CATR: Can you tell us a little bit about your work in the field of cannabis?

Dr. D’Souza: For the past 25 years, I’ve been interested in the pharmacology of cannabis and cannabinoids. At first my interest was in relation to psychosis, but then it expanded to include the pathophysiology and treatment of cannabis use disorder (CUD). I have also been working with state legislators in Connecticut as they consider cannabis legislation, trying to inform them about the health consequences of cannabis, especially in young people.

CATR: Let’s say a patient walks into your office and tells you they have a medical marijuana card. What does that mean?

Dr. D’Souza: The usual scenario starts when a patient goes to a physician who is certified within their state’s medical marijuana program. The physician first must diagnose that patient with a condition that is approved for treatment with cannabis. Once the patient is certified, they can enroll in the state’s medical marijuana program. After enrollment, they can then go to a state dispensary and purchase a cannabis product.

CATR: It seems strange that cannabis is illegal at the federal level, but is approved as a medicine and/or for recreational use in some states. How did we get here?

Dr. D’Souza: Yes, it’s confusing. The federal government still sees cannabis and its principal active constituent—meaning delta-9-tetrahydrocannabinol (THC)—as a Schedule I substance. By definition, cannabis doesn’t have a therapeutic use and has a high abuse liability. Some states have bypassed that by using a legal loophole. Technically, physicians are not prescribing marijuana, because that would be illegal. Instead, physicians are certifying patients for a condition that a state has decided qualifies for medical marijuana. And once certified, patients can then obtain medical marijuana through a state-sanctioned dispensary.

CATR: So it is up to states to decide which conditions qualify and which ones don’t? This is different than other medications.

Dr. D’Souza: It’s totally different. Other medications go through an approval process at the FDA, which is quite rigorous. The FDA standard typically requires two double-blind, randomized controlled trials with sample sizes of over 100 patients—sometimes thousands of patients. But cannabis approval gets around that, again due to various legal loopholes and technicalities. So, cannabis approval, whether it’s medical or recreational, is decided by a state legislative body. The process differs from state to state, and the standard of evidence is overwhelmingly lower than that of the FDA. And keep in mind that each state has its own list of medical and psychiatric conditions for which medical cannabis is approved. There are various medical conditions on that list, and perhaps most relevant to your readers, a host of psychiatric conditions including autism, agitation, Alzheimer’s disease, generalized anxiety, and PTSD. In addition, some states have given fairly broad latitude to certifying physicians: If the physician believes that cannabis will be helpful, then it can be prescribed. So, effectively, in those states there are no guidelines—it’s left to the physician’s discretion.

CATR: Could you summarize the current state of evidence for cannabis as a therapeutic agent?

Dr. D’Souza: I’ll restrict my comments to psychiatric indications. My group reviewed this back in 2016 and concluded that there was very low-quality evidence to support the use of marijuana for any psychiatric condition (Wilkinson ST et al, Annu Rev Med 2016;67:453–466). A few other studies since then have come to essentially the same conclusion (Black N et al, Lancet Psychiatry 2019;6(12):995–1010). PTSD, which is perhaps the indication that has received the most attention, is a good example of the state of the field. There is one randomized controlled trial with THC (Bonn-Miller MO et al, PLoS ONE 2021;16(3):e0246990). Researchers took military veterans with PTSD and experience using cannabis and randomized them to receive high-dose THC, high-dose cannabidiol (CBD), a combination of the two, or placebo. They found no differences between the treatment groups (Editor’s note: See Research Update in this issue for more on this study). There are several cohort studies as well that all show similar results. Other studies, some of which show some promise, are too underpowered to draw any definitive conclusions.

CATR: So we just don’t know if cannabis works or not.

Dr. D’Souza: That’s right. And we have to weigh the efficacy data, or lack of data, with the negative consequences of cannabis use. In sum, taking the very weak evidence for efficacy and robust knowledge of adverse effects, at the present time it’s hard to justify recommending cannabis for any psychiatric disorder.

CATR: Would you say that cannabis is ever contraindicated?

Dr. D’Souza: Cannabis and its derivatives can worsen the course of psychotic disorders, so people with an established psychotic disorder should avoid these substances. Furthermore, there is a concern that cannabis could precipitate a first episode of psychosis and trigger a chronic psychotic disorder in people who have a family history or who are clinically high risk. So these people shouldn’t use cannabis either. I would apply that to bipolar disorder as well, especially those who become psychotic during mood episodes. Anxiety disorders are interesting—many people who use cannabis recreationally do so for its anxiolytic effects. But in some individuals, it can induce panic and anxiety. We see that in our laboratory studies; some subjects become very anxious and have panic attacks. It’s been reported in the literature. So, cannabis can be a double-edged sword as it relates to anxiety. People with anxiety disorders might find cannabis anxiolytic initially, but once tolerance develops with regular use, they could experience significant withdrawal and rebound anxiety, which they then have to treat with larger doses, creating a vicious cycle (Connor JP et al, Addiction 2022;117(7):2075–2095). So, I would say people with anxiety disorders should also avoid it.

