A History of LSD: Discovery, the Law and Clinical Research

“Psychedelic substances, if they are used in proper ways, are very helpful to mankind,” said Albert Hofmann, the man who discovered LSD.

This article will look at the status of pre-clinical and clinical research into the use of LSD to treat a range of conditions and provide insights into the future of research involving this drug. This not a list of past and current clinical trials – which can be found in a number of excellent recent reviews – but an overview and critical analysis of the background to the current vogue for psychedelic research, and an examination of some key issues facing the clinical development of LSD.

The origins of LSD

Plant extracts and natural preparations have been used for millennia as therapeutic agents across a range of conditions. The fungi that produce ergot alkaloids are known to parasitize over 600 species of monocotyledons, largely grasses, including cereal grasses such as rye, barley, corn, wheat, sorghum, and so on.   

It has been known for millennia that compounds produced by the ergot fungi are biologically active, and in particular cause profound peripheral vasoconstriction, leading to intense pain and gangrene. But the compounds also produce hallucinations, muscle spasms, convulsions, and severe diarrhea. The condition caused by ergots, when these signs occur together, is known as St Anthony’s Fire.

The effect of ergot in producing strong uterine contractions led to its medicinal use in childbirth, and subsequently as a post-partum intervention to help expel the placenta. Its vasoconstrictor effects also appear to confer some benefit in migraine.¹

It was in the medicinal chemistry laboratories at Sandoz in Basel, Switzerland, that Dr Albert Hofmann was screening semi-synthetic ergot compounds for effects on uterine smooth muscle. One of the compounds that he produced (in 1938) was lysergic acid diethylamide (LSD), a compound found to have little effect on uterine smooth muscle, and therefore discarded. For various reasons, Hofmann decided some years later to test the compound again and, while synthesizing it, must have accidentally ingested some. His consequent hallucinations have been well-described. In fact, he then took a large dose on purpose, and again experienced hallucinations. He continued to take LSD throughout his life, although in much smaller doses, and died aged 102, in 2008.

Hofmann had a conviction that LSD offered definite benefits: “It gave me an inner joy, an open-mindedness, a gratefulness, open eyes and an internal sensitivity for the miracles of creation.”² The Sandoz version of LSD, with the trademark Delysid, was marketed for use in psychiatry/psychotherapy in 1947, right at the beginning of the Cold War.

Soon afterward, the United States Central Intelligence Agency began using LSD in a series of experiments that constituted a more or less clandestine program called MK-Ultra. While this program was subsequently investigated and criticized by the US Government, in fact, it probably was largely responsible for increasing the use of LSD by parts of the psychiatric community and introduced some of the most prominent LSD advocates to the compound.

Despite the enthusiasm of many commentators, especially from the world of psychiatry, there has been no widespread community movement calling for the legitimization of the medicinal use of LSD, although it has been recommended for its "mind-expanding" potential. When LSD was first introduced, in 1947, as a therapeutic agent, it was recommended for the treatment of psychoneuroses, especially anxiety states and obsessional neuroses, and as a means of inducing a model psychosis in normal individuals.

The legal setting

It is often stated that Richard Nixon initiated the War on Drugs that resulted in the Controlled Substances Act of 1970, which consigned LSD (and other drugs including cannabis) into Schedule 1, essentially labeling it highly addictive and of no recognized medicinal value. But in fact, LSD was banned in California and Nevada in 1966, three years before Nixon became president, and marijuana had been effectively banned for many years before that.³ Both states, incidentally, continued to permit its use for scientific investigation. In fact, the term War on Drugs was not used by Nixon until 1971. These legal moves, together with an intensely hostile editorial in the New England Journal of Medicine in 1966, effectively put an end to research into LSD and other psychedelics. 

Renewed interest in LSD as a medicine

From the 1990s onwards, there has been a renewed interest in the potential therapeutic role of LSD and other psychedelic agents. Strangely, there seems to be more research activity with psilocybin than with LSD, despite much more legacy data being available for LSD. The reasons for this renewed interest are unclear. Possibly, the relative failure of existing pharmacotherapy to effectively target the areas in which LSD had previously been studied – notably alcohol misuse and anxiety disorders – has provoked a renewed interest. Or perhaps the establishment of a well-defined pharmacology for the activity of LSD has given greater impetus to research. Imaging studies that help explain some aspects of the effect of LSD on the brain has added academic legitimacy to clinical development. We will look briefly at the advances in understanding the pharmacology of LSD.

