Meet the Experts: Interview with Staci Gruber

By Guillermo Moreno-Sanz

Dr. Moreno-Sanz has authored more than 30 scientific articles and 3 patents describing the role of the endocannabinoid system in pain perception. Graduated in Biochemistry and Organic Chemistry from the University of Zaragoza, he obtained his PhD in Neuroscience from the Complutense University of Madrid, in Spain. He gained extensive international experience with long-term fellowships in the Netherlands, Italy, and the United States, developing most of his academic career at the University of California, Irvine, where he discovered a new class of cannabinoid analgesic with high clinical potential. In 2017, he acted as a consultant to the National Academies of Sciences of the United States in the preparation of the report "The health effects of cannabis and cannabinoids" and later founded Abagune Research to offer scientific advice and R&D solutions to the international cannabis industry. In 2020 he assumes the scientific and medical direction of Khiron Life Sciences in Europe.

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.

Meet the Experts: Interview with Staci Gruber

Dr. Staci Gruber is the Director of the Cognitive and Clinical Neuroimaging Core at McLean Hospital's Brain Imaging Center and an Associate Professor of Psychiatry at Harvard Medical School. Dr. Gruber's clinical research focuses on the application of neurocognitive models and brain imaging to better characterize risk factors for substance abuse and psychiatric conditions. She has been studying the impact of marijuana on the brain for over two decades using neurocognitive, clinical, and diagnostic assessments and multimodal brain imaging techniques.

In 2014, Dr. Gruber launched Marijuana Investigations for Neuroscientific Discovery (MIND), the first ever program of its kind designed to clarify the specific effects of medical marijuana use. MIND utilizes valid, robust research models and supports numerous projects designed to address the impact of medical marijuana on several important variables including cognition, brain structure and function, clinical state, conventional medication use, quality of life, pain, sleep, and other health-related measures. Dr. Gruber is also the Principal Investigator of the first ever clinical trial of a whole plant-derived, high CBD product specifically formulated to treat anxiety, and has several other clinical projects pending.

Guillermo Moreno-Sanz: How did you first get involved with cannabis research? Did you know about the endocannabinoid system back then?

Staci Gruber: I started doing cannabis research many moons ago! I started at McLean decades ago when I was still in college, doing a summer internship and I ended up just staying. In my first studies, we looked at the impact of recreational use in cognitive performance in college students. These studies were conducted in the 90s, believe it or not, so I have been involved with cannabis reserach in some ways for many years. Regarding the endocannabinoid system (ECS), it was a completely different time, and these studies were designed specifically to look at the real-world impact of what we would consider chronic heavy recreational cannabis consumers and whether there was an impact on cognitive performance. It was well before the discussion of medical cannabis because, at the time, there was not state legislation. California was the first in 1996. All these folks were illegal recreational users, and I started my own set of studies looking specifically at the age of initiation of using cannabis and differences in cognition between those who started earlier in life, when the brain is neurodevelopmentally vulnerable and those who started later in life. And the answer of course is, yes! Now we know, thanks to those studies and the work of colleagues globally that is not just whether you use or not cannabis, really is very important to look at when someone started consuming, and how much and how often they use cannabis.

GMS: You are a great, prolific speaker, and I have noticed you do embrace the term "marijuana" when referring to cannabis, which seems to be the word everyone is leaning more towards these days.

SG: I use the term Medical Marijuana because we have medical Marijuana laws across the country. In truth, we really should call it medical cannabis because cannabis is the plant from which all this things stem, and the term Marijuana has a derogatory connotation to it. I was really reticent to call my program MIND (Marijuana Investigations for Neuroscientific Discovery), but I did it again because Medical Marijuana laws dictate that nomenclature, and I did not want people to be confused.

GMS: Tell us about the MIND program. What is it and how did it get started?

SG: As I said, I have been involved in recreational cannabis research for years and when I looked up in the literature for the long-term impact of medical cannabis on things like cognitive performance, quality of life, quality of sleep, measures of brain structure or function, clinical outcomes, anything other than the primary symptom we were investigating, I found nothing despite we had legal medical cannabis in this country since 1996. And as it turned out, it was because there really had not been any longitudinal observational studies. So, we decided it would be smart to start a program dedicated to study the impact of medical cannabis over time. We knew what we were seeing for recreational consumers, but would we see the same thing in medical patients? That is really the question. From a longitudinal observational study perspective we are just looking at patients that are using their own products but we had the opportunity to assess those patients before they ever began consuming cannabis. We see them again every three months and we monitor their consumption. We also analyze the cannabinoid content of the most used products, so we do not need to trust what is written in the label.

GMS: What research programs are you actively pursuing at MIND?

SG: The MIND program was based on the idea that we had to look at the impact of medical cannabis on all these outcome measures, in addition to these longitudinal studies in which we basically watch people doing their own thing: veterans, special women's health program, we also have surveys studies that we do. And finally, about a year and half ago, we had our first clinical trials approved. A whole-plant full-spectrum extract for patients with moderate to severe anxiety. We have several IND approvals for various indications for which we create proprietary products to address these conditions. We also use non-invasive neuroimaging techniques to help us. We have already seen some rather striking changes over time as people use cannabis and cannabinoid-based interventions. It will be interesting to see the impact on cognition, clinical state, measures of brain structure and function, in vivo metabolites, conventional medications, sleep, quality of life...I believe is going to be a very exciting next few years for sure.

GMS: Have you felt the stigma associated to cannabis in your professional career?

