Lysergic acid diethylamide (LSD) has a long and colorful history in psychiatric research. Over the last 75 years, waves of excitement have been quickly tempered by waves of fear. For decades, controversies, counterculture, and conservative crackdowns have dampened its potential as a powerful treatment for mental health.
LSD: A Colorful History
Lysergic acid diethylamide is an ergot-derived substance that began as an accident. Swiss chemist Albert Hofmann first discovered LSD in 1938, but it wasn’t until he accidentally came into contact with his creation a few years later that its hallucinogenic characteristics became apparent. On what is now lovingly known as Bicycle Day, Hofman was the first person in human history to experience the effects of this profoundly psychedelic substance.
Initially, Hofman was studying solutions for reducing postpartum hemorrhage, but after his unexpectedly psychedelic bicycle ride, LSD’s effects showed their value for the field of psychiatric medicine instead. In the years that followed, researchers began exploring LSD for applications in mental health, with early studies investigating its potential for a wide range of disorders, including depression, anxiety, and addiction.
Surprisingly, given LSD’s current status as a Schedule 1 drug, it was already on the market back in the 1950s, sold by Sandoz laboratories under the name Delysid. A handful of psychiatric hospitals also used it at their facilities. Not to mention the fact that the CIA and the US military famously dabbled with LSD, hoping they could deploy it as a weapon to incapacitate enemy soldiers.
But, as LSD’s hallucinogenic effects became increasingly well known, it found itself in trouble. After inspiring an entire counterculture generation, the US government cracked down in 1967. The Controlled Substances Act still lists LSD as a Schedule 1 controlled substance.
But, times are changing.
Does LSD Deserve a Rethink?
According to a systematic review of randomized clinical controlled trials published in 2020, “LSD does not entail physical dependence as withdrawal syndrome;” “emotional, physical and mental stability is quickly recovered” following a single dose; and it has a “very low physiological toxicity, even at very high doses.”
Experts now consider LSD “one of the safest psychoactive recreational substances,” so should we reconsider its psychiatric potential?
Firstly, we now have an improved understanding of the mechanics behind LSD’s effects — thanks to better study designed in this new era of research. For example, a paper published in 2020 established the dose-dependent curve of effects from LSD and confirmed, “The full psychedelic effects of LSD are primarily mediated by serotonin 5-HT2A receptor activation.”
According to these results (based on a double-blind, randomized, placebo-controlled, crossover study design working with 25, 50, 100, and 200 µg of LSD), the ‘good’ drug effects reached a ceiling at 100 µg. Beyond this, larger doses triggered higher anxiety levels and greater ego dissolution.
Recent trials have also made more significant efforts to improve the “set and setting” of the experience compared with the studies from the mid-20th century. This means more comprehensive preparation for the participants, better interpersonal environments, and, in some cases, even a musical component.
According to the systemic review mentioned above, there is enough evidence from high-quality clinical studies to warrant further exploration of LSD for the treatment of alcohol use disorder, anxiety, heroin use disorder, depression, psychosomatic illnesses, and chronic disease-related anxiety.
Modern Clinical Trials Working with LSD
With research into psychedelics reemerging after decades of opposition, a growing database of contemporary clinical trials is building. ClinicalTrials.gov currently lists ten studies using LSD, many of which have been completed and are awaiting results.
The University Hospital Basel in Basel, Switzerland, is quickly establishing itself as a world leader in LSD research, already with seven studies in various stages of development. They are currently exploring the potential of this powerful psychedelic for a range of conditions, including cluster headaches, major depression, and anxiety.
In 2014, the results of one of these modern-day clinical trials were published in the Journal of Nervous and Mental Disease. The small study, sponsored by Multidisciplinary Association for Psychedelic Studies (MAPS), examined the efficacy of LSD-assisted therapy for 12 patients with anxiety related to life-threatening disease.
Although it had a small number of participants, the authors reported no adverse effects (acute or chronic) beyond the day of treatment. At the two-month follow-up, “anxiety was significantly reduced,” and these effects lasted for 12 months. These results helped pave the way for LSD reentering into contemporary psychiatric medicine.
A Strong Argument for the Future of LSD in Medicine
The recent refocus on psychedelic research has spawned an explosion of excitement, coinciding with regional regulatory changes and national media hype. But, much of the attention thus far has focused on psilocybin and ketamine, with LSD research lagging behind its psychedelic counterparts.
After all, it is still a Schedule 1 controlled substance. In addition, LSD still suffers from the lingering repercussions of its counterculture roots.
But, the momentum has started to pick up thanks to MAPS, and the University Hospital in Basel, Switzerland. As more robust clinical trials get underway, their findings will continue to refine the pharmacokinetics of this powerful hallucinogen, prove its safety profile, and strengthen the argument for LSD’s inclusion in modern psychiatric medicine.