What we know (and what we don't) about clinical use of psychedelic drugs

The clinical evidence has yet to catch up with the emerging interest in psychedelic-assisted therapy for treating mental health disorders. “The data thus far is promising, but it is from small studies and trials that have their own individual limitations,” said Dr. Ishrat Husain, clinical scientist and staff psychiatrist in the general and health systems psychiatry division at the Centre for Addiction and Mental Health in Toronto. “Although it is promising, and we should encourage the investigations of new treatments, really, the psychedelics are not yet ready for any regulated clinical use.” Psychedelic-assisted psychotherapy is where a patient takes a psychedelic drug and then participates in a psychotherapy session. It is done under supervision and in the setting of an existing and continuing therapeutic relationship. The treatment is mostly being studied for substance-use disorders, PTSD and major depressive disorder. Drugs under study include psilocybin (an active ingredient in magic mushrooms), MDMA ((3,4-methylenedioxymethamphetamine, also known as 'ecstasy'), ayahuasca and lysergic acid diethylamide (LSD). The anesthetic ketamine is often included in discussions about using psychedelics to treat mental health disorders, although it has a different mechanism of action, targeting glutamate where psychedelics influence serotonergic pathways. Read: London clinic now offering 'ketamine-enhanced' therapy for patients with depression Interest will prompt questions Public interest in the treatment has soared, sparked by hope in a successful therapy for people with mental health disorders and a curiosity of drugs notorious for experiments (clinical or otherwise) conducted in the past. “Canadian physicians are going to be encountering questions about psychedelics in their practice from patients, families, and communities,” said Dr. Anees Bahji, addiction medicine research fellow at the British Columbia Centre on Substance Use. He said that “as exciting and interesting as the findings from some of these studies have been, it’s still very early in the psychedelic-assisted therapy field. There is a need for a lot more research for us to understand their role amongst established mental health treatments.” As more studies come, physicians should consider referring patients on to research, Dr. Husain said. “I think that’s very important. It’s been shown patients referred to research and taking part in trials tend to get better and the quality of care is good.” Dr. Sukhpreet Klaire, an addiction medicine physician at St. Paul’s Hospital in Vancouver and clinical instructor in the department of family practice at the University of British Columbia, was involved in research examining MDMA-assisted therapy. Physicians will have to work with researchers to keep patients safe, he says, noting, “the patients that are being evaluated to benefit are often the most vulnerable and often ones who have the most symptoms at baseline.” Researchers in the MDMA trial worked with the participants’ clinical providers to ensure the patients could engage in the process, had appropriate support, were able to safely go off medications and that it was a good option for the patient and a good time in their lives to engage in a new treatment. While engaging in well-designed clinical research is encouraged, experiments at home are not. Physicians should make patients aware of the potential adverse effects if patients are self-medicating and obtaining these agents illegally. “Psychedelics aren’t without any harm. There have been reports that they can have adverse effects such as increased anxiety, paranoia, even auditory hallucinations,” Dr. Husain said. Read: MDMA shows promise as PTSD treatment aid MDMA Of the treatments being studied, MDMA-assisted therapy for PTSD has the most robust evidence supporting its use. Researchers from the U.S., Canada and Israel have conducted a randomized controlled trial examining MDMA-assisted therapy for patients with severe PTSD. Ninety participants with severe PTSD were randomized into two groups, one receiving MDMA-assisted psychotherapy and one getting a placebo and psychotherapy. The participants first had two 90-minute-long therapy sessions to establish a therapeutic relationship, and then three sessions after taking either MDMA or the placebo. The MDMA group had significant improvements in PTSD symptom scores (CAPS-5) and the Sheehan Disability Score (SDS) after two months of treatment. There was no increase in suicidality with MDMA and no increase in substance abuse potential. “What that means functionally is that these patients had a great reduction in daily symptoms of PTSD, so premonitions, flashbacks, negative thoughts and other PTSD symptoms; and had higher degree of function and engaging in everyday life,” Dr. Klaire said. The trial results were published in the June 2021 issue of Nature. Some patients had such an improvement in scores that they no longer met the requirement for PTSD, he added. While the trial did not include people with active substance use, sub-group analyses suggested that alcohol use significantly decreased in the MDMA group “The next target of a study could be and should be looking at people with both alcohol-use disorder and PTSD,” Dr. Klaire said. He presented the sub-analysis results at the annual meeting of the Canadian Psychiatric Association held in October 2021. Further research is needed to clarify the right amount of therapy, how it should be delivered and which patients will benefit most from therapy. Read: What do researchers know so far about psychedelic-assisted mental health therapy? Psilocybin An April 2021 open-label study by Dr. Robin Carhart-Harris (PhD) and colleagues at the Imperial College of London showed positive results of psilocybin-assisted therapy for patients