The pharmacology of LSD

While serotonin itself had been isolated and then synthesized for many years, the serotonin (5-HT) receptor family was only identified from the late 1980s onwards. The action of ergots on the serotonin receptor family facilitated rapid advances in identifying and cloning the various serotonin receptor families and sub-families.⁴ This millennium, no new serotonin receptors have been identified. LSD was found to be a potent agonist at the 5-HT2A receptor, and its activity at this receptor is considered to be primarily responsible for its ability to alter psychological processes, and to produce the psychedelic effect. These effects can be blocked by the use of 5-HT2a receptor antagonists.

However, there is evidence that LSD also has meaningful activity at the dopamine D2 receptor, and this may also play a part in its pharmacodynamic effect.⁵ Analytical Cannabis asked Gary Gilmour, a prominent neuropharmacologist and currently head of preclinical research at Compass Pathways, whether our current understanding of the pharmacology of LSD was sufficient to identify the optimal therapeutic target.

He said, “Broad receptor screening profiles to know exactly what the relative affinities of LSD are across a range of receptors, coupled with a robust PK/PD model (i.e. linking LSD plasma exposure to 5HT2A receptor subtype engagement via PET imaging or in vivo receptor occupancy) would help to provide a rationale for the choice of aiming for particular exposure levels in clinical studies.” In short, we should be looking for a robust pharmacologic rationale for our choice of indication and dosage, and not only relying on empirical evidence from prior clinical trials.

Clinical trials with LSD

The backlash against the use of LSD, which started in California and Nevada in 1966, and then spread across the US, meant that clinical trials effectively ceased. Up to the 1960s, the two main areas of therapeutic interest were in the treatment of alcohol abuse, and in the use of LSD as a psycholytic therapy in a range of psychoneuroses, including mood disorders, but with a focus on anxiety.

The support (set and setting) given to the patient to allow them to manage and then integrate the experience of taking LSD into their view of the world was considered important, especially in avoiding unwanted psychological consequences. It’s probably fair to say that none of these studies provided good quality evidence that LSD was safe and effective in any single indication, although many cases have been cited where individuals had major improvements, across a range of indications. 

When academic interest revived, the primary targets for clinical trials lay in the same conditions that had been investigated back in the 1950s and 1960s. For LSD, these were primarily alcohol use disorder and anxiety disorders, with a sideways look at pain. A 2012 meta-analysis of studies looking at the role of LSD in treating alcohol use disorder concluded that there was a significant short-term benefit, but that this benefit was not maintained in the long-term (6-12 months).⁶ 

With regard to pain and anxiety disorders, Kast and Collins looked at patients with severe chronic illness and found that pain was reduced by the use of LSD to a greater degree than the established analgesics dihydromorphinone or meperidine, but that LSD was poorly tolerated – few patients were prepared to repeat the experience, despite the apparent improvement in their pain.⁷Gasser et al have reported on the potential therapeutic benefit of LSD on anxiety, especially in patients with life-threatening chronic illnesses.⁸

When asked what he thought was the most likely indication for LSD, Professor Guy Goodwin, previously head of the department of Psychiatry at Oxford University, and CMO at Compass Pathways, told Analytical Cannabis, “Anxiety/depression and its extension into chronic or life-threatening medical conditions where comorbidity amplifies the burden of distress.”

