The Role of Psychedelics in Treating Psychiatric Disorders

Post by Lani Cupo

What are psychedelics?

The term “psychedelics” can bring a lot of things to mind: The Beatles’ iconic song, “Lucy in the Sky with Diamonds,” notorious CIA-funded truth-serum experiments, tapestry-draped college dorm rooms filled with the mingled smoke from cannabis and incense. Less frequently in the 21st century, but still prominent, are horror stories centering on the dangers of psychedelics: violent outbursts or psychotic breaks. While psychedelics have been accepted as integral to spiritual and medicinal practices worldwide for millennia, more rigorous scientific exploration of the possible therapeutic potential of psychedelics has primarily emerged over the past 15 years. But before the effects of these substances can be discussed, they must be defined.

Psychedelics, also known as hallucinogens or entheogens, comprise substances with distinct and varied sources, compositions, and effects. Classic psychedelics that will be discussed here are partial agonists at 5-HT2A serotonin receptors and include various compounds such as tryptamines (e.g., psilocybin), N,N-dimethyltryptamine (e.g., DMT, naturally present in ayahuasca), phenethylamines (e.g., mescaline found in peyote cacti), and ergotamines (e.g., lysergic acid diethylamide, LSD). MDMA (3,4-methylenedioxy-methamphetamine) which is often classified as a psychedelic, has mechanisms of action on serotonin receptors, and has also emerged as a focus for research as a potential therapeutic. 

What do psychedelics do?

The subjective experiences associated with a psychedelic “trip” can be categorized into three main groups: altered emotional processing, self-processing, and social processing, all of which can be accompanied by perceptual alterations or hallucinations. Acute exposure to psychedelics not only enhances positive mood, sometimes inducing euphoria, but also reduces the processing of negative emotions and stimuli, particularly beneficial to those with a negative emotional bias like major depressive disorder. While difficult to assess in the clinical setting, altered perception of self is a hallmark of many experiences with psychedelics. Ego dissolution (or ego death) refers to a feeling of oneness with the environment and a loss of sense of self. Ego death can be accompanied by dread related to loss of control (which is rare in clinical settings), but altered perception of self is considered integral to psychedelics’ therapeutic potential, especially for those who struggle with rumination. In healthy participants, LSD and psilocybin can increase emotional empathy (feeling ‘with’ other people), with increased positive/altruistic social effects reported 4 to 12 months after administration. Since loneliness and social disconnect can often exacerbate or even contribute to the emergence of mental illness, increased social empathy could provide therapeutic benefits. The therapeutic potential of perceptual changes (most commonly altered visual perception) is not well understood, however such changes are one the most reliable features of psychedelic experiences and therefore cannot be excluded from a consideration of the impact of psychedelics.

One hypothesis for how psychedelics may contribute to altered consciousness focuses on the cortico-striato-thalamo-cortical loop that connects cortical and subcortical (e.g., striatum and thalamus) brain regions responsible for regulating internal and external sensory experiences. Preliminary neuroimaging evidence from humans suggests psychedelics can a) reduce thalamic filtering of information pertaining to both the internal state of the body (interoceptive) and the external world (exteroceptive) and b) increase synchronization between sensory cortical brain regions. This evidence is also consistent with a hypothetical model known as the “relaxed beliefs under psychedelics (REBUS)” model, which hypothesizes that psychedelics decrease the strength of expectations and assumptions about the world and enhance the amount of bottom-up sensory information. While early studies lend support for both of these hypothetical models, they remain far from definitive and more work in this area is necessary.

What psychiatric disorders can psychedelics treat?

Recently published studies investigate the potential for psychedelics to treat cancer- and illness-related anxiety and depression, major depressive disorder (MDD), obsessive compulsive disorder (OCD), substance use disorders (SUD), and post-traumatic stress disorder (PTSD).

In clinical trials, psychedelics are most commonly administered either at moderate-high doses once or twice or in a microdosing regimen, where extremely low doses are administered multiple times. Moderate dosages have been shown to reduce symptoms of anxiety and depression at 6 months following administration. Improvement has even been seen in participants whose depression resisted two or more first-line antidepressant treatments. Reductions in anxiety and depression are also widely documented in patients with terminal illnesses. Preliminary evidence also suggests a reduction in OCD symptoms, although studies with larger sample sizes are necessary to confirm these results. 

