From the Editor
“It’s the only thing that helps with my anxiety.”
It’s closing in on midnight, and the ED patient I’m seeing is adamant that cannabis has helped him with his generalized anxiety disorder. My day has been long, but I choose to push a bit. Why cannabis? He notes how challenging it was to access mental health care. When he finally did see a psychiatrist, he feels he was offered a prescription after only a few minutes, and the trial of sertraline left him feeling more anxious. Cannabis, in contrast, helps him sleep and takes an edge off the anxiety.
More and more, our patients are talking up cannabis. Google “medical marijuana,” and there are over 166 million hits. And, yes, industry has noticed. There are a half a dozen cannabis dispensaries within a 10-minute walk from the CAMH ED, where I work. In the spring, a former prime minister joined the board of Acreage Holdings, a marijuana company, explaining that he was excited by the potential of cannabis to treat PTSD.
But is any of this evidence based?
This week, we look at a new paper from The Lancet Psychiatry. University of New South Wales’ Nicola Black and her co-authors do a systematic review and meta-analysis. Considering a variety of psychiatric disorders including depression, they draw on the literature to try to understand the effectiveness and safety of cannabinoids. “There is scarce evidence to suggest that cannabinoids improve depressive disorders and symptoms, anxiety disorders, attention-deficit hyperactivity disorder, Tourette syndrome, post-traumatic stress disorder, or psychosis.”
We consider this big paper on the hot topic.
We also discuss the comment paper that accompanies this study. Yale University’s Deepak Cyril D’Souza writes: “The process of drug development in modern medicine is to first demonstrate efficacy and safety in clinical trials before using the drug clinically. With cannabinoids, it seems that the cart (use) is before the horse (evidence).” For the record, I don’t think Acreage Holdings will be distributing either paper to shareholders.
Please note that there will be no Reading next week.
“Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis”
Nicola Black, Emily Stockings, Gabrielle Campbell, Lucy T Tran, Dino Zagic, Wayne D Hall, Michael Farrell, Louisa Degenhardt
The Lancet Psychiatry, 28 October 2019 Online First
Countries are increasingly allowing cannabinoids to be made available for medicinal purposes, including for the treatment of mental disorders. In our study, based on previous agreed terminology, we use the term ‘medicinal cannabinoids’ as an umbrella term encompassing all plant-derived and synthetic derivatives. We use ‘medicinal cannabis” to refer to any part of the cannabis plant and plant material, such as buds, leaves, or full plant extracts (eg, Cannabis sativa). We use the term ‘pharmaceutical cannabinoids’ to refer to pharmaceutical-grade medicinal extracts with defined and standardised tetrahydrocannabinol (THC) with or without cannabidiol (CBD) content (eg, THC, CBD extract, or THC-CBD combinations such as nabiximols) and synthetic cannabinoid derivatives. Given the increasing interest in CBD products for various medical conditions, we also separately grouped studies that only used pharmaceutical CBD.
After chronic non-cancer pain, mental health is one of the most common reasons for using medicinal cannabinoids…
We aimed to examine the available evidence for all types of medicinal cannabinoids and all study designs (controlled and observational) to ascertain the impact of medicinal cannabinoids on remission from and symptoms of depression, anxiety, post-traumatic stress disorder, and psychosis, as well as symptoms of attention deficit hyperactivity disorder (ADHD) and Tourette syndrome, either as the primary disorder or secondary to other disorders; and the impact of medicinal cannabinoids on outcomes including global functioning, quality of life, and patient or caregiver impression of change. We also examined the safety of medicinal cannabinoids for mental health symptoms and disorders, including all-cause, serious, and treatment-related adverse events and study withdrawals.
So begins a paper by Black et al.
Here’s what they did:
- They searched a variety of databases, including MEDLINE, for papers published between January 1980 and April 2018. Search terms included “medical cannabis.”
- Studies were considered with any type andformulation of medicinal cannabinoid. “We included studies examining the use of medicinal cannabinoids in adults aged 18 years or older for the purpose of treating depression, anxiety, ADHD and Tourette syndrome, post-traumatic stress disorder, and psychosis either as the primary condition or secondary to other medical conditions.”
- While different types of studies were included, they needed at least one primary outcome.
- Two reviewers then selected the papers.
- Data extraction was done and analyzed.
Here’s what they found:
- “83 eligible studies were identified…” These included 40 randomised controlled trials involving 3 067 participants. By diagnosis:
- Depression. 42, with 23 RCTs, including one unpublished study; n=2 551.
- Anxiety. 31, with 17 RCTs; n=605.
- Tourette syndrome. Eight, with two RCTs; n=36.
- ADHD. Three, with one RCTs; n=30.
- PTSD. 12, with one RCTs; n=10.
- Psychosis. 11, with six RCTs; n=281.
- “Medicinal cannabinoids were mostly investigated as adjuvant medicines.” (!)
