A Scientific Path to Discover the True Effects of Medical Cannabis

Dr. Staci Gruber, Director of the Cognitive and Clinical Neuroimaging Core, Director of Marijuana Investigations for Neuroscientific Discovery (MIND) at McLean Hospital, and Associate Professor of Psychiatry at Harvard Medical School discusses her interest in medical cannabis, the medical cannabis research areas that MIND is focusing on, and her interest in veterans and the 2019 Veterans Health and Medical Cannabis Study.

What is medical cannabis? How is it different from recreational or adult use cannabis? The answers to those questions can be confusing because of the state-level rules governing cannabis in the United States. Since cannabis is still illegal at the federal level, there is no clear distinction or guidance from the usual governing bodies, such as the Food and Drug Administration (FDA) who typically provide approval or oversight for medications. A common distinction between medical cannabis and adult use is the intended use by the consumer or patient; recreational users typically seek products high in tetrahydrocannabinol (THC) in order to feel high. Although medical cannabis patients may choose products high in THC, many patients do not want to feel a “high” or psychoactive effect. Therefore, they may choose products with less or even no THC, but with higher levels of other cannabinoids believed to have therapeutic effects, including cannabidiol (CBD). Interestingly, many who do not want to get high still chose products with low levels of THC given the idea that use of these "whole plant" products may have greater therapeutic effects at lower doses relative to single "purified" compounds from the plant.

One thing is clear in the medical cannabis field though: the patients are driving the issue and bringing it to the attention of medical professionals across the country. As of 2017, there were approximately 4.3 million registered medical cannabis users throughout the 33 states in which medical cannabis is legal, as well as in the District of Columbia (1). Whether it be anecdotal evidence from multiple patients or a demand for more information about the effects of medical cannabis and what it may or may not help with, medical professionals are starting to come around to the idea and they need more scientific research to provide guidance.

The type of research and clinical trials that medical professionals take seriously have been stalled in the US because of the Schedule I status of cannabis by the Drug Enforcement Administration (DEA). Dr. Staci Gruber, the director of the Cognitive and Clinical Neuroimaging Core and director of the Marijuana Investigations for Neuroscientific Discovery (MIND) Program at McLean Hospital, and an Associate Professor of Psychiatry at Harvard Medical School, is one researcher taking the leap to find more information. She recently discussed her interest in medical cannabis, her role in the 2019 Veterans Health and Medical Cannabis study, and other medical cannabis research areas her group at MIND is focusing on.

The Science and Mission Behind MIND

According to the MIND website (2), the program is designed to address a series of questions regarding the effects of medical cannabis. Some of the questions MIND is designed to address include: How do recreational and medical cannabis use differ? What is the impact of medical cannabis on adults with regard to both short- and long-term use? As stated on their website (2), “MIND is designed to begin to address some of these questions as, thus far, little data is available regarding the short and long term impact of medical cannabis on measures of cognition, sleep, clinical state, quality of life, conventional medication use and brain-related measures.”

In her role, Dr. Gruber has been working in psychiatry and trying to understand the neurobiological bases of different psychiatric disorders and conditions for many years. Part of her focus had been on the use of recreational cannabis and its impact on cognitive performance and measures of brain structure and function. She explained that she and her team have found consistent evidence of relationships between heavy recreational cannabis use and poorer cognitive performance, and that they have spent considerable time assessing the impact of earlier versus later exposure to cannabis (3–6). Her findings led to questions about medical cannabis use and if the same relationships existed there.

“Despite the fact that medical cannabis has been around since 1996 when it was first legalized in California, I could find nothing in the literature about the longitudinal, or long-term, impact of medical cannabis use on these same outcome measures—cognitive performance, clinical state, brain structure, brain function, sleep, quality of life, and so on,” said Dr. Gruber.

This lack of information related to medical cannabis use led Dr. Gruber to create the Marijuana Investigations for Neuroscientific Discovery (MIND) program, which is dedicated to looking at the impact of medical cannabis use on all of those different aspects. Dr. Gruber’s first study with MIND—which is still ongoing—is a longitudinal observational study of patients using medical cannabis for various conditions and indications.

“Basically, what we do is we enroll individuals who are interested in using medical cannabis but who have not yet started. That is a critically important part of this, they have not yet started using cannabis,” said Dr. Gruber. “They go through very comprehensive clinical, cognitive, and diagnostic assessments.”

Some of these measures are self-report while others are examiner-driven. Then, patients that are eligible also have multimodal neuroimaging done. Dr. Gruber explained that the neuroimaging techniques assess brain structure, brain function, and brain chemistry.

