In recent years, there has been a resurgence of interest in the therapeutic potential of Lysergic acid diethylamide (LSD), colloquially known as Lucy, which is a psychedelic drug. Beyond its recreational use, LSD is captivating the attention of researchers and clinicians alike for its potential applications in medicine. Join us on this journey as we explore the evolving landscape of LSD’s role in medicine and its potential to transform mental health treatments.
The Unmet Need
Mental health disorders affect 1 in 4 people globally and cost the United States of America (USA) economy $1.6 trillion in 2019. Worryingly, about half of patients with generalised anxiety disorder (GAD) do not respond to first-line treatment whilst 30% of patients with depression are treatment-resistant. The National Survey on Drug Use ran from 2008 to 2019 in the United States of America and surveyed 478,492 adults. One of the questions it investigated was the prevalence of LSD use in people with a clinical diagnosis of major depression disorder (MDD). Throughout the study period, there was an increase in the number of patients with depression, particularly those who were younger adults and who came from homes with lower incomes [1].
Aside mental illness, LSD is also being investigated as a treatment for cluster headaches. Cluster headaches, colloquially known as “suicide headaches” are a type of trigeminal autonomic cephalalgia disorder where patients may experience up to 8 recurrent highly painful attacks. These attacks are often described by patients as being as painful as kidney stones or giving birth. The lifetime prevalence of cluster headaches is estimated at 1.24/1,000 people with an average age of onset 20 to 40 years of age. The mean annual direct and indirect costs of cluster headaches are estimated to be >€11,000 per patient in Europe. Verapamil is the first-line preventative treatment for cluster headaches, however, only 50% of patients achieve a reduction in the frequency of attacks and just 27% of patients become attack-free [2]. The second-line preventative treatment, lithium, only reduces the frequency of cluster headaches by 37% [2]. Lithium must be dosed carefully to avoid toxic serum levels that would adversely affect kidney, liver, and thyroid function. Cluster headaches are highly debilitating and an estimated 47 to 55% of patients experience suicidal thoughts.
Interestingly, a clinical study involving 756 people with cluster headaches in the Netherlands found that this population was 7.9% more likely to partake in illegal substances. Only 5 people reported using LSD for headaches of which 3 users reported a decrease in the frequency of attacks. Only 20% reported a decrease in the duration of the attacks [3]. A similar study in Italy reported that 85.7% of 54 patients with cluster headaches did not perceive psychedelics as any less safe than conventional treatments. Three of the 4 patients in this study perceived LSD to be effective [4]. This highlights an unmet need for new and effective treatments that further reduce the frequency of attacks [3].
A Brief History of LSD
In 1938, a Swiss scientist called Albert Hofmann synthesised LSD from ergot, a grain fungus. He began investigating whether LSD had promise as a cardiovascular stimulant. Alas, it did not, and he deemed LSD to be useless [5]. He stood by his assertion until 1943 when he accidentally absorbed LSD through his skin and noticed he felt dizzy and had an extremely stimulated imagination. After 2 hours the colourful kaleidoscope of images and shapes disappeared. Hofmann began to wonder whether LSD could have mind-altering properties. His curiosity about this led to the famous “Bicycle Day” experiment [6]. Hofmann decided to experiment with consuming what he assumed was a small dose of LSD, 250 mg [5,7]. Just 40 minutes later he began to feel dizzy, anxious, and had a feeling of paralysis [6]. When he realised, he could no longer speak intelligibly he asked his laboratory assistant to take him home; as this was during World War II, their only means of transport was a bicycle [6,8]. On the ride home, he felt like time had slowed down and that he was paralysed on the spot [6]. Hofmann was not going insane as he believed he might be at the time, but he was simply experiencing LSD-induced hallucinations, colloquially known as an “acid trip” [7].
In the 1950s and early 1960s, researchers began to investigate LSD as a treatment for alcohol use disorder (AUD). The results from these studies were somewhat inconsistent, with some studies showing the benefits of LSD while others reporting no benefit. The inconsistent results from these early studies may be caused by methodological problems. Studies at this time often failed to adequately define treatment groups, the absence of adequate control groups and blinding, and adverse events (AEs) were often not reported. [7,9]. LSD was also tested as a treatment for neuroses. The results from these studies were largely positive, although it should be noted that studies often did not have a control group and results were based on clinician opinion and were therefore subjective. However, in 1967 LSD was classed as a Schedule I substance in the UN Convention on Drugs, hampering further research [9].
LSD: Mechanism of Action
LSD is a partial agonist at the 5-HT2A receptor, and this antagonism is thought to be responsible for its psychedelic effects [7]. The activation of the 5-HT2A receptor increases glutamate release in the synaptic cleft, which in turn may increase social behaviours [10]. This is more potent than psilocybin, N, N-Dimethyltryptamine or DMT, mescaline, and other psychedelic compounds [11]. LSD also binds to other serotonin receptors including 5-HT1A/1B/1D, 5-HT2A/2C, 5-HT5A, 5 HT6, and 5-HT7 receptors [7].
The plasma half-life for LSD is between 2.2 to 3.4 hours whilst the subjective effects of LSD last 8.2 to 11.6 hours [12].
A hallmark of depression is atrophy of neurons in the prefrontal cortex. LSD can increase neuritogenesis and spinogenesis in both in vitro and in vivo models. Whilst other psychedelics such as ketamine and DMT are also capable of increasing neuritogenesis, LSD was ~10x more potent than ketamine [13].
The brain-derived neurotrophic factor (BDNF) receptor, tropomyosin receptor kinase B (TrkB) is a common target for antidepressants, helping to promote neuroplasticity. LSD promotes neuroplasticity by binding to the BDNF receptor TrkB. Interestingly, LSD had a 1,000-fold higher affinity for TrkB in preclinical models compared to antidepressants including fluoxetine. This increased affinity may account for the prolonged benefits reported in some clinical trials for MDD by increasing neuroplasticity [14].
You can learn more about the mechanism of psychedelics here: How Psychedelics Work | LinkedIn
Clinical Trials for LSD
At the time of writing, just 24 clinical trials are listed on ClinicalTrials.gov, the world’s largest clinical trial database. Switzerland is currently leading the way with over 70% of all registered clinicals taking place there. Of those listed. only 2 of the 17 completed clinical trials have delivered results. Clinical trials investigating the potential medicinal use for LSD are still in the early stages with 62% being in early Phase 1 and Phase 1 stages. Most of these clinical trials aim to understand the effects LSD has on the body and its tolerability. However, some potential indications include anxiety disorders, attention deficit hyperactivity disorder, cluster headaches, major depressive disorder, and end-of-life care [15].
LSD’s Safety Profile
For LSD to be used as a treatment for mental illnesses, its safety profile must be considered. It is known that LSD is non-toxic at 50 to 200 mg [16]. For LSD to be a viable treatment option for mental illness or any medical condition, LSD must show a similar or favourable safety profile compared to the standard of care treatment(s). At the time of writing, no such studies exist, presumably due to the early nature of clinical research for LSD. With the rapid interest and increase in clinical research, it is not unfathomable to assume LSD may also have to compete with other psychedelics (n=27, p=0.011) [17]. AEs typically last for 10 to 24 hours and the most common of these were moderate increases in blood pressure, heart rate, pupil size etc. LSD was relatively safe when used per safety