Naturally occurring hallucinogens have been around for centuries and are used for a myriad of reasons from recreational to spiritual. The first synthetically-made hallucinogen was created in 1938 by a chemist named Albert Hofmann who was exploring the chemical and pharmacological properties of ergot fungus in treating migraines [1][2]. Five years later, when he was inspired to do new experiments with his creation, he accidentally discovered its hallucinogenic properties after he absorbed some of the drug through his skin and noticed its strange effects [3]. This new hallucinogenic drug that Hofmann discovered is formally named lysergic diethylamide (LSD) and colloquially goes by the name acid. You may have heard about the psychological experience of taking LSD: the trippy hallucinations, the out-of-body experience, and the feelings of general euphoria or creativity. While the drug is widely known for these common effects of recreational use, renewed research efforts into the drug’s mechanisms suggest that it also has serious applications in medicine, especially in the battle against depression and anxiety.

History

Before talking about this research, it is important to know the origin of LSD. LSD is synthesized from a byproduct of the ergot fungus, a type of fungus that attacks rye and other cereal grasses [4]. It was well known throughout history that this fungus caused hallucinations - bad batches of bread made with wheat infected with this fungus caused entire towns to have wild and scary hallucinations [5]. Albert Hofmann had been working with derivatives of this fungus and trying to synthesize a drug to treat migraines when he created lysergic acid and subsequently LSD.

After its discovery, LSD became the center of many experiments as a proposed “miracle drug” because of its massive effects from a relatively low dose. The CIA bought into this “miracle drug” and started looking to LSD to be a mind control drug with a series of covert experiments in the early 1950s called MK-ULTRA [1]. These experiments focused on using LSD as a sort of truth serum where, after its effects wore off, the victim would not remember if they had spilled secrets. Some early experiments showed promise when a drugged government official divulged information with no knowledge of the occurrence afterward [1]. However, the CIA soon ran into issues because information could not always be reliably obtained from those under the influence who had bad trips. It was also not always the case that participants didn’t remember their trip or the information that had been extracted from them; participants also often recognized that they were under the influence of a drug and promptly refused to talk or give anything away. In another attempt to use this drug for espionage, it was thought that it could be used as a “lie serum” akin to a cyanide pill to be taken before interrogation to confuse the interrogators. Even with this approach, the CIA ran into issues of operatives not being able to control the subject’s trip and consequently the information they got out of it. Thus, while the CIA gave up on using LSD in this way, the public and psychiatrists still had many hopes for its uses.

LSD caused quite a cultural and scientific stir, being named as the start of the “Psychedelic Revolution” and a “miracle drug” [1]. As LSD became increasingly associated with student riots, anti-war sentiments, and general public controversy, the government intervened and criminalized this drug. The Controlled Substances Act became law in 1970 and dramatically reduced the funding that major grant-giving agencies like the National Institute of Mental Health gave to studies involving LSD and other psychedelic drugs.

Limitations of initial LSD experiments

When LSD was first discovered, there was much hope for this drug in all sorts of contexts: the CIA was hoping for a truth serum, psychologists were hoping for a drug to aid psychotherapy and reformation therapy, and most people were just looking for a trip. Of all of those endeavors, only the general public found what they had been hoping for; the rest of LSD’s uses did not come to fruition because of experimental flaws, cultural stigma, and insufficient funding.

Previous psychological research to discover how LSD affected the brain in the 1950s and 60s was limited to simple brain scans and studies. While it was a good start to get a general idea of what was happening, it by no means provided a full picture of LSD’s mechanisms of action in the brain [6]. Many of the controlled studies going on during the 1950s only focused on alcoholics and hoped to help them recover from substance abuse. While there were some positive trends with this research, this sample size of people was not diverse enough to say anything about how the general population would take to LSD therapy [7].

One challenge that scientists of the 1960s faced was the rise in popularity of the “gold standard” of experimental design: the double-blind study. In this type of study, neither the experimenters nor the participants know who is receiving a particular treatment. This experimental design is difficult with LSD studies, because there is not yet a drug that mimics the effects of LSD without also having other side effects, meaning that patients and researchers alike would recognize who was given a control and who was given LSD [6]. It was also hard to prove the efficacy of LSD as a drug treatment because therapists used LSD as a way to achieve a state of mind for the patient, not as a treatment in and of itself.

Another challenge that LSD research faced in the 1960s was a cultural backlash following some unfortunately public incidents involving LSD. Media outlets reported that a child consumed sugar laced with LSD and had to be hospitalized, while another report claimed a man murdered his mother-in-law while on LSD and had no recollection of it [8]. These types of reports as well as many other more common stories of good kids turning “bad” as a result of LSD and other drugs led to this drug being culturally stigmatized despite its potential in the medical field.

