By Macarena Cortina, Psychology ‘21 

Author’s Note: As a psychology major who used to be a plant biology major, I’m very interested in the arenas where these two fields interact. Such is the case with psychoactive plants and fungi that produce significant alterations in brain chemistry and other aspects of the human psyche. That is why I chose to write about psychedelics and their rebirth in both research and culture. In the past few months, I have seen increasing media coverage of new scientific findings about these substances, as well as legal advancements in their decriminalization, making this a relevant topic in the worlds of psychology and ethnobotany. The history of psychedelics is a long and complicated one, but here I attempt to cover the basics in hopes of demystifying these new powerful therapeutic treatments and informing readers about the latest horizon in mental health. 

After decades in the dark, psychedelic drugs are finally resurfacing in the world of science and medicine as potential new tools for mental health treatment. Psychedelics, otherwise known as hallucinogens, are a class of psychoactive substances that have the power to alter mood, perception, and cognitive functions in the human brain. They include drugs such as LSD, magic mushrooms, ayahuasca, MDMA, and peyote [1]. The US has a long and complex history with these drugs, and the resulting criminalization and stigma associated with them have kept psychedelics in the shadows for many years. However, a major shift in society’s opinions of psychedelics is taking place, and a reawakening is happening in the scientific community. Researchers from various disciplines are becoming increasingly interested in unlocking the therapeutic powers of these compounds, especially for those who are diagnosed with mental disorders and are resistant to the treatments that are currently available for them. Whether or not the world is ready for it, the psychedelic renaissance has begun.

Psychedelics have been used by Indigenous communities around the world as part of their cultural, spiritual, and healing traditions for thousands of years. In the Western world, psychedelics were rediscovered in the 1940s by Swiss chemist Albert Hofmann, who accidentally absorbed LSD through his skin while conducting tests for a potential medicine [2]. What followed was an “uninterrupted stream of fantastic pictures, extraordinary shapes, with intense, kaleidoscopic play of colors” [7]. Once LSD was disseminated throughout the world, psychologists began to experiment with it as a psychotomimetic, or a drug that mimics psychosis, in hopes of gaining a better understanding of schizophrenia and similar mental disorders [2, 3]. In the 1950s, as a result of the US government’s fear that communist nations were using mind control to brainwash US prisoners of war, the CIA carried out the top-secret project MK-Ultra, drugging even unwitting subjects with psychedelics in an attempt to learn about potential mind control techniques [4]. Recreational use of psychoactive substances proliferated in the counterculture movement of the 1960s, eventually leading to their criminalization and status as Schedule 1 drugs [5]. This classified them as substances with no medical value and a high potential for abuse—two descriptors we know are not factual [6].  

Now, people seem to be reevaluating their outlook on these formerly demonized drugs and are instead looking for ways to harness psychedelics’ medicinal properties for mental and physical improvement. Momentum is building quickly. Clinical trials are beginning to show real potential in the use of psychedelics for the treatment of depression, anxiety, post-traumatic stress disorder (PTSD), addiction, eating disorders, and emotional suffering caused by diagnosis of a terminal illness. The US Food and Drug Administration (FDA) has already approved the use of ketamine for therapeutic purposes with MDMA and psilocybin set to follow [7]. Psilocybin has also been decriminalized in cities across the US and was completely legalized for medical use in the entire state of Oregon in November 2020. Entrepreneurs and investors are flocking to startups such as MAPS Public Benefit Corporation and Compass Pathways, which are currently developing psychedelic drugs for therapeutic application. Research centers have been cropping up across the country as well, even at prestigious institutions like John Hopkins School of Medicine and Massachusetts General Hospital. 

So how do psychedelics work? In truth, scientists still don’t know exactly what happens to neural circuitry under the influence of these mind-altering drugs. While more research is required to fully understand how psychedelics affect the brain, there are some findings that help clarify this mystery. For example, the major group of psychedelics—called the “classic psychedelics”—closely resembles the neurotransmitter serotonin in terms of molecular structure [8]. This group includes psilocin, one of the important components of magic mushrooms; 5-MeO-DMT, which is present in a variety of plant species and at least one toad species; and LSD, also known as acid [8]. What they all have in common is a tryptamine structure, characterized by the presence of one six-atom ring linked to a five-atom ring [8]. This similarity lends itself to a strong affinity between these psychedelics and serotonin receptors in the cerebral cortex, particularly the receptor 5-HT2A [8]. The implication of this is that psychedelics can have a significant and widespread influence on brain chemistry, given that serotonin is one of the main neurotransmitters in the brain and plays a major role in mood regulation [9].

