What inspired you to pursue research in using cannabis to treat medical conditions?

Gruber: It all began when I couldn't find anything in the literature that looked at the long-term impact of medical cannabis use. Almost everything we know about cannabis today, comes from studies of primarily healthy, recreational consumers.   

I'm a neuroscientist, so I’m interested in looking at brain structure and function. I couldn't understand why there were no long-term studies using imaging or looking at medical marijuana from a cognitive perspective.  

That’s why we started the Marijuana Investigations for Neuroscientific Discovery (MIND) program that’s dedicated to looking at the long-term impact of medical cannabis use. Our flagship, longitudinal study from this program has also generated data that have paved the way for our innovative clinical trials of cannabinoid-based products. 

Gilman: There's a lot of coverage in the media and mythology out there about cannabis. Unfortunately, with the way cannabis for medical use is currently regulated, you really don't know what's real. 

Cannabis is interesting to me because it's a psychoactive substance–like alcohol, nicotine, cocaine and heroin–but it's treated somewhat differently. People have a perception that it’s low risk, and think that no one gets addicted to cannabis, but that’s not what the data shows—there is the potential for problematic use in some individuals. 

On the other hand, I am very interested in the potential medicinal properties of cannabis. I think there is potential for certain components of the cannabis plant to be used therapeutically.  

The issue with medical cannabis–and I don't even like to use the term “medical cannabis” because it's just cannabis, there’s nothing distinguishing “medical” and “recreational” cannabis. Unlike FDA-approved medications, we don't know exactly what is in these products. 

I think when it comes to cannabis for medical conditions, there is enthusiasm but not a lot of data. That's why I'm doing the studies that I do. I'm trying to collect rigorous data on these outcomes. 

Could you explain a recent cannabis-based study of yours?

Gruber: We launched the first observational study to look at patients who are interested in starting medical cannabis as a treatment for various conditions.   

We took baseline observations of medical cannabis patients before they started use and assessed everything from clinical and diagnostic assessments to neuropsychology, quality of life, sleep, and measures of brain structure and function. Then we did a comprehensive assessment of their cannabis use–what they're using, where they got it, how much they use, and how frequently they use.   

This longitudinal observational study has been a game changer, and it continues today. We have published several papers from this study documenting important changes in medical cannabis patients, which are in stark contrast to what we’ve previously observed in young recreational cannabis consumers.

Over time, medical cannabis patients have exhibited improvements in clinical outcomes (anxiety, depressive symptoms, pain, sleep), quality of life, and cognitive performance after initiating use. Neuroimaging data also revealed increases in white matter coherence in frontal regions of the brain, likely indicative of better organization of these fibers. Despite using cannabis regularly–daily, for many–patients generally did not exhibit signs of problematic cannabis use or CUD. 

Gilman: I completed a trial where we studied people who started to use cannabis for pain, anxiety, depression and insomnia. Participants could choose their own doses and pick the cannabis products they wanted. We then looked at how their symptoms changed. 

We found that pain, anxiety, and depression did not improve following cannabis use. Insomnia improved a little, but the thing that really struck me is that some participants, despite using cannabis for medical conditions, started developing symptoms of CUD.  

CUD is characterized by symptoms of problematic cannabis use–using more than you intended, having trouble stopping use, using in risky situations, or using despite negative consequences. 

Do you have any ongoing studies on medical cannabis?

Gruber: The first longitudinal, observational study assessing medical cannabis patients over the course of one year of treatment has been ongoing for over 10 years and was recently extended to examine patients for up to five years.

We’re also completing a second longitudinal study looking at older adults with chronic pain who use opioids and benzodiazepines, where we examine changes between those who initiate medical cannabis use and those who continue their conventional treatments over time.

We also have a study for veterans, so there's lots of different observational studies within the MIND program. 

In addition, we have several novel FDA-approved clinical trials examining sublingual (under the tongue) cannabinoid-based products that I’ve custom formulated to be non-intoxicating but therapeutically powerful.

If you know what you're targeting from a medical standpoint, you can create a product that's optimized for that condition without some of the psychoactive effects of cannabis.

There's a huge difference between administering something that's rich in tetrahydrocannabinol (THC)–the primary intoxicating component of cannabis–and something that is low in THC but rich in another compound like cannabidiol (CBD). 

Currently, I have a clinical trial of patients with Alzheimer's-related dementia where we're looking at a high-CBD product as a treatment for agitation and anxiety.

I have several clinical trials for chronic pain, including a study designed to address chronic musculoskeletal pain and one for individuals with endometriosis-related symptoms and pain, which is run through the Women’s Health Initiative at MIND.