This stigma then led to a lack of funding for this type of research, and as a result of that, as well as the rise of the double-blind study as a standard, these types of experiments were dropped and LSD was banned. However, in recent years renewed interest in LSD as a treatment has allowed research into this drug to begin again, and we finally have some insights into how LSD affects brain function. Additionally, early-phase clinical trials have shown promising results for the medical use of certain hallucinogens, including LSD [9]. These trials have shown substantial and often sustained symptom reductions in patients suffering from depression, OCD, and substance use disorder.

What We Know About How LSD works

After decades of being taboo, LSD research is finally being rebooted, building on those first studies done in the 1950s. Because of the restrictions on LSD research, it was not until recently that scientists actually knew how LSD altered the brain to cause such physiological effects. LSD is able to bind to endogenous neuronal receptors, which are groups of proteins within cells in the nervous system that bind molecules known as neurotransmitters [6]. In particular, LSD has a high affinity for the serotonin 2A receptor. This receptor has been studied in depth and shows irregular activity in people with depression, schizophrenia, and other disorders. A study done in 2016 used electroencephalography (EEG) to show that LSD causes changes in the brain’s blood flow, electrical activity, and neural network patterns that all relate to the experiences volunteers had while on LSD [6]. Specifically, the “out of body” feeling many experience during a trip was found to be related to a weakened rhythm of alpha brain waves. The brain produces alpha waves when you are awake but not thinking about anything in particular. Decreased alpha rhythms are also related to a decrease in coordinated activity in regions of the brain that make up the default mode network (DMN), which is a collection of regions in the brain that monitor sensory information and consciousness [6]. Less coordinated activity in the DMN leads to parts of the brain that are not normally involved in visual processing to suddenly contribute to the visual experience, which is thought to be the cause of the hallucinations people have while on LSD.

Other current experiments with LSD

In 2014, Switzerland began the first controlled trial using LSD in over 40 years, used in conjunction with talk therapy to improve the quality of life for 12 terminally ill patients [10]. The study found that those who had received a full 200 gdose of LSD during the two months of weekly therapy improved their anxiety by about 20% [11]. This was measured using the State-Trait Anxiety Inventory, which is a standard test that evaluates the current state of a patient’s anxiety. However, the study showed that those who had received lower dose (20 g) which also was used as the placebo for the trial, experienced more anxiety and negative thoughts about their situation after the therapy [12]. After the initial two- month study period was over, patients on the lower dose were allowed to switch over to the full dose, and after a year the study found that those who had switched to the full dose of LSD enjoyed the same effects as the initial group. This study was a promising start of a new era of LSD experiments.

In early 2020, a study done with rats showed that LSD and psilocybin, a naturally-occurring hallucinogenic compound found in mushrooms, produced persistent antidepressant-like effects, whereas ketamine-- a drug that is currently being used in conjunction with most antidepressants due to its powerful immediate antidepressant effects in most people-- had only transient effects [13]. This research study also suggested that, because rats do not seem to be as self-aware as humans and therefore cannot experience existential crisis during a trip, a subjective existential experience is not necessary for the positive effects to take place [13]. After injection of either psilocybin, LSD, ketamine, or saline (control), the rats performed a series of tests, including a mobility test. The rats injected with psilocybin did better than the groups that were administered LSD or ketamine, indicating that psilocybin was better at reducing depression-like symptoms in the rats. The rats given ketamine did almost as well as the rats with LSD and psilocybin, but their results dropped off after 2 weeks, demonstrating the short life span of this treatment plan. One drawback of the study is that previous studies using psilocybin provided the researchers with the correct dosage to use, whereas for LSD, the researchers had to speculate on a correct dosage due to its novelty in research. These results demonstrate that therapies involving the serotonin receptor targeted by psilocybin and LSD have more long-term and stronger effects than ketamine-based treatments.