“Following this long, comprehensive assessment, we send them on their way,” said Dr. Gruber. “They begin their own medical cannabis treatment program, but we follow them and talk to them every other week.”

Dr. Gruber and her team keep track of what products the study subjects use, where they got it, when they use, and how much they use. For the most commonly used products, Dr. Gruber and her team have them analyzed by an outside laboratory for cannabinoid constituent profiles; in other words, these analyses tell them what is in each product.

“We do the outside laboratory testing because I’m not supplying the product like I do in my clinical trials,” she explained. “This way, we don’t have to guess what they’re really getting . Sometimes what the laboratory results say is exactly the opposite of what they’ve been told or what the label on the product says and sometimes the results are absolutely spot on.”

The study subjects come back into Dr. Gruber’s laboratory at three months, six months, 12 months, 15 months, 18 months, and 24 months for re-evaluations. She explained that time is the critical factor in studies such as this. They are trying to understand how medical cannabis affects different domains over time. This first study also includes a group of “treatment as usual” patients—these individuals have similar conditions and indications to the medical cannabis patients but have no plan or intention to use cannabis.

“Our first study is observational and it’s very challenging because with long term studies of people doing things on their own, you have to rely on them to come back in,” said Dr. Gruber. “You need a minimum of three months of treatment before they can even come back for their first follow up, so studies like this take a long time, which is why it’s still ongoing. The data has been quite stunning so far.”

Some of the data Dr. Gruber uncovered with this research was surprising even to her. She explained that in her studies of recreational cannabis she found relationships between higher cannabis use, earlier onset of use, and greater magnitude of use. For example, Dr. Gruber found that the younger people are when they start using recreational cannabis and the more cannabis they use, the poorer they perform on tests of cognitive function; they look a little less “able” than those who aren’t using cannabis. However, with medical cannabis use, Dr. Gruber is seeing the opposite trend.

“What we’re seeing in the medical cannabis patients between baseline and three months, baseline and six months, and now we’re looking at data at a year from baseline and beyond is actually very different,” she said. “In these patients, who are primarily aged 50 and older, there is an actual improvement in a number of different cognitive areas, including measures of executive function which are tasks controlled by the frontal cortex. The very tasks that appear compromised in our recreational consumers who begin cannabis use early on (when the brain is still ‘under construction’) appear to be getting somewhat better over time in our medical cannabis patients. That’s a surprise to most people. It actually makes sense though if you take a step back and realize two things—first, the medical cannabis patients not only started using medical cannabis later in life, after critical periods of brain development are complete, but also their goals for use are very different from recreational consumers, which drives the products they choose and how they use them. These factors likely make a real difference”.

A natural next question would be what is causing these results—are there specific cannabinoids related to these outcomes? Dr. Gruber explained that the cannabis plant is made up of hundreds of constituents, not just THC and CBD, the two that get so much attention. “Some of the lesser known cannabinoids, as well as terpenoids and flavonoids, are actually very important, and we spend a fair amount of time on them in my laboratory,” she said.

“For right now, we’re actually looking specifically at what we call 'quantifiable exposure' to THC and CBD, because that’s what the world is most interested in and most familiar with at the moment,” said Dr. Gruber. “And really THC and CBD are the two most predominant constituents in most products that people are using these days. Determining what the relationships are between THC and CBD and some of these things we assess in terms of mood versus cognitive measures is going to be very interesting.”

MIND and Veterans

Dr. Gruber’s research has led her to different collaborations including helping Dr. Marion McNabb with the 2019 Veterans Health and Medical Cannabis Study as well as her own study with a cohort of veterans.

According to Dr. McNabb, Dr. Gruber provided high level technical assistance for the design of the 2019 Veteran’s Health and Medical Cannabis Study tool prior to the launch. Dr. Gruber provided technical input to the survey and advice on the design and analysis of the data.

Dr. Gruber explained that her veteran’s study is set up very similarly to the larger observational study of medical cannabis patients described above. However, all participants are veterans who chose to begin using a hemp-derived, high-CBD sublingual product after a baseline visit. The high-CBD product is provided at no cost from the product manufacturer (Charlotte’s Web) as part of a veteran support program. In addition, there are two different groups of patients (called cohorts) in this study. One cohort of veterans have not used cannabis before—they are referred to as naïve veterans because they haven’t been exposed to cannabis—and the second cohort are veterans that have already been using cannabis regularly. Both groups take the same product during the study period. Dr. Gruber said that study samples remain small so far and of course the COVID-19 pandemic has negatively impacted recruitment of additional study subjects.