- “Randomised controlled trials were typically very small (with median sample sizes of 10-39 participants across mental disorders), with short follow-up periods (median trial length 4-5 weeks).” (!)
- The studies tended to be newer (all 23 depression papers, as an example, were published since 2001) and came from North America or Europe (20 of 23 depression papers).
To our knowledge, this is the most comprehensive systematic review and meta-analysis examining the available evidence for medicinal cannabinoids in treating mental disorders and symptoms. There is a notable absence of high-quality evidence where mental disorders are the primary target of treatment, and most evidence is derived from studies where mental disorders are secondary to another medical condition, commonly chronic noncancer pain and multiple sclerosis. Most of the included studies were done among individuals in whom depression or anxiety was secondary to another medical condition, and in these studies we found no impact of pharmaceutical THC (with or without CBD) on depression symptoms, and a small reduction in anxiety symptoms.
A few thoughts:
- This is a good paper.
- The authors are clear in their conclusions.
- As is always the case with a review, we should ask: how extensive was this effort? After all, not all reviews are created equal. The authors drew on the literature with varying degrees of success. They found many papers for depression (42 in all), but for ADHD, not so many (three). That’s not a criticism of their methodology, but a comment on the state of the research. It’s fair to say that the research is evolving, and this paper will seem dated in the not too distant future. The authors write: “We need high-quality randomised controlled trials to properly assess the effectiveness and safety of medicinal cannabinoids, compared with placebo and standard treatments, for the treatment of mental disorders.”
- What to make of CBD? There is particular enthusiasm for this form of cannabis, with it found now in so many products (sleeping masks, burgers, dog treats, to name a few examples). Yet this review found limited formal study and very little evidence. Focusing on depression: “Pharmaceutical THC-CBD did not significantly improve symptoms of depression compared with either active comparators or placebo in randomised trials, including one unpublished study.” CBD alone? There were no RCTs for depression. (!)
- Still, in terms of reviewing the current literature, this paper is solid.
- How to put this in a larger context? The accompanying commentary is lucid.
“Cannabis in psychiatric disorders: the cart before the horse?”
Deepak Cyril D’Souza
There is a pressing need to develop new medications for the treatment of psychiatric disorders. There is growing public interest in the use of cannabis and its principal constituent cannabinoids, Δ⁹-tetrahydrocannabinol (THC) and cannabidiol, for a plethora of conditions, including psychiatric disorders. In parallel, there is considerable commercial interest in touting these products as treatments for various disorders. As a result, health practitioners need to be well informed about this topic.
Deepak Cyril D’Souza
Dr. D’Souza makes several comments.
- “In light of the results of this comprehensive review and meta-analysis, it would be hard for practitioners to justify recommending the use of cannabinoids for psychiatric conditions at this time.”
- “For these psychiatric conditions, approved medications (eg, selective serotonin reuptake inhibitors, antipsychotic drugs, stimulants) already exist. And although one might argue that these medications have little efficacy and significant side-effects, at least they were tested in adequately powered, large, double-blind, randomised controlled trials and then subjected to a rigorous regulatory approval process.”
- “In the era of modern medicine it will be imperative to understand the mechanism or mechanisms by which cannabinoids treat these conditions or provide symptom relief… From a mechanistic standpoint, it is uncertain how or why cannabinoids could be effective in treating depression, ADHD, psychosis, anxiety, and post-traumatic stress disorder – conditions that share no obvious common pathophysiology. Perhaps, as suggested elsewhere, cannabinoids provide non-specific subjective relief, similar to the non-specific effects of benzodiazepines.”
- “Before these compounds can be used clinically, some basic questions need to be addressed. What are the optimal doses of cannabinoids for the various conditions, the dosing frequency, the duration of treatment, and the ratio of THC to cannabidiol? Most of the existing evidence is based on small studies and relied mainly on subjective outcome measures.”
In conclusion, in light of the paucity of evidence, the absence of good quality evidence for efficacy, and the known risk of cannabinoids, their use as treatments for psychiatric disorders cannot be justified at present.
A few thoughts:
- This commentary is sharp – and well argued.
- The comment about a common mechanism is particularly sharp, and worth repeating: “it is uncertain how or why cannabinoids could be effective in treating depression, ADHD, psychosis, anxiety, and post-traumatic stress disorder – conditions that share no obvious common pathophysiology.”
- Of course, for many of us clinicians, the question isn’t whether we are persuaded by our patients’ description of cannabis but how to move them off from significant use; think of my ED patient, adamant that cannabis is so helpful. Dr. Jonathan Bertram, an addiction physician, suggests that we speak about the sustainability of ongoing cannabis use. “I usually tell them what works, and what you feel works, are not the same thing as what’s going to work long term. And so sustainability versus effect are two very, very different courses and they very much define or influence what a person is going to decide to take.” You can find my full podcasts interview with him here: https://www.porticonetwork.ca/web/podcasts/quick-takes/cannabis-oct2018.
Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.