped with sub-ohm atomizers and when the system is triggered, the atomizer heats to a specified temperature that results in vaporization of the extracts contained in the tank. The vacuum air flow pulls the vaporized extract into the chamber, and there is an outlet at the back of the chamber that allows for evacuation of vapor. At post-natal day 70, which roughly corresponds to the onset of adulthood in rats, we trained these offspring to perform an attentional set-shifting task that is analogous to the Wisconsin Card Sorting task that is often used to assess prefrontocortical damage in neuropsychiatric patients. We found that adult offspring exposed to a high dose (but not a low dose) of cannabis vapor during gestation performed significantly worse on the set-shifting task. Contrary to our initial expectations, we found that these rats were more likely to commit regressive and never-reinforced errors during the task, which implies a deficit in acquiring and maintaining the new optimal strategy. This study is one of the first experiments to demonstrate dose-dependent effects of prenatal cannabis exposure on higher-order cognitive tasks in adulthood.
FC: What other studies have been done using this cannabis vapor administration system?
RM: At the moment we are also examining long-term effects of adolescent- vs. adult-onset cannabis use on prefrontocortical structure and function. In these studies, we have incorporated response-contingent delivery of vapor in an effort to more accurately model drug self-administration, rather than forced exposure. Having volitional control over drug exposure (e.g., self-administration by rodent subjects vs. passive exposure) is a very important factor when assessing the effects of drug exposure on the brain and behavior, as it has been demonstrated that the neurochemical effects of drugs of abuse are qualitatively different depending on whether drug exposure is forced vs. volitional. Moreover, we are exploring whether the effects of cannabis use are dependent on the phytocannabinoids present in the extract, as we are employing extracts rich in CBD as well as those rich in THC.
FC: Cannabis industry seems to be changing the landscape for academic research. How do you feel about more companies being involved and interested in societies such as ICRS or IACM?
RM: I am very happy to see that these companies are beginning to embrace ongoing academic research. At the moment, cannabis users must rely on anecdotal evidence from friends, budtenders, etc. about which particular strain or type of cannabis produces desired effects. This has propagated some misinformation regarding these different chemotypes, so I am pleased to see that industry companies are using the knowledge generated by well-controlled research studies to better inform their clientele.
FC: Many renowed academics are advising salient companies. Presenters at ICRS were instructed to declare any conflict of interest before their presentations. Do you have any relationship with the industry?
RM: I do not have relationship with industry partners, as this could possibly create a conflict of interest with my research program.
FC: How does Federal legislation affect your research? In states like California or Colorado, tax money coming from cannabis sales is being reinvested as research funds for public universities. What is the situation like in Washington State?
RM: Federal legislation has certainly introduced barriers for those interested in running exploratory studies, but apart from the time required to obtain a Schedule 1 license, it hasn't really affected my research much. However, I have had to temper my expectations with regard to the research questions that I can ask. When I moved to Washington State, I was eager to conduct research with different strains/chemotypes of cannabis that are currently available in the recreational and medicinal market (i.e., indica vs. sativa, high vs. low THC products, etc.), but I have had to suspend that line of research because we are limited in the cannabis we can obtain. At the moment, all US researchers conducting research with cannabis must use the NIDA Drug Supply program, which is fairly limited in the variety of strains available. So despite there being legalized cannabis at the state level, I cannot simply go down to the local cannabis shops downtown and purchase cannabis from these sources as it is still a federally illegal substance. Until reform is enacted regarding the scheduling of cannabis, this type of research will be very difficult to conduct.
FC: Many states of the Union are passing legislation to allowed cannabis use for both medical and "adult" use, Washington being one of the early adopters. What is your opinion about the current system?
RM: I think that time will tell whether this legalization experiment was a success or not, but looking at cannabis use statistics in Washington State since recreational legalization, it does not appear that rates of use are increasing as dramatically as initially thought, and the tax revenue generated by cannabis sales currently exceeds $740 million.
FC: In states like California or Colorado, tax money coming from cannabis sales is being reinvested as research funds for public universities. What is the situation like in Washington State?
RM: The tax money generated from these sales not only facilitates further cannabis-related research, but that revenue can also be used to fund cannabis outreach programs to educate people of the risks associated with cannabis use, and even to improve the general health and well being of citizens in Washington State. In Washington, a small portion (~1%) of the excised tax revenue generated by cannabis sales is appropriated into research funding competitions at WSU and UW through the Alcohol and Drug Abuse Research Program and the Alcohol and Drug Abuse Institute, respectively. As an early-stage investigator, these funding programs have been critical for my research and they also offer a potential funding mechanism for more established investigators that are interested in exploring effects of cannabis at different multiple levels.
Thank you so much for your time, Ryan. We wish you the best on your research endevors!