Another group earlier this year sought to clarify how psychedelics could be used as a treatment for depression, end-of-life distress, OCD, and substance use disorders by using psychedelics as an aid for patients undergoing cognitive behavioral therapy (CBT). CBT is a psychological technique that relies on promoting acceptance rather than avoidance. Many symptoms of disorders can be categorized as “avoidance”; for example, behavioral patterns seen with anxiety disorders can be thought of as techniques to evade stressful and anxiety-fueling situations. For depression, it might be withdrawal and rumination to avoid painful emotional experiences, and for substance abuse disorders this behavior shows itself when patients get highly intoxicated. Acceptance-based CBT is similar to practicing mindfulness in that the aim of it is to reduce harmful patterns of avoidance, which it does by increasing a patient’s readiness to engage with aversive experiences [9]. Psychedelics are used to aid this sort of therapy by encouraging the patient to turn their attention on themselves, and while closing their eyes and listening to a specific playlist of music, they experience an acute psychedelic trip. Qualitative interviews with patients after their trips often indicate that patients who did experience fear and anxiety-inducing thoughts were only able to get back into a more positive state when they “let go” and developed an accepting attitude. This acceptance theme in many patients’ trips is what aids the CBT acceptance-based therapy. Many people tend to reflect on their trips as life changing experiences, and scientists seek to harness this power of the psychedelic to bring positive life changes to their patients.

It remains largely unclear how psychedelic therapy produces such positive results as relatively few studies using LSD have been done and within those studies, there have been low numbers of volunteers [9]. Another limitation to the studies is that multiple different types of brain scans cannot be done at once, and any measurement of brain activity can be fairly taxing and time consuming for volunteers [6]. Finally, it is very difficult to get approval and funding for experiments involving psychedelic drugs such as LSD or psilocybin due to the perception that all drugs are dangerous, despite research showing that the adverse side effects from LSD are relatively rare. However, there is much to be hopeful about with these studies, including a potential low-dose, non-addictive drug to help with depression, anxiety, addiction and other afflictions of the psyche.

References

1. Lee, Martin A., and Bruce Shlain. 1992. Acid Dreams: The Complete Social History of LSD : The CIA, the Sixties, and Beyond. Grove Press. https://books.google.com/books/about/Acid_Dreams.html?hl=&id=e39s92O14EsC.
2. Dyck, Erika. 2005. “Flashback: Psychiatric Experimentation with LSD in Historical Perspective.” Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie 50 (7): 381–88. https://doi.org/10.1177/070674370505000703.
3. Delgado, João. 2020. “Intoxication from LSD and Other Common Hallucinogens.” https://www.uptodate.com/contents/intoxication-from-lsd-and-other-common-hallucinogens?search=LSD&source=search_result&selectedTitle=1~22&usage_type=default&display_rank=1.
4. The Editors of Encyclopaedia Britannica. 2019. “Ergot: Fungal Disease of Plants.” Encyclopedia Britannica. February 11, 2019. https://www.britannica.com/science/ergot.
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7. McGlothlin, W. H., and D. O. Arnold. 1971. “LSD Revisited. A Ten-Year Follow-up of Medical LSD Use.” Archives of General Psychiatry 24 (1): 35–49. https://doi.org/10.1001/archpsyc.1971.01750070037005.
   
8. Oram, Matthew. 2014. “Efficacy and Enlightenment: LSD Psychotherapy and the Drug Amendments of 1962.” Journal of the History of Medicine and Allied Sciences 69 (2): 221–50. https://doi.org/10.1093/jhmas/jrs050.
   
9. Wolff, Max, Ricarda Evens, Lea J. Mertens, Michael Koslowski, Felix Betzler, Gerhard Gründer, and Henrik Jungaberle. 2020. “Learning to Let Go: A Cognitive-Behavioral Model of How Psychedelic Therapy Promotes Acceptance.” Frontiers in Psychiatry / Frontiers Research Foundation 11 (February): 5. https://doi.org/10.3389/fpsyt.2020.00005.
10. Carey, Benedict. 2014. “LSD, Reconsidered for Therapy.” The New York Times. March 3, 2014. https://petergasser.ch/wp-content/uploads/2019/05/lsd-for-therapy-NY-Times-4-3-14.pdf.
11. Kim, Victoria. 2014. “Swiss LSD Study Yields Incredible Results for Terminally Ill Patients.” Mic. Mic. March 5, 2014. https://www.mic.com/articles/84383/swiss-lsd-study-yields-incredible-results-for-terminally-ill-patients.
12. Gasser, Peter, Dominique Holstein, Yvonne Michel, Rick Doblin, Berra Yazar-Klosinski, Torsten Passie, and Rudolf Brenneisen. 2014. “Safety and Efficacy of Lysergic Acid Diethylamide-Assisted Psychotherapy for Anxiety Associated with Life-Threatening Diseases.” The Journal of Nervous and Mental Disease 202 (7): 513–20. https://doi.org/10.1097/NMD.0000000000000113.
13. Hibicke, Meghan, Alexus N. Landry, Hannah M. Kramer, Zoe K. Talman, and Charles D. Nichols. 2020. “Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression.” ACS Chemical Neuroscience 11 (6): 864–71. https://doi.org/10.1021/acschemneuro.9b00493.