Rewiring Psychiatry: The Return of Psychedelics
Quick Summary
- Psychedelics are a class of psychoactive substances that produce changes in perception, mood and cognitive processes.
- The FDA has acknowledged the potential of some psychedelic-assisted therapies by granting drug-development programs a breakthrough therapy designation (BTD) in order for these programs to potentially get expedited drug approval.
- It is important to note that these interventions are fundamentally reliant on controlled dosages, guided psychotherapy and a supportive environment.
Over 14 million Americans live with a mental illness, and over 8 million of them rely on prescription medication to treat their condition. While many evidence-based treatments are effective, many patients do not benefit enough and there remain patients who suffer from treatment-resistant conditions. These unmet challenges have driven interest in novel therapeutic approaches: one such emerging area of research interest being psychedelic-assisted therapy.
Psychedelics are a class of psychoactive substances that produce changes in perception, mood and cognitive processes. Some psychedelics occur naturally and others are created in a lab. These substances are classified into two groups: classic and non-classical. Classic psychedelics, including Ayahuasca, LSD and psilocybin, are grouped together due to their action on the serotonin 2A receptors in the nervous system. Non-classical psychedelics, including ibogaine, ketamine and MDMA, are those that affect other neurotransmitter systems such as dopamine and glutamate; they may also affect the serotonin 2A receptors. Many psychedelics remain federally illegal, categorized as Schedule I drugs: substances with high abuse potential and no recognized medicinal use. However, laws are changing as more and more scientific research emerges supporting the therapeutic use of psychedelics. The FDA has acknowledged the potential of some psychedelic-assisted therapies by granting drug-development programs a breakthrough therapy designation (BTD) in order for these programs to potentially get expedited drug approval.
It is important to note that these interventions are fundamentally reliant on controlled dosages, guided psychotherapy and a supportive environment. Psychiatrists play a critical role in these trials as they prepare participants for the experience and optimize psychological variables such as personality, expectation, suggestibility etc that affect how the experience goes. The patient is also attended to by therapists throughout the experience. The psychedelic is thought to facilitate or catalyse an introspective psychotherapeutic process. Following the dosing experiences are integration sessions where the therapist and the patient discuss what they learnt during the experience and how to integrate these lessons into their everyday life. So, self-medication definitely won’t produce the desired effects. Psychedelics in recreational use are often associated with persisting negative mood fluctuations and depressive symptoms, sometimes even lasting months after use. Psychedelics are also being studied for treatment of particular conditions, and are not recommended to those with a predisposition to psychotic disorders or bipolar disorders.
MDMA-assisted psychotherapy for PTSD has been the most extensively studied. Several small trials have shown that such a treatment may meaningfully improve PTSD symptoms severity and lead to remission in the short term. A recent MDMA clinical trial at UCSF showed that more than 71% of its participants no longer met the criteria for PTSD diagnosis after treatment, compared with 48% for the placebo group. MDMA is thought to target memory reconsolidation and fear extinction processes, allowing for expanded perspectives and positive, affirming experiences. As an empathogen (i.e., a drug that increases empathy and feeling of connection), it can promote unlearning of distorted beliefs formed through traumatic experiences by unlocking the brain’s ability to learn from social rewards making it cognitively flexible.
Though MDMA is further along in the FDA review process, there has also been an explosion of research on psilocybin in the last several years. Psilocybin has been reported to produce feelings of bliss and connectedness, dissolution of the self/ego (i.e., loss of a sense of self or the first-person experience), and mystical-type experiences. These psychedelic experiences are often of great personal significance and can lead to productive integration and psychotherapy sessions. In one study, researchers found that a single dose of psilocybin lowered depression scores by an average of more than six points on the MADRS scale. Current interventions for treatment-resistant depression generally reduce scores by two to four points on the same scale. A notable benefit of psychedelic therapy is the rapid action of these treatments. Benefits are reportedly felt as early as the day after the treatment and for 12 weeks. The current first line treatment for depression, SSRIs, take six to eight weeks for their full effect. The difference can be life saving for some patients.
Ketamine is a legal anaesthetic which has a derivative called esketamine that is increasingly being used in low doses for treatment-resistant depression (approved use). Unlike other psychedelics being researched, the dosing sessions are much shorter. The FDA requires providers to monitor patients for only 2 hours after administering the nasal spray form.
Despite the growing evidence and excitement, major scientific and regulatory concerns persist. The FDA still requires better evidence from larger and more rigorous studies to approve these treatments. One major trial design challenge is that while the double-blind randomized controlled trial (RCT) is considered the gold standard design for clinical trials, the strong physical and psychological effects produced by psychedelics make it difficult to maintain true “blinding”. Participants and investigators can typically tell if the person received the psychedelic or a placebo thus breaking the blind and potentially distorting the evidence being presented. Additionally, the results of many studies are not generalizable and need to include diverse populations and settings.
While still in its early stages, psychedelic therapies present a rare opportunity for a novel therapeutic approach to psychiatric conditions. Larger, multisite clinical trials including diverse populations and longer follow-up periods and treatment procedures will help better understand the therapeutic potential and clarify the balance of benefits vs. harms.
Sources:
https://adf.org.au/drug-facts/psychedelics/
https://psychedelics.berkeley.edu/substances/
https://psychedelics.berkeley.edu/law/
https://www.ncbi.nlm.nih.gov/books/NBK586533/
https://www.uclahealth.org/news/article/do-psychedelics-have-role-psychiatric-treatment
https://pmc.ncbi.nlm.nih.gov/articles/PMC7447679/
https://adf.org.au/drug-facts/empathogens/
https://www.ncbi.nlm.nih.gov/books/NBK586533/
https://www.ptsd.va.gov/professional/treat/txessentials/psychedelics_assisted_therapy.asp