SG: I think that there is a lot of individuals that have very strong feelings in one way or the other. Cannabis is an extremely hot topic and people do not have lukewarm feelings about it. It has been really interesting to me as a scientist who is invested in understanding the good, the bad and, really, the truth of the use of this substance: it is an extraordinarily complex plant with extraordinarily intriguing potential and reasons for concern in the other side. But when we talk to people, even colleagues, they all have very strong opinions about how we should go about it, which is a bit different from other substances. There is tremendous stigma for both consumers and patients, which results in unfortunate scenarios. Many patients use medical cannabis to address symptoms such as difficulty to sleep and anxiety, but they are so concerned about being judged by their family, friends, and even their healthcare providers that they often do not disclose it, which is also problematic because that can lead to unwanted drug-drug interactions.

GMS: You have been in the news because of the "largest ever cannabis research grant" being granted to MIT and Harvard school including, among others, your research group. What has been your experience obtaining funding to conduct research with cannabis?

SG: Securing funding to conduct research with cannabis can be very difficult for several reasons. First and foremost, cannabis remains a controlled substance at a federal level, so there is a lot of concern from institutions and academics to accept funding to conduct research with it. The grant from the Broderick foundation was $9 million and funded many projects between MIT and Harvard Medical school, but we only received a small amount of funding to look at differences in efficacy of CBD isolated compared to the whole-plant full-spectrum extract which includes other minor cannabinoids and plant actives. Securing funding is not an easy road. It has gotten better, but it is something we still struggle with compared to other substances such as alcohol.

GMS: These differences between the effects of single-molecules and "full spectrum cannabis oil" is an "old" argument that started with Marinol being in general poorly tolerated compared to smoked cannabis, to then become ubiquitous in any cannabis-related debate since Dr. Ethan Russo hypothesized an "entourage effect" of terpenoids and THC. What is your opinion on the topic?

SG: I am wholly invested in understanding the differences between purified compounds and whole plant extracts because there seems to be something to the idea that there is a synergistic effect between cannabinoids, terpenoids and flavonoids working together. If you think about it, we know that CBD is likely to modulate effects at least in part through serotonin receptors while THC activates cannabinoid receptors, you are likely to end up with a bigger bang for your buck if you hit several systems and not just one. I also think this directly affects dosing schedules. When you look at Epidiolex, which contains 100mg/mL of purified CBD, the doses that result in clinical efficacy are very different from the doses that you see people taking for sleep or anxiety. I am not sure you need so much CBD if it is taken as a full-spectrum product. Again, I am cautiously optimistic with open-label data, but so far, the magnitude of improvement is quite striking. But if it is true, then you need significantly lower doses of a whole-plant, full-spectrum extract because you are engaging several systems and receptors at the same time.

GMS: Many researchers are moving away from THC and towards CBD, maybe because the more favorable regulatory scenario. However, we do not know much about the pharmacology of CBD compared to that of THC, which remains the only tool we have to engage cannabinoid receptors in the clinical practice. Which cannabinoid do you believe holds more promise? What type of clinical conditions are you most interested in studying?

SG: The first thing is to define the goal of use. If it is to alleviate a medical condition that is very different from trying to "become intoxicated". That is going to dictate product of choice and very often individuals who use cannabis for medical purposes are looking for products that may contain THC but also have a broader cannabinoid profile while the recreational user is mainly focused on high THC content. I think a lot of researchers are now turning to CBD because the society has gotten behind this. And because people think there is no downside to using this type products and they may have an immense benefit, of course they want to use them. As scientists we need to understand how best to guide and educate patients and consumers. We started with clinical trials focused on anxiety because of the sheer number of individuals who suffer from this condition even at subthreshold levels, in which you may not meet the DSM-V criteria for an anxiety disorder, but you are still debilitating. We see it all the time with this horrific pandemic that we are suffering, people are having terrible time with anxiety, depression, difficulty to sleep, and are very interested in supplement of even substitute other products to try to help.

GMS: At MIND, you have developed some impressive research over the last few years. Could you please share with us which have been in your opinion your most significant findings?

SG: For the people that say that all we have are anecdotal findings, I must say all great discoveries begin with anecdotal findings. That is where we start, not where we finish. I have been absolutely stunned at the change that I have seen in patients over time, some of which are almost unrecognizable after 3 or 6 months of use, in many cases they "get their lives back". Also, in ways that have nothing to do with me, they are choosing their own regimens. Once I walked pass my own patient in the waiting room which has never happened to me before because I did not recognize her. She had put on 15 pounds on that she needed for living and she had overcome her extreme anxiety.

I think the data from the clinical trial has been also quite stunning, I did not expect the magnitude of improvement that we have seen but, again, it is open label. I think being able to study the long-term effects of medical cannabis, just understanding real world patients using real world products has absolutely changed our view of what our classic model of a "cannabis patient" looks like, and that is very, very important. These are not people sitting in cars, looking to get stoned, the medical patients that we see say: "Dr. Gruber I do not want to get high; I just want to take a walk with my husband, or go shopping, or sleep through the night". Back to your point about stigma, very often people consider the individuals who are looking to use medical cannabis as those who are just trying to use illicit drugs in a legal way.

GMS: What is the contribution that you are most proud of?

SG: I find tremendously rewarding the fact that we have been the very first ever to look at the long term impact of medical cannabis use on all these clinical outcomes, the first group ever to do neuroimaging in these patients and that exciting, I hope to continue to be the "first ever" with regards to looking at the impact on some of these, hopefully beneficial study products in patients with debilitating conditions such as anxiety.

GMS: Thank you so much for your time, Dr. Gruber, and for sharing your experiences with our readership!

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