Using Acid Against Addiction: The Dawn of Psychedelic Assisted Therapy

One of the world’s most powerful psychedelic drugs, lysergic acid diethylamide (LSD), was never meant to be discovered. Albert Hoffman, commonly known as “the Father of LSD”, unexpectedly came across the drug while working as a research chemist in the 1930s. His job was to repeatedly break down ergot, a fungus that grows parasitically on rye plants, into various types of lysergic acid. During the initial testing of his 25th substance, the soon-to-be famous LSD-25, he noted that the experimental animals became restless, but the substance garnered no special interest [1].

Five years later, Hofmann decided to resynthesize LSD-25. As he completed the final steps of the process, Hofmann suddenly became lost in “an uninterrupted stream of fantastic pictures of extraordinary plasticity with intense, kaleidoscope-like plays of colors” [1], most likely due to trace amounts of the substance coming into contact with his fingertips and absorbing through the skin. Fascinated by the experience, Hofmann took more LSD. Unaware of the drug's potency, he orally consumed 0.25 milligrams - five times the recommended dose. As its effects set in, he slipped into a psychedelic nightmare. His vision wavered and distorted as if he was looking into a curved mirror. The room spun in circles around him, and his furniture took on increasingly threatening forms. Hofmann felt for a moment as if he was losing his grip on reality and knocking on the doorstep of insanity, but as the drug’s effects dwindled, he instead found himself enjoying the remarkable sensations - sounds being transformed into vivid optical perceptions, fantastic mental images culminating in kaleidoscopic explosions, and a new world revealing itself to be explored. Hofmann woke up the next day to feelings of well-being and renewed life force flowing through him. He saw the world as if it was newly created, and with that, the mystery of LSD-25 officially began [1].

At the molecular level, this mystery was facilitated by specific chemical receptors inside Hofmann’s brain - serotonin 5-hydroxytryptamine, or 5-HT2A, receptors [2]. Normally, these receptors are activated by serotonin, a multifaceted brain chemical that affects mood, cognition, and aspects of the autonomic nervous system [3]. However, due to LSD’s structural similarity with serotonin, it can activate these receptors and their respective brain cells, called neurons. This causes a powerful pattern of neuronal activation largely responsible for LSD’s psychedelic effect [2]. More specifically, LSD and other psychedelics lead to increased neuronal activation in the brain’s visual cortex, which is thought to produce LSD’s otherworldly hallucinations [4]. LSD also leads to decreased activation within the brain’s default mode network, which is a series of connected brain structures responsible for introspective aspects of cognition, mind-wandering, and one’s sense of self [5]. This results in the loss of ego and transcendence of reality first experienced by Hofmann eight decades ago [4]. 

Although Hofmann was the first to experience the effects of LSD, he was far from the first person to encounter the magic of psychedelic drugs. For example, carbon-dated ashes from a ceremonial fireplace in Mexico trace the use of the psychedelic Peyote cactus as far back as fifteen thousand years ago. Shamans in the Amazon jungle have been administering the spiritual psychedelic brew, Ayahuasca, for over a thousand years, and in ancient Greece, the elite members of society gathered annually to consume a psychedelic drink known as Kykeon. Yet, upon embracing Christianity as its official religion, the Roman Empire banned psychedelic sacraments, erasing their presence in modernized society  [6].   

As news of LSD’s effects spread beyond the walls of Hofmann’s laboratory, scientists across the globe raced to get their hands on the substance. Psychedelic research exploded. The promise and excitement surrounding LSD led to the investigation of other psychedelic substances, such as psilocybin and MDMA, more commonly known as magic mushrooms and ecstasy, and by the mid 1960s, over 1,000 scientific papers on psychedelics had been published [7]. Psychedelia also had a massive role in popular culture. As the Vietnam war raged on and social unrest characterized the American landscape, counterculture movements cited psychedelic drugs as their inspiration for questioning government decisions and the ideals of mainstream society. LSD and other psychedelics quickly gained a negative reputation among political leaders, including President Lyndon Johnson who warned that psychedelics “threaten our nation’s health, vitality, and self- respect” [8]. In 1965, Congress passed the Drug Abuse Control Amendments, which permitted the governmental regulation of stimulants, depressants, and hallucinogens and made it nearly impossible for researchers to utilize psychedelics in human experiments [8]. Then in 1970, the Nixon administration passed the Controlled Substances Act, which listed LSD and psilocybin as Schedule I drugs, meaning they had a high potential for abuse and no potential as a medical treatment. This designation may have been politically motivated as there was no evidence at the time to back these claims. Unfortunately, the scientific methods of the past could not provide an adequate understanding of the pharmacology and toxicology of these substances [9]. However, modern scientific methods have allowed for a psychedelic renaissance.