“Basically, so far, this study echoes the larger findings in the observational longitudinal study, which is that we have these folks who have never used cannabis, who start using a full spectrum high CBD, low THC product that’s available commercially,” she said. “In general, what we see is that both groups appear to be getting better over time with regard to clinical variables,” said Dr. Gruber. “That’s important. Our goal is to increase sample sizes and look at potential changes in different areas such as cognitive performance, clinical state, sleep, quality of life, medication use, PTSD symptoms, and a number of related measures.”

Dr. Gruber utilizes multiple research techniques, including magnetic resonance imaging (MRI) to examine how medical cannabis use may change brain structure, function, and chemistry

Dr. Gruber and her team also complete neuroimaging at baseline and again at the end of the trial for the cannabis-naïve veterans. “As we increase the sample size, we expect to see additional patterns emerge—this is a critical population to study as so many veterans are so desperate for anything to give them relief and empirically sound data will certainly help.”

From Dr. Gruber’s experience with these cohorts of veterans, she believes they are looking for help with sleep, anxiety, and possibly even other issues. “I think that given the increasing numbers of people across the country and really around the world using cannabis, and especially our veteran population, who report having some symptomatic relief, the big question will be what the relationship is between symptom change and medical cannabis use,” she said.

Dr. Gruber gave the example that sometimes something like sleep will improve, and as a result of this improvement, people feel better and can think more clearly, thus they perform better on cognitive function tasks.

“Does that mean the cannabis is directly improving cognitive performance or is it indirectly improving cognitive performance? More research is needed to determine this relationship. For our veterans, it’s going to be very important to understand what products or product types can help with certain specific indications that they may be suffering from—not just sleep but, for example, PTSD or anxiety,” she said. “Not all cannabinoids are the same, and some are more likely to exacerbate rather than ameliorate issues or problems. So, we want to be mindful of that.”

Dr. Gruber stressed that cannabis is not one thing—it’s comprised of hundreds of compounds and they all exert different effects. “It’s important to have studies like this because we’re interested not just in the good, but also the bad and ultimately just the truth. It’s about figuring out what works,” she said.

The next steps for Dr. Gruber’s veterans’ studies are to increase their sample size and get a comprehensive picture of what veterans look like before and after treatment with different types of cannabis or cannabinoid-based products.

“I think the next logical steps are also to look at potential changes in these clinical and cognitive measures. For example, if we get large enough samples, we can actually really make informed decisions about what types of things might help versus what types of things may not be so helpful in veterans looking for relief,” she said. “We’re not all created equally. We don’t all have the same difficulties or problems, and that’s important to consider. So, what you use, want, or need for pain versus sleep versus anxiety versus PTSD will vary. And it will also vary as a function of the individual using it.”

“I’d like to see an expansion of the veteran’s program—a large expansion,” said Dr. Gruber. “Really, it would be great to have a center that was just focused on that type of investigation for our veterans. They deserve it.”

LEFT TO RIGHT: Gabriel Conde, Dr. Marion McNabb, Dr. Staci Gruber, Ann Brum, Stephen Mandile, and Sydney (Syd) at a Cannabis Advancement Series event. Photo credit: Dubside Photography.

Patients Driving Medical Cannabis Science Forward

As stated earlier, a unique aspect of the medical cannabis community is that patients are pushing for more information and asking their trusted medical advisors about it (doctors, nurses, pharmacists). Then, these medical professionals are, in turn, seeking studies and scientific data to determine the merit behind the anecdotal evidence of medical cannabis use.

Dr. Gruber agreed, stating that the one thing that is different in the medical cannabis realm from other areas is that you basically have patients sharing information with their healthcare providers or friends. Then doctors and researchers start doing studies to see whether empirically sound data supports the anecdotal evidence, as opposed to the norm of a doctor informing a patient about a drug study and suggesting it as a treatment.

“Patients and consumers are leading the charge here, and they’re informing their healthcare providers and other individuals who are then forced to become more educated and more familiar with the rather complex, but extraordinarily compelling world of cannabis,” said Dr. Gruber.

Despite the push from patients, the stigma surrounding cannabis is still evident even in the medical cannabis world—perhaps even more so. Dr. Gruber stressed that more research and education is incredibly important to help overcome the stigma and concerns about medical cannabis.She related a few patient stories that go against the stigma of using cannabis just to get “high.” “When I look at a 78-year-old who can’t walk or a 53-year-old who’s so anxious they can’t sit at their kid’s soccer game—those aren’t people who are looking to get high,” said Dr. Gruber. “They’re looking to live their life. I think more research and greater dissemination of some of these types of data will help change the perception of medical cannabis use.”