What follows is a poorly understood cascade of effects that causes disorganized activity across the brain [10]. At the same time, it seems that the brain’s default-mode network gets inhibited. British researcher Robin Carhart-Harris recently discovered this by dosing study participants with either psilocybin or LSD and examining their neural activity with the help of fMRI (functional magnetic resonance imaging). Rather than seeing what most people expected—an excitation of brain networks—Dr. Carhart-Harris found a decrease of neuronal firing in the brain, specifically in the default-mode network. According to Michael Pollan, author of the best-selling book on psychedelics How to Change Your Mind, this network is a “tightly linked set of structures connecting the prefrontal cortex to the posterior cingulate cortex to deeper, older centers of emotion and memory.” Its function appears to involve self-reflection, theory of mind, autobiographical memory, and other components that aid us in creating our identity. In other words, the ego—the conscious sense of self and thus the source of any self-destructive thoughts that may arise—seems to be localized in the default-mode network. This network is at the top of the hierarchy of brain function, meaning it regulates all other mental activity [10].

Therefore, when psychedelics enter the system and quiet the default-mode network, suddenly new and different neural pathways are free to connect, leading to a temporary rewiring of the brain [10]. In many cases, this disruption of normal brain functioning has reportedly resulted in mystical, spiritual, and highly meaningful experiences. Psychedelics facilitate neuroplasticity, thereby helping people break negative thinking patterns and showing them—even temporarily—that it’s possible to feel another way or view something from a different (and more positive) perspective. 

This kind of experience can be immensely helpful to someone who is struggling with a mental health disorder and needs a brain reset. While other techniques, such as meditation and general mindfulness, can help cultivate a similar feeling, they require much more time and effort, something that is not always feasible—and never easy—for those who are severely struggling with their mental health [10]. Psychedelics can help jump-start the process of healing, and their effects can be made even more powerful and long-lasting when coupled with psychotherapy [11]. Talking with a psychiatrist or psychologist after the drug treatment can help integrate and solidify a client’s newly acquired thinking patterns [11]. 

In a study published in The New England Journal of Medicine in April 2021, researchers found that psilocybin works at least as well as leading antidepressant escitalopram [12]. In this double-blind, randomized, controlled trial, fifty-nine participants with moderate-to-severe depression took either psilocybin or escitalopram, along with a placebo pill in both cases. After six weeks, participants in both groups exhibited lower scores on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report (QIDS-SR-16), indicating an improvement in their condition. The difference in scores between the two groups was not statistically significant, meaning that a longer study with a larger sample size is still required to show if there is an advantage to treating depression with psilocybin over conventional drugs [12]. However, one notable difference was that psilocybin seems to take effect faster than escitalopram [13]. As an SSRI (selective serotonin reuptake inhibitor), escitalopram takes a couple months to work, something that’s not helpful for those with severe depression. Psilocybin, then, is suggested to provide more immediate relief to people battling depression [13]. 

In June 2020, a team of researchers at John Hopkins published a meta-analysis of nine clinical trials concerning psychedelic-assisted therapy for mental health conditions such as PTSD, end-of-life distress, depression, and social anxiety in adults with autism [14]. These were all the “randomized, placebo-controlled trials on psychedelic-assisted therapy published [in English] after 1993.” The psychedelics in question included LSD, psilocybin, ayahuasca, and MDMA. Following their statistical meta-analysis of these trials, they found that the “overall between-group effect size at the primary endpoint for psychedelic-assisted therapy compared to placebo was very large (Hedges g = 1.21). This effect size reflects an 80% probability that a randomly selected patient undergoing psychedelic-assisted therapy will have a better outcome than a randomly selected patient receiving a placebo” [14]. 

There were only minimal adverse effects reported from this kind of therapy and no documentation of serious adverse effects [14]. When compared to effect sizes of pharmacological agents and psychotherapy interventions, the effects of psychedelic-assisted therapy were larger, especially considering the fact that participants received the psychedelic substance one to three times prior to the primary endpoint, as opposed to daily or close-to-daily interventions with psychotherapy or conventional medications. Overall, results suggest that psychedelic-assisted therapy is effective—with minimal adverse effects—and presents a “promising new direction in mental health treatment” [14].