Psilocybin has been effective at reducing the use of alcohol and nicotine in patients with a substance use disorder, with up to 32-week follow-up. Psychedelics have also shown promise in the treatment of Post-Traumatic Stress Disorder (PTSD), and clinical trials are currently underway. PTSD is a complex, multifaceted disorder, and heightened arousal and sensitivity to sensory stimuli may present a challenge to this approach. Psychedelics appear particularly promising for treating conditions that include a narrowed, internalized mental state, seen in symptoms such as rumination and obsessive, or intrusive thoughts. Psychedelics show promise in treating other disorders such as anorexia or bulimia as well, but future research is required to confirm this.

On the other hand, studies that have examined microdosing regimes show mixed effects. In one study examining the impact of low or high doses of LSD on anxiety symptoms, one study reported decreased anxiety after high doses, but increased anxiety after low doses, a symptom that was only reduced after the group was switched to the high dose in a crossover experimental design. Slight increases in anxiety were observed in healthy participants in the microdosing regime as well. Future studies are needed to investigate the effects of administration doses and regimens, especially as most microdosing research conducted thus far has been in healthy participants.

What are the current debates?

While much of the preliminary data suggests great therapeutic benefit from psychedelics in treating select psychiatric disorders, there is debate as to whether the subjective experience associated with psychedelic use is necessary for the beneficial effects. In fact, in a special issue of the Journal of ACS Pharmacology in 2020, two papers with opposing views on this debate were published side-by-side (see references Olson, Yaden). Olson posits that while some participants report breakthroughs with mystical experiences associated with their psychedelic treatment, other participants who do not report mystical experiences still exhibit improved symptomatology. Additionally, not all patients who do have a psychological breakthrough during treatment see a benefit to their symptoms. The author also points out that these experiences may be an indication of 5-HT2A receptor activation, perhaps representing a dose-response relationship. In other words, mystical psychedelic experiences could be due to more of the drug binding to receptors in the brain. In contrast, Yaden and Griffiths present evidence suggesting a major role for mystical experiences in the lasting beneficial outcomes of treatment with psychedelics. They suggest that in order to discern whether psychedelics can be effective treatments without the subjective psychedelic experiences, one could test psychedelic and placebo treatments while participants are fully unconscious, encoding no memories of the experiences themselves. Therefore, the question of what role the subjective experience of psychedelics plays in treatment response remains open.

What’s the hope for the future?

So, can psychedelics be used as an effective treatment for psychiatric disorders? Given the accumulating research evidence, psychedelics represent a promising tool for the treatment of psychiatric disorders—many of which have few pharmacological treatments (such as PTSD) or are characterized by high rates of treatment resistance (such as MDD). Given the mild, infrequent side-effects associated with psychedelics when administered in a safe, clinical setting, the potential benefit is high. It is important to note, however, that much of the research conducted thus far has been in relatively small sample sizes which often lacked a placebo control. Yet, clinical trials are already underway — such as MDMA-assisted therapy for PTSD — and based on this research, the coming decades may see Food and Drug Administration approval for psychedelics to be used as a treatment for a variety of psychiatric conditions.

References

Andersen et al. Therapeutic Effects of Classic Serotonergic Psychedelics: A Systematic Review of Modern-Era Clinical Studies. Acta Psychiatrica Scandinavica. (2021). Access the original scientific publication here.

Erritzoe et al. In Vivo Imaging of Cerebral Serotonin Transporter and serotonin2A Receptor Binding in 3, 4-Methylenedioxymethamphetamine (MDMA or ‘ecstasy’) and Hallucinogen Users. Archives of General Psychiatry (2011). Access the original scientific publication here.

Krediet et al. Reviewing the Potential of Psychedelics for the Treatment of PTSD. The International Journal of Neuropsychopharmacology. (2020). Access the original scientific publication .

Kuypers. The Therapeutic Potential of Microdosing Psychedelics in Depression. Therapeutic Advances in Psychopharmacology. (2020). Access the original scientific publication here.

Olson. The Subjective Effects of Psychedelics May Not Be Necessary for Their Enduring Therapeutic Effects. ACS Pharmacology & Translational Science (2021). Access the original scientific publication here.

Vollenweider. Psychedelic Drugs: Neurobiology and Potential for Treatment of Psychiatric Disorders. Nature Reviews. Neuroscience (2020). Access the original scientific publication here.

Yaden, David B., and Roland R. Griffiths. The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects. ACS Pharmacology & Translational Science (2021). Access the original scientific publication here.