Dr. Gruber also explained that there are some legitimate concerns when it comes to medical cannabis. For instance, some raise concerns regarding exposure to medical cannabis in individuals with a predisposition or family history of psychosis, or with other potential comorbid conditions, or legitimate concerns about drug-drug interactions. “It’s incredibly important for consumers and patients to understand the potential benefits and risks associated with use, which will be different for each person and will depend on products selected and use patterns”, she said.

Research Challenges

Despite the willingness and genuine interest of so many researchers, doctors, and other medical professionals in the US to study medical cannabis, it is still a road fraught with obstacles because of the Schedule I status. Dr. Gruber explained that observational studies are more straightforward because there are no concerns regarding administration of cannabis products, as patients take what they choose on their own. However, clinical trials, where patients are administered a drug or product, especially those that are double blind, are the gold standard in the medical community, but are much more difficult to conduct.

To conduct a clinical trial in the US, products that are cannabis-derived currently have to be sourced from the National Institute on Drug Abuse (NIDA), explained Dr. Gruber. In order to even get these products from NIDA for a clinical trial, researchers must have a Schedule I license.

“In general, research with anything that is a Schedule I substance is more difficult than something that isn’t,” said Dr. Gruber. “Cannabis has been a very complex and rather dynamic landscape. It’s a difficult terrain to navigate very often because of the state versus federal laws not necessarily being commensurate with each other.”

“For example, you could be in compliance with your state and in violation of federal law,” she added. “You have to be very, very careful about how you approach these things because you want to maintain scientific rigor and maintain the ability to have what I would call ecologic or external validity­which ensures that the data are meaningful and can be applied to people in the ‘real world’—but you also have to stay within the confines of the law.”

Dr. Staci Gruber custom formulates cannabinoid study products for her clinical trials.

There has been much debate about the quality of cannabis products coming from NIDA. An issue that another researcher, Dr. Sue Sisley has been tackling for a number of years (7). However, Dr. Gruber said that the drug supply program at NIDA has expanded exponentially over the past 8–10 years. “That doesn’t mean that they can supply researchers like me with products that our patients or veterans can avail themselves of at a dispensary,” said Dr. Gruber. “There’s no such thing as a vape cartridge that you can get from NIDA or what we call concentrates.”

“Primarily NIDA offers varieties of cannabis flower, as well as a handful of cannabis extracts. Despite expanding the drug supply, NIDA’s products don’t necessarily resemble the profiles and types of products available to our recreational consumers and medical patients currently, which is an inherent limitation,” Dr. Gruber added. “We find ways around that as best we can.”

If the products used in these studies are not the same type or quality that can be found at a dispensary, does that mean research has to be done again in the future assuming that access to cannabis products changes? Dr. Gruber did not think that was necessarily the case. “Well, the thing is, it’s not that you redo them, you simply add to them,” she said. “I think there’s a huge difference between saying, I got this product from NIDA and even though it’s not exactly what people are using, I’m going to use it as it gives us information and, quite frankly, that’s valuable.”

Dr. Gruber added that they are not currently doing smoke inhalation studies in clinical trials like Dr. Sisley has been conducting; instead they are using other approaches, including sublingual oils. For some of Dr. Gruber’s clinical trials, she has acquired cannabis extracts from NIDA, which have then been reformulated by her and her team to become a sublingual solution to be used as a study product. “We reformulate in order to make the extract into something that’s analogous to what you would perhaps see being sold at a dispensary,” she said. She also has clinical trials involving hemp.

Future Research Plans

Dr. Gruber has lot of ambitious goals for the MIND program in the future. Aside from expanding her veterans’ research project, she has also launched several other important research initiatives. Dr. Gruber explained that the MIND program itself has several areas of investigation, some of which are already underway and some of which are still in the planning stages. There is a program dedicated to women called the Women’s Health Initiative at MIND (WHIM), which is focused on disorders that disproportionately or exclusively impact women such as perimenopause, menopause, or postmenopausal difficulties.

“We’re also about to launch a study, the very first of its kind in patients with Alzheimer’s, in terms of looking at agitation and anxiety,” said Dr. Gruber. “We have other projects planned for individuals not just with chronic pain, but other types of inflammatory processes and other things going on such as mood disorders. We also have a sleep study in the works as well as several others.”