In 2000, researchers at John Hopkins University were the first in the United States to receive regulatory approval to resurrect psychedelic research. Six years later, they published a paper describing the safety and lasting positive effects of a single psilocybin dose, and in doing so, renewed scientific interest in psychedelics worldwide [10]. Today, in contrast with the information provided by the Nixon administration, psychedelics, such as LSD and psilocybin, are heralded for their incredibly low physiological toxicity and lack of addictive symptoms upon cessation of use [11]. Furthermore, evidence suggests that psychedelics have long lasting effects that are neuroprotective, encourage brain cell survival, and regulate the brain’s neuroimmune systems [12]. Evidence also suggests that psychedelics promote neuroplasticity - the brain’s ability to reorganize itself and form new connections between neurons throughout one’s life [13]. These discoveries, among others, have further emphasized the therapeutic potential of psychedelics and warranted investigations into the efficacy of psychedelic treatment for a wide variety of conditions, including addiction, depression, anxiety, existential distress, Alzheimer’s Disease, and Obsessive-Compulsive Disorder [14]. In recent years, the promising results of clinical trials have earned both psilocybin (depression, anxiety, and end of life distress) and MDMA (PTSD) the FDA’s Breakthrough Therapy Designation [15,16]. 

References:

1. Hofmann, A. (1979). How LSD originated. Journal of Psychedelic Drugs, 11(1-2), 53-60. https://doi.org/10.1080/02791072.1979.10472092 

2. Nichols, D. E. (2016). Psychedelics. Pharmacological Reviews, 68(2), 264-355. https://doi.org/10.1124/pr.115.011478 

3. Barnes, N. M., & Sharp, T. (1999). A review of central 5-HT receptors and their function. Neuropharmacology, 38(8), 1083-1152. https://doi.org/10.1016/s0028-3908(99)00010-6 

4. Carhart-Harris, R. L., Muthukumaraswamy, S., Roseman, L., Kaelen, M., Droog, W., Murphy, K., . . . Nutt, D. J. (2016). Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proceedings of the National Academy of Sciences of the United States of America, 113(17), 4853-4858. https://doi.org/10.1073/pnas.1518377113 

5. Buckner, R. L., Andrews-Hanna, J. R., & Schacter, D. L. (2008). The brain's default network - Anatomy, function, and relevance to disease. Year in Cognitive Neuroscience 2008, 1124, 1-38. https://doi.org/10.1196/annals.1440.011

6. Austin, P. F. (2022). Mastering microdosing: How to use sub-perceptual psychedelics to heal trauma, improve performance, and transform your life. Houndstooth Press. 

7. Belouin, S. J., & Henningfield, J. E. (2018). Psychedelics: Where we are now, why we got here, what we must do. Neuropharmacology, 142, 7-19. https://doi.org/10.1016/j.neuropharm.2018.02.018 

8. Bonson, K. R. (2018). Regulation of human research with LSD in the United States (1949-1987). Psychopharmacology, 235(2), 591-604. https://doi.org/10.1007/s00213-017-4777-4  

9. Nutt, D. J., King, L. A., & Nichols, D. E. (2013). Effects of Schedule I drug laws on neuroscience research and treatment innovation. Nature Reviews Neuroscience, 14(8), 577-585. https://doi.org/10.1038/nrn3530 

10. Johns Hopkins Medicine. (n.d.). Psychedelics Research and Psilocybin Therapy. https://www.hopkinsmedicine.org/psychiatry/research/psychedelics-research.html

11. Fuentes, J. J., Fonseca, F., Elices, M., Farr, M., & Torrens, M. (2020). Therapeutic use of LSD in psychiatry: A systematic review of randomized-controlled clinical trials. Frontiers in Psychiatry, 10, 14, Article 943. https://doi.org/10.3389/fpsyt.2019.00943

12. Calvey, T., & Howells, F. M. (2018). An introduction to psychedelic neuroscience. In T. Calvey (Ed.), Psychedelic Neuroscience (Vol. 242, pp. 1-23). Elsevier Science Bv. https://doi.org/10.1016/bs.pbr.2018.09.013 

13. Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., Barragan, E. V., Wilson, P. C., . . . Olson, D. E. (2018). Psychedelics promote structural and functional neural plasticity. Cell Reports, 23(11), 3170-3182. https://doi.org/10.1016/j.celrep.2018.05.022

14. Johns Hopkins Center for Psychedelic & Consciousness Research. (n.d.). About. https://hopkinspsychedelic.org

15. Barber, G. S., & Aaronson, S. T. (2022). The emerging field of psychedelic psychotherapy. Current Psychiatry Reports, 24(10), 583-590. https://doi.org/10.1007/s11920-022-01363-y 

16. McClure-Begley, T. D., & Roth, B. L. (2022). The promises and perils of psychedelic pharmacology for psychiatry. Nature Reviews Drug Discovery, 21(6), 463-473. https://doi.org/10.1038/s41573-022-00421-7