The Promise of Psychedelic Science

This commentary (2021) to a special psychedelic edition of ASC Pharmacology & Translational Science highlights the psychedelic science being conducted, and the interdisciplinary efforts that are required to advance the field forward.

Abstract

From the first paragraph (as this commentary has no abstract): “The use of psychedelics as medicines is perhaps one of the most exciting developments in neuropsychiatry given that these drugs appear to produce both rapid and sustained therapeutic effects across multiple neuropsychiatric disorders, including depression, post-traumatic stress disorder (PTSD), and substance use disorder (SUD). Understanding exactly how these powerful drugs affect brain function will require all the tools of modern science as well as the combined efforts of chemists, molecular biologists, neuroscientists, psychologists, and clinicians.“

Author: David. E. Olson

Notes

The chemical structure of (psychedelic) molecules is (partly) responsible for the function that they serve. This is also called the structure-activity relationship (SAR). New techniques, which are also being used in other studies in the same publication, are showing that computer simulations of SAR will play a key role in learning more about psychedelics and their activity.

The disconnect between the psychedelic/hallucinogenic and therapeutic response that Olson and colleagues (Cameron et al., 2020) found with tabernanthalog, is also being found by other researchers. Flanagan and colleagues (2020) “found that there is no correlation between anti-inflammatory and hallucinogenic effects, suggesting that psychedelics might be used as lead structures to identify non-hallucinogenic compounds capable of reducing inflammation.”

The ability of psychedelics to help neurons (re)grow is also highlighted. Ly and colleagues (2020) have for instance shown that a short stimulation of neuronal cells with LSD or ketamine led to sustained growth. The race is now on to find out how psychedelics work to increase plasticity, to both understand this process and then to design (possibly) even ‘better’ molecules that can serve this function.

The discussion about the need for subjective acute psychedelic effects for enduring effects is also highlighted. A topic that has been (very collegially) been discussed in Yaden and Griffiths (2020) who argue for this point, and Olsen (2020) who argues that it isn’t necessary.

As we better understand psychedelic compounds, we keep on discovering potential new uses for them. Research by Bhat and colleagues (2020) engineered ibogaine analogues which can help with monoamine transporter folding defects (making the transportation of neurotransmitters between neurons more difficult).

Psychedelics can possibly also help in the prevention of suicides, although research in this area is only just starting. Research by Ross and colleagues (2020) on psilocybin-assisted psychotherapy is highlighted. In our database, you can find even more about suicidality, with most studies being done with ketamine.

Olson also highlights the research that has been done by Strickland and colleagues (2020) on music genres, but do note that the sample size here is terribly small (n=10).

Relevant to bringing psychedelics into the clinic (and beyond that) will be predictors of how someone will react to them. Psychological factors such as anxiety were studied by Stauffer and colleagues (2020) and a systematic review on this topic was done by Aday and colleagues (2021). They found that traits of absorption, openness, acceptance, and surrender correlated with more positive and mystical (MEQ30) experiences.

Improving the psychedelic experience by incorporating mindfulness techniques is further explored by Payne and colleagues (2021). Their perspective article proposes various synergies between mindfulness practice and psychedelics. The authors argue that psychedelics can form the compass (direction setting) and mindfulness the vehicle (integration).

We do need to tread lightly and as Johnson (2020) argues, not impose our own beliefs upon the participants/patients. Further ethical and intellectual property concerns are raised by Gerber and colleagues (2021).

Olson ends this commentary with the following note of caution: “While psychedelics have demonstrated enormous promise for combatting these illnesses, we must guard against hype, move cautiously toward therapeutic applications, and most importantly, conduct psychedelic research with the rigor demanded of modern science.”

Summary

Psychedelics have been shown to produce rapid and sustained therapeutic effects across multiple neuropsychiatric disorders, including depression, post-traumatic stress disorder, and substance use disorder. More research is needed to understand how these powerful drugs affect brain function.

Psychedelic drugs are small molecule drugs with complex chemical structures. Structureactivity relationship studies are essential for understanding how psychedelics affect the nervous system and are critical for efforts aimed at optimizing the therapeutic properties of psychedelics.

Many phenethylamine-containing compounds possess psychedelic properties, and compounds possessing an N-methoxybenzyl group, so-called NBOMe compounds, have gained a lot of attention due to their high potencies. Stove and coworkers performed modeling using the active-state cryo-EM structure of the 5-HT2A receptor.

Psychedelics have been shown to promote neural plasticity and dampen immune responses, and Nichols and coworkers found that there is no correlation between anti-inflammatory and hallucinogenic effects.

Understanding the therapeutic mechanisms of psychedelics will be key for maximizing both efficacy and safety. The psychoplastogenic effects of psychedelics have received a lot of attention, but the subjective effects of psychedelics are often cited as being among the most meaningful experiences in a person’s life.

As the field moves toward using psychedelics as medicines, it will be important to establish robust biomarkers for evaluating efficacy and understanding how these drugs impact brain function. Ibogaine, for example, may be able to treat a medical condition called monoamine transporter folding defects.

In this issue, Johnson and coworkers investigate the influence of music genres on psychedelic therapy. They found that overtone-based music occasioned more mystical-type experiences and increased smoking abstinence compared to Western classical music.

Researchers have identified several factors that may predict how a patient will respond to psychedelic therapy. These factors include baseline attachment anxiety and baseline attachment avoidance, as well as preoccupation, apprehension, and confusion.

Johnson warns against clinicians/researchers imposing their religious/spiritual beliefs on patients, and Schenberg and coworkers raise an ethical concern regarding the cultural appropriation of psilocybin-related traditional medicines.

To fully understand how psychedelics impact brain function and human health, we need to embrace multiple perspectives, work across length scales, and take advantage of the latest scientific tools.