“We have a fairly lengthy list of projects that are pending,” Dr. Gruber added. “The goal is to really try to understand the potential therapeutic role of cannabis or cannabinoids in a range of conditionsby utilizing potentially non-intoxicating compounds in conjunction with those that might be intoxicating to a lesser degree. That’s the goal.”

Future of Medical Cannabis

Aside from her own research endeavors, Dr. Gruber has high hopes for the medical cannabis community in general and what she would like to see happen in the near future.

“I would certainly like to see increased ability for those of us conducting these types of studies to use what I would call ecologically valid products in our work,” said Dr. Gruber. “It would be great to be able to do a clinical trial of a product that patients are actually already using.”

Dr. Gruber also explained that since the US Farm Bill passed in 2018, so-called hemp derived products do not fall under the Controlled Substance Act and are not scheduled. That has caused things to change a little bit, but researchers are still not allowed to use commercially available hemp products in clinical trials.

“Imagine products that are widely available even through recreational or adult use dispensaries or let’s say they are hemp derived, and you can order them and have them shipped to all 50 states. I can’t do a clinical trial of those products,” said Dr. Gruber. “That seems crazy. You see your patients taking products for whatever they’re taking it for. And those of us invested in trying to figure out if it’s good or bad, can’t study it. It’s not that we won’t. It’s that we can’t. So how do we guide people?”

“I think it’d be great to have increased ability to use products—’real world’ products—in clinical trials,” she said. “I think some of these restrictions make it a little bit more challenging to conduct the studies that are actually most needed, so I’d like to see that change.”

Dr. Gruber would also like to see that kind of perspective be part of the mainstream. “We should be studying things that people are actually taking as opposed to formulating similar products and seeing what happens,” she said.

Conclusion

Despite first being legalized in 1996 in California, medical cannabis slowly made its way across the country over the course of the last two decades. However, the medical use of cannabis goes back to ancient times. There is evidence of medical cannabis dating back 5000 years ago and it was even included in the United States Pharmacopoeia in 1850 (8). The truth is that this plant deserves to be studied and medical professionals are willing to take on that work, if they are allowed to.

Dr. Gruber added that these research problems aren’t going to be solved with just one approach, saying it will take a village. “I think the one other thing that’s important in the world of cannabis research is that there are so many questions and so many areas to explore and really tackle,” said Dr. Gruber. “There’s plenty for all of us to do. It’s better when we work together as opposed to trying to reinvent the wheel. I always think good collaborations are really critical.”

“This is the most important work I think I’ve ever done or will ever do because there are so many people who are so desperately in need and anything that can be done to help the cause—whether it’s exploring the good, highlighting the bad, or just getting to the truth—is really much more important than I ever imagined,” said Dr. Gruber.

The truth might be different for each patient. But perhaps that’s why the term personalized medicine has some real meaning behind it—and medical cannabis could be the key for many but we won’t know until further research is conducted.

References

1. https://www.mpp.org/issues/medical-marijuana/state-by-state-medical-marijuana-laws/medical-marijuana-patient-numbers/
2. https://www.drstacigruber.com/mind.
3. K.A. Sagar and S. Gruber, Interactions between recreational cannabis use and cognitive function: lessons from functional magnetic imaging, Annals of the New York Academy of Science, 1-29 (2018). doi: 10.1111/nyas.13990.
4. K.A. Sagar and S. Gruber, Marijuana matters: reviewing the impact of marijuana on cognition, brain structure and function, and exploring policy implications and barriers to research, International Review of Psychiatry, 1-17 (2018). doi: 10.3389/fphar.2017.00983.
5. S.A. Gruber, K.A. Sagar, M.K. Dahlgren, A. Gonenc, R.T. Smith, A.M. Lambros, and S.E. Lukas, The Grass Might Be Greener: Medical Marijuana Patients Exhibit Altered Brain Activity and Improved Executive Function after 3 Months of Treatment, Frontiers in Pharmacology, 8 (2018). doi:10.3389/fphar.2017.00983.
6. S.A. Gruber and K.A. Sagar, Marijuana on the Mind? The Impact of Marijuana on Cognition, Brain Structure, and Brain Function, and Related Public Policy Implications, Policy Insights from the Behavioral and Brain Sciences,4(1), 104-111 (2017). doi:10.1177/2372732216684851.
7. https://www.cannabissciencetech.com/view/dr-sue-sisley-advocating-medical-cannabis-research-patients-and-reform.
8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312634/.