CATR: What about PTSD? Aren’t there data to show that it can worsen outcomes?

Dr. D’Souza: There are some associational data, yes. Some colleagues looked at almost 50,000 veterans and found that those who used cannabis seemed to have worse PTSD outcomes (Wilkinson ST et al, J Clin Psychiatry 2015;76(9):1174–1180). So, PTSD patients should be advised to abstain from cannabis as well, until we have good-quality data showing beneficial effects.

CATR: Are there any other groups that should avoid cannabis in particular?

Dr. D’Souza: Young people should avoid cannabis—their developing brains are especially vulnerable to its effects. People with addictions to other substances should be cautioned that they are at an increased risk of developing CUD if they use cannabis.

CATR: You’re painting a picture in which cannabis can be harmful to large groups of patients with little to no evidence of any mental health benefits. Yet state governments are saying that cannabis is safe, even beneficial. It sounds confusing.

Dr. D’Souza: It is very confusing, unfortunately. Explaining the difference between FDA and state approval and the lack of evidence for medical cannabis is sufficient for some patients. But others won’t be convinced and will want to continue using it “medicinally.” For me, the two most challenging groups are young people—an entire generation who have grown up with the concept of medical cannabis—and patients who have been using it for a long time already. They say, “See, we told you all along that it’s OK.” You won’t convince many patients to change their use in one session; it has to be an ongoing conversation.

CATR: What tips do you have for those conversations?

Dr. D’Souza: Explore the negative consequences of use for each patient, and what benefits there might be for them if they quit or cut back. Maybe it’s that they’re spending too much money. Other reasons are “I don’t want to do this in front of my kids” or “I want to apply for a certain job but I don’t think I’m going to pass a workplace drug test.” Sometimes it comes down to another person in the patient’s life: “My spouse is frustrated that our vacation plans are limited because I can’t travel without my cannabis.” Some of my patients with psychotic disorders tell me cannabis improves their psychotic symptoms, even though the details of their situation clearly show that is not the case. Usually, over time I’m able to point out to them that every time their use of cannabis increases, they end up in the hospital. Sometimes it takes several hospitalizations to solidify the connection. Or with bipolar patients, they get manic when they increase their use, and maybe it takes one or two times for them to see the link.

CATR: What about patients who are adamant that their use carries no negative consequences?

Dr. D’Souza: Sometimes it takes a bit of exploration to find the consequences that exist. For young people, I might ask, “Tell me about your pattern of cannabis use.” They might say, “Thursdays, Fridays, Saturdays, and Sundays. I don’t smoke on Mondays, Tuesdays, and Wednesdays.” When I ask why, they say, “I have classes.” And they’ll begrudgingly concede that when they smoke, they don’t have the motivation to study or they forget what they’re learning. For a middle-aged adult who absolutely insists they don’t have any negative consequences, I might ask, “Would you be OK with your teenage son or daughter smoking cannabis?” Then the conversation takes a different tone. They’ll say, “Actually I’m not so sure about that...” And that leads to an opportunity to discuss why.

CATR: Sounds like motivational interviewing.

Dr. D’Souza: You’re right. My approach is not deliberately motivational interviewing, but I guess it developed in that direction. (Editor’s note: See Addiction Report, March/April 2021 for more on motivational interviewing.)

CATR: And what if patients continue to use anyway, saying that they enjoy cannabis? How do you discuss cannabis use with your patients within a framework of harm reduction?

Dr. D’Souza: I definitely have patients who will continue to use, despite my best efforts. The key here is THC content—that is what drives addiction. I would prefer that if patients are going to use cannabis, they use forms with high CBD or at least a low THC:CBD ratio. In fact, my colleagues in the UK have suggested that the government should make low-THC/high-CBD cannabis legally available in order to cut down on the use of recently developed forms of cannabis with very high THC content like shatter, dab, or some vaping products with 80% or 90% THC. Before the 1990s, typical THC content was around 4%.

CATR: Given how rapidly things are changing, how do you recommend that clinicians stay up to date on this topic?

Dr. D’Souza: One great resource is an organization called Systematically Testing the Evidence on Marijuana (STEM), which is a collaboration between the Department of Veterans Affairs and the University of Oregon (www.cannabisevidence.org). They have brief summaries on specific topics that are continually updated as new information comes forth. Each summary is easily digestible and takes only a few minutes to read but provides links to the primary literature. In terms of legislation, clinicians should familiarize themselves with the website of their state’s public health department. To my knowledge, most states have a website detailing approved indications for cannabis, patient and provider eligibility, etc. Finally, I think that clinicians should really be paying attention not just to legalization, but to commercialization. Alcohol and tobacco have been around for centuries, but the game changer for both was the commercialization of those products. Likewise, the commercialization of cannabis is going to be a huge part of how our patients perceive, access, and use it. An environment in which companies are selling cannabis for profit is very different from allowing people to grow a few plants in their backyard for home consumption.

CATR: Thank you for your time, Dr. D’Souza.