The Subjective Effects of Psychedelics May Not Be Necessary for Their Enduring Therapeutic Effects

This opinion paper (2020) argues that the neurological effects of psychedelics alone (vs subjective experience) are enough to lead to enduring therapeutic outcomes.

Abstract

“Psychedelics represent one of the most promising classes of experimental medicines for the treatment of neuropsychiatric disorders due to their ability to promote neural plasticity and produce both rapid and sustained therapeutic effects following a single administration. Conventional wisdom holds that peak mystical experiences induced by psychedelics are a critical component of their therapeutic mechanisms of action, though evidence supporting that claim is largely correlational. Here, I present data suggesting that the subjective effects induced by psychedelics may not be necessary to produce long-lasting changes in mood and behavior. Understanding the role of subjective effects in the therapeutic mechanisms of psychedelics will have important implications for both basic neuroscience and for increasing patient access to the next generation of medicines developed as a result of psychedelic research.”

Author: David E. Olson

Notes

This paper was published at the same time, and argues (partly) against ‘The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects‘.

Two reasons why David Olson (founder of Delix Therapeutics) argues for this perspective are the 1) high costs/duration of psychedelic therapy, and 2) limited population who would be open to such an experience (both from personal preferences as family history of mental illness).

He argues that the psychological insights and mystical experiences (MEQ) do correlate with therapeutic effects, but that doesn’t imply causation, nor necessity of subjective effects.

The paper also notes the positive outcomes of MDMA-assisted psychotherapy where the level of mystical-type experiences is much lower (but do note that there is a very large and distinct subjective experience).

As noted in the opposing paper, more research with psychedelics that produce no subjective effects is necessary if this question is to be answered with more satisfaction.

Summary

Psychoplastogens, such as ketamine, are effective at treating stress-related neuropsychiatric diseases, such as depression, post-traumatic stress disorder, and addiction, by rewiring neural circuitry by engaging plasticity mechanisms.

Dissociative, deliriant, and hallucinogenic drugs have emerged as some of the most effective psychoplastogens. However, it is still unclear whether the acute subjective effects are necessary for long-lasting therapeutic responses.

Psilocybin treatment is demonstrating impressive clinical efficacy across a broad range of stress-related neuropsychiatric diseases, but the significant healthcare costs associated with it limit the use of this treatment strategy.

The substantial healthcare costs associated with using psychedelics as medicines may discourage some patients from participating in psychedelic-assisted therapy, but new medicines and treatment approaches may be devised to improve patient access to therapies inspired by psychedelic research.

Clinical studies on psychedelics have been challenged by the unique ability of these drugs to induce profound altered states of consciousness, making it exceedingly difficult to design truly double-blind, placebo-controlled studies.

Patients who are treated with psychedelic-assisted therapy often attribute the amelioration of their symptoms to a psychological breakthrough achieved during a psychedelic-induced altered state of consciousness.

Studies associating mystical experiences with improved patient outcomes are quite intriguing, but correlation does not imply causation. Thus, mystical experiences may not be necessary to produce antidepressant, anxiolytic, and antiaddictive effects.

The correlation between psychedelic-induced therapeutic outcomes and mystical-type effects may simply be a good indicator of 5-HT2A receptor activation, and further experimentation is needed to claim any causal relationship between mystical experiences and therapeutic outcomes.

Despite conventional wisdom, increasing evidence suggests that the therapeutic properties of psychedelics and related psychoplastogens can be dissociated from their subjective effects. Thus, peak mystical experiences may not be necessary for these drugs to treat mental illness.

Ketamine’s subjective effects may not be necessary to produce long-lasting therapeutic effects. Furthermore, the R-enantiomer of ketamine is a more potent psychoplastogen than the S-enantiomer, producing longer-lasting antidepressant-like effects in preclinical animal studies.

Like R-ketamine, MDMA is an atypical psychedelic of the entactogen family that does not produce psilocybin-like mystical effects. However, MDMA potently promotes neural plasticity and has shown enormous potential in the clinic for treating stress-related neuropsychiatric diseases such as PTSD.

Administration of low, subhallucinogenic doses of psychedelics may shed light on the role of mystical-type experiences in therapeutic responses, but double-blind, placebo-controlled clinical trials are currently lacking.

Even if psychedelic microdosing ultimately proves to be efficacious, regulatory hurdles and issues related to abuse potential will need to be overcome. The development of nonhallucinogenic compounds capable of producing psychedelic-like therapeutic effects would solve these issues and greatly improve patient access.

Until recently, it was unknown if nonhallucinogenic psychoplastogens could produce beneficial behavioral effects comparable to psychedelics. However, a nonhallucinogenic analogue of 5-MeO-DMT (TBG) promotes cortical neuron structural plasticity through activation of 5-HT2A receptors and has demonstrated preclinical therapeutic effects.

Psychedelics could be administered to patients under anesthesia to solve the blinding issue, but care must be taken as some anesthetics promote neural plasticity.

Although several studies have demonstrated that intraoperative ketamine can improve postoperative mood, these patients were not severely depressed. Thus, studies administering ketamine under general anesthesia to patients with major depressive disorder are warranted.

The combination of a pharmacologically induced state of heightened neural plasticity with a profound subjective experience may prove invaluable for treating those who are especially ill or who have attempted other treatments without success.

Although psychedelic-assisted therapy produces promising therapeutic responses, the intense subjective effects of these drugs make it unlikely that they will ever become widespread treatments for disorders such as depression.

■ ACKNOWLEDGMENTS

This work was supported by the National Institutes of Health. The author thanks Boris Heifets, Max Vargas, Lindsay Cameron, and Lee Dunlap for helpful discussions.