with treatment-resistant major depressive disorder, and the reduction in depressive symptoms was sustained for six months post-treatment. Yet, when compared with another treatment, psilocybin-assisted therapy did not prove to be superior. A recent randomized controlled trial by Dr. Carhart-Harris and colleagues in patients with moderate to severe major depressive disorder found no significant difference in symptoms of depression between psilocybin-assisted psychotherapy and psychotherapy plus the daily use of the SSRI escitalopram in patients with treatment-resistant depression. Dr. Husain said what the research found “signals to me that perhaps this treatment should be reserved for people with more refractory forms of illness who don’t get better with first-line treatments, given the resources involved.” Proof-of-concept trials in 2014 and 2015 initially examined psilocybin-assisted psychotherapy for smoking cessation and alcohol-use disorder. Health Canada has granted exemptions to allow the use psilocybin for psilocybin-assisted psychotherapy, mostly for end-of-life anxiety. A 2016 paper published in Journal of Psychopharmacology showed psilocybin therapy improved measures of mood and anxiety compared to a placebo dose in patients with terminal cancer. Read: Where do 'magic mushrooms' belong in patient treatment? Ketamine, LSD and ayahuasca There has been research into using these agents to assist psychotherapy, but the studies have all been small and did not have a randomized control design. Ayahuasca, a South American psychedelic drink used in ceremonies, has been studied as a potential treatment for substance use. LSD-assisted therapy has been studied for end-of-life anxiety and other mental health disorders, but in few patients. Ketamine studies usually involve the administration of the anesthetic in patients with depression, without providing psychotherapy at the same time. Limitations of current clinical studies Despite some initial success of psychedelic-associated treatment, there is still not enough evidence to support its use. “I wouldn’t say we’re at the point where it can be readily adopted into clinical practice,” Dr. Klaire said. “There certainly needs to be a framework and regulations on how these therapies are going to be delivered before family physicians see patients undergoing or having access to these types of therapies.” The trial results may not give an accurate picture of effectiveness and safety in a real-world clinic because of the controlled environment and small sample size. Conducting the clinical trials with these drugs is difficult. For example, blinding is problematic with drugs that have a powerful psychological effect. There’s also the expectation that there will be an effect, which potentially distorts the results. Trials conducted to date often have small sample sizes, short follow-up periods, lack of comparators and other design factors that limit their usefulness. Many questions remain, such as dose, what patients will benefit most, and what agents are most effective. Read: Psychedelic drugs for treatment of mental illness focus of UofC research chair Mechanism of action Psychedelic drugs are partial agonists of the 5-hydroxytryptamine type 2A (5-HT2A) receptor and so have an effect on the serotonergic system. They also may affect neuronal circuitry. Whether a patient needs to have a mind-altering or psychedelic experience to gain benefit from psychedelic-assisted therapy is not yet known. MDMA may work as a catalyst to advance psychotherapy. In their paper, Dr. Klaire and fellow researchers suggest the drug allows patients “to revisit and process traumatic content without becoming overwhelmed or encumbered by hyperarousal and dissociative symptoms.” The drug also influences social behaviour, which the researchers write may strengthen the therapeutic bond between the clinician and the patient. Research using functional MRI conducted by Dr. Carhart-Harris and colleagues suggests that psilocybin (and, in another study, LSD) affects a circuit in the brain called the default-mode network. This network is thought to be quite active in internalizing processes (i.e., rumination) in mental health disorders like depression, anxiety and PTSD. The functional MRI study showed psilocybin reduced activity in the default-mode network of patients with depression, which was returned to normal post-treatment when improvements in mood were observed. The researchers suggested a “reset mechanism” to return to more normal functioning. Their study was published in Scientific Reports in 2017. Dr. Husain noted the importance of understanding how these compounds work in the brain. Functional MRIs and other studies could help identify which patients respond best to psychedelic-assisted therapy and treatment could be targeted to those who get the most benefit. “I don’t think these drugs are a panacea and a one-size-fits-all that will help everybody. I think there will be a subgroup of people that improve with it and we need to identify that that group will be,” Dr. Husain said. “It is a very resource-heavy intervention. There are a lot of hours of psychotherapy involved,” he said. Further research may show that psychedelic-assisted therapy may benefit some patients who have tried everything else and have not responded. Dr. Bahji said that these refractory cases could stem from not knowing what causes many mental health disorders. Treatments are often discovered through trial and error, he noted. “In some ways, I wonder if psychedelic-assisted therapy might help us understanding the causes of some forms of mental illness. Historically, we have studied the way people respond to treatment as an indirect study of the disease that we are trying to treat,” he said.

What we know (and what we don't) about clinical use of psychedelic drugs

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