Clinical trial design issues

There are several unresolved issues with regard to clinical trial design with LSD and other psychedelics.  Almost all the evidence supporting their use is empirical. While clinical trials exist, they are for the most part open-label or small. The link between agonism at the 5-HT2A receptor and a therapeutic response in anxiety, alcoholism or pain is missing. Indeed, much of the literature speculates that it is the very personal effect of the psychedelic experience, and the setting in which it is experienced, that leads to differences in the way that the patient views the world. Imaging studies have suggested that this may be explained by particular patterns of neuroplasticity, and no doubt more evidence will emerge along these lines, but for the time being the link between the pharmacology of LSD and the therapeutic effect is unclear.⁹ 

The second key issue is dose justification. Because the clinical development of LSD has not followed conventional lines with regard to establishing, in pre-clinical studies, a dose for human studies, the dose is more or less based on the intensity of the psychedelic experience. Unfortunately, the intensity of the psychedelic experience has not yet been established as a biomarker for efficacy. And at least in the study of pain, there is some evidence proposing that there is no such link.¹⁰And since the psychedelic experience is an intensely personal experience, it is hard to see how it could act as a surrogate. This confusion about dose is reflected in the fact that some investigators are using micro-doses, where the patient does not experience a ‘trip’ at all.

This issue is in part a reflection of the relative lack of appropriate pre-clinical models. As Gilmour notes, “In the context of depression, for example, it’s important not to fall into the trap of conducting studies with traditional antidepressant assays (forced swim, tail suspension, etc.), which really do not offer any predictive validity at all for efficacy. Adopting a more considered approach to the assessment of different neuropsychological constructs (e.g. learning, memory, affective valence) would help to understand the biological impact of LSD in more detail.”

In a similar vein, the optimal dose frequency is very unclear. In the early days of the therapeutic use of LSD, intermittent dosing was common, but more recently conducted clinical trials have used a single dose and observed the effects over prolonged periods. It is not really clear why this approach has been taken – the old literature generally used repeated-dose regimens.

When asked what he thought were the biggest hurdles to the clinical development of LSD, Goodwin said, “Uncertainty about the appropriate dosing and the rather prolonged effects at high doses which necessitate medical supervision.”

Thirdly, it is not yet known whether the assessment of clinical trial outcome at the regulatory stage will conclude that bias is a major confounder because the intensity of the patient experience seems very likely to unblind the patient to their treatment allocation. When designing a controlled study, all possible means of reducing or eliminating this bias must be used – for example, blinded third-party assessors, and possibly some form of active control.

Finally, the accepted endpoints in clinical trials have been established for many years and may be inappropriate for therapies that rely on the nature of the patient experience. The clinical development of LSD may require a fresh approach to how we define efficacy, at least in the field of psychiatric therapy.

References

1. Sharma N, Sharma VK, Manikyam HK and Krishna AB.  Ergot Alkaloids: A Review on Therapeutic Applications. European J Med Plants. 14: 1-17 (2016).
2. https://www.wired.com/2006/01/lsd-the-geeks-wonder-drug/ 
3. Time Magazine.  The States:  The Law and LSD.  June 10th 1966.  http://content.time.com/time/subscriber/article/0,33009,941998-1,00.html 
4. Gothert M, Bonisch H, Malinowska B and Schlicker E.  Serotonin discovery and stepwise disclosure of 5-HT receptor complexity over four decades. Part II. Some contributions of Manfred Göthert.  Pharmacological Reports. 72: 271–284 (2020).
5. S Giacomelli 1, M Palmery, L Romanelli, C Y Cheng, B Silvestrini.  Lysergic acid diethylamide (LSD) is a partial agonist of D2 dopaminergic receptors and it potentiates dopamine-mediated prolactin secretion in lactotrophs in vitro.  Life Sci. 63: 215-22 (1998).
6. Krebs TS, Johansen P-O.  Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials.  J Psychopharmacol.  26: 994-1002 (2012).
7. Kast EC and Collins VJ.  Study of lysergic acid diethylamide as an analgesic agent. Anesth Analg 43: 285–291 (1964).
8. Gasser P, Kirchner K, Passie T. LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: a qualitative study of acute and sustained subjective effects. J. Psychopharmacol  29:57–8.
9. Robin L. Carhart-Harris, Suresh Muthukumaraswamy, Leor Roseman et al.  Neural correlates of the LSD experience revealed by multimodal neuroimaging.  PNAS.  113:  4853-4858 (2016).
10. Ramaekers JG, Hutten N, Mason NL et al.    A low dose of lysergic acid diethylamide decreases pain perception in healthy volunteers. J. Psychopharmacol.  2021; 35:398–405