At UC Davis, researchers in the Olson Lab recently engineered a drug modeled after the psychedelic ibogaine [15]. This variant, called tabernanthalog (TBG), was designed to induce the therapeutic effects of ibogaine minus the toxicity or risk of cardiac arrhythmias that make consuming ibogaine less safe. TBG is a non-hallucinogenic, water-soluble compound that can be produced in merely one step. In an experiment performed with rodents, “tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behavior, and produce antidepressant-like effects.” These effects should be long lasting given that TBG has the ability to modify the neural circuitry related to addiction, making it a much better alternative to existing anti-addiction medications. And since the brain circuits involved in addiction overlap with those of conditions like depression, anxiety, and post-traumatic stress disorder, TBG could help treat various mental health issues [15]. 

As the psychedelic industry begins to emerge, members of the psychedelic community are voicing their concerns about the risks that come with rapid commercialization [7]. Biotech companies, researchers, and therapists should be careful about marketing psychedelics as a casual, quick fix to people’s problems. Psychedelics can occasion intense and profound experiences and should be consumed with the right mindset, setting, and guidance. There are still many unknowns about psychedelic use, especially its long-term effects. Not all individuals should try treatment with psychedelics, especially those with a personal or family history of psychosis. It will also be important to move forward in a way that is respectful to Indigenous traditions and accessible to all people—particularly people of color—without letting profit become the main priority. Some advocates worry that commercialization and adoption into a pharmaceutical model might strip psychedelics of their most powerful transformational benefits and that they will wind up being used merely for symptom resolution [7]. As long as psychedelics’ reintroduction to mainstream medicine is handled mindfully, the world may soon have a new avenue for effective mental health therapy that honors its Indigenous heritage and is accessible to all. 

References:

1. Alcohol & Drug Foundation. Psychedelics. October 7, 2020. Available from https://adf.org.au/drug-facts/psychedelics/. 
2. Williams L. 1999. Human Psychedelic Research: A Historical And Sociological Analysis. Cambridge University: Multidisciplinary Association for Psychedelic Studies. 
3. Sessa B. 2006. From Sacred Plants to Psychotherapy:The History and Re-Emergence of Psychedelics in Medicine. Royal College of Psychiatrists.
4. History. MK-Ultra. June 16, 2017. Available from https://www.history.com/topics/us-government/history-of-mk-ultra. 
5. Beres D. Psychedelic Spotlight. Why Are Psychedelics Illegal? October 13, 2020. Available from https://psychedelicspotlight.com/why-are-psychedelics-illegal/. 
6. United States Drug Enforcement Administration. Drug Scheduling. Available from https://www.dea.gov/drug-information/drug-scheduling.
7. Gregoire C. NEO.LIFE. Inside the Movement to Decolonize Psychedelic Pharma. October 29, 2020. Available from https://neo.life/2020/10/inside-the-movement-to-decolonize-psychedelic-pharma/. 
8. Pollan M. How to Change Your Mind: What the New Science of Psychedelics Teaches Us About Consciousness, Dying, Addiction, Depression, and Transcendence. New York: Penguin Press; 2018.
9. Bancos I. Hormone Health Network. What is Serotonin? December 2018. Available from https://www.hormone.org/your-health-and-hormones/glands-and-hormones-a-to-z/hormones/serotonin#:~:text=Serotonin%20is%20the%20key%20hormone, sleeping%2C%20eating%2C%20and%20digestion. 
10. Pollan M, Harris S, Silva J, Goertzel B. December 11, 2020. Psychedelics: The scientific renaissance of mind-altering drugs. YouTube: Big Think. 1 online video: 20 min, sound, color. 
11. Singer M. 2021. Trip Adviser.Vogue. March issue: 198-199, 222-224. 
12. Carhart-Harris R, Giribaldi B, Watts R, Baker-Jones M, Murphy-Beiner A, Murphy R, Martell J, Blemings A, Erritzoe D, Nutt DJ. 2021. Trial of Psilocybin versus Escitalopram for Depression. N Engl J Med [Internet]. 384:1402-1411. doi: 10.1056/NEJMoa2032994.
13. Lee YJ. Business Insider Australia. A landmark study shows the main compound in magic mushrooms could rival a leading depression drug. April 14, 2021. Available from https://www.businessinsider.com.au/psilocybin-magic-mushroom-for-depression-takeaways-from-icl-report-nejm-2021-4. 
14. Luoma JB, Chwyl C, Bathje GJ, Davis AK, Lacelotta R. 2020. A Meta-Analysis of Placebo-Controlled Trials of Psychedelic-Assisted Therapy. Journal of Psychoactive Drugs [Internet]. 52(4):289-299. doi: 10.1080/02791072.2020.1769878.
15. Cameron LP, Tombari RJ, Olson DE, et al. 2020. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature [Internet]. 589:474–479. https://doi.org/10.1038/s41586-020-3008-z.