We’re doing the first study of a whole-plant, full-spectrum, high-CBD product for patients with glioblastoma, an aggressive form of brain cancer, and we’ve also launched a study of a broad-spectrum (THC-free) product for patients with bipolar disorder. 

Gilman: We have two ongoing trials. One is studying Epidiolex–an FDA-approved CBD medication used to treat childhood epilepsy–as a treatment for chronic pain.

Chronic pain is associated with neuroinflammation–inflammation of the central nervous system, including the brain.

We want to see if CBD, which may have anti-inflammatory effects, can reduce neuroinflammation. We're doing PET scans of the brain before and after treatment and assessing participants’ pain. 

A second study is on people with chronic non-cancer pain who are on prescription opioids. 

Approximately 50 million adults in the United States suffer from chronic pain, a debilitating medical condition that is complex to manage.

The majority of those with chronic pain are treated with opioids but evidence supporting long-term effectiveness of opioid drugs for pain and improved functional status is weak and increases risk for opioid use disorder (OUD) and opioid overdose death.

There has been a rush to address this problem with cannabis, though evidence to support the effectiveness of cannabis for chronic pain is controversial, and evidence for cannabis to treat OUD, or to promote successful opioid tapering, is virtually non-existent.

With this study, we want to test whether adding cannabis to participants’ opioid prescriptions can help them decrease their opioid doses, as some studies have claimed. 

Why is it important to conduct research on cannabis?

Gruber: For many indications that range from anxiety, chronic pain, sleep disruption, different cancers, to neurodegenerative conditions like Alzheimer’s, there may be an opportunity for novel or adjunctive treatment using cannabinoids–chemical compounds found in cannabis.  

People often utilize these products based on anecdotal information without rigorous data backing these claims, but providing them with empirically sound data will allow them to make better decisions about their own care. 

Gilman: We need data to inform our decision making. My goal is to strengthen public health messaging by providing scientifically grounded evidence about the neural and psychological effects of cannabis use, instead of simply listening to the companies that sell these products. 

For instance, there are restrictions on what tobacco companies are allowed to say on packaging and in advertising, but there are fewer regulations for cannabis, and we really need science to back up these claims. 

Are there any misconceptions about cannabis?

Gruber: The primary misconception is that medical cannabis and recreational cannabis are the same. While the plant doesn't care what you use it for, and products may be similar, the goal of use, whether medical or recreational, creates differences.   

People using it for recreational purposes are looking to change their current state of being, so they generally choose products with notable THC content.

Medical patients want to address certain symptoms and most often do not want to feel altered or high, so they may choose products with more varied cannabinoid profiles, including several non-intoxicating compounds like CBD.  

A related misconception is if patients are using cannabis or any cannabinoid therapies, they're going to be high. Absolutely not. Most of my patients don’t want to or cannot be high. Essentially, goal of use dictates product choice. Product choice dictates outcomes.  

Another misconception is, “I can use the same product as someone else and have the same experience.” What works for one person does not necessarily work for another. Someone might have a genetic profile that doesn't lend itself to having a positive experience with cannabis. Everybody is different. 

Gilman: I think that the greatest misconception is that it's risk-free. If cannabis is helpful for medical conditions, we need to know that, but there is also risk to using cannabis in some individuals. It can affect memory and cognition, and in some cases can lead to psychosis.

Some people think, “Oh, it's no big deal, it's just cannabis.” But we know that there are three things that make cannabis risky. One is the age of onset of use–the younger you are, the worse it is.

Cannabis does worse things to the brain at age 14 versus age 40. The second is the frequency of use. If you're using cannabis, once a month, you’re probably going to be OK. If you're using cannabis every day, maybe you're not OK. 

The third thing is that the potency of products has increased tremendously. I often hear, “Well, we've been using cannabis for thousands of years.” But today's products–the gummies, candies, oils–have extremely high THC content and that affects how the drug affects the brain. 

Are there any regulation changes that you would like to see enacted?

Gruber: It’s currently illegal to do a clinical trial on a product that's commercially available. That's a limitation. We can't evaluate commercial products in a systematic way from a scientific perspective. I've always thought that for certain types of research, there should be an exception. 

On another hand, states make their own decisions about cannabis. That leaves consumers in a tough spot when they want to go state-to-state with their products. A product could be legal in one state but not another.

Even if someone is traveling with a product that is legal in two states, if someone flies between those two states with the product, they’re violating federal law. That's unfortunate from the patient side. 

Gilman: I think potency limits and regulating home delivery of cannabis are important. Requiring plain packaging without advertisements and increasing the visibility of health warnings–could help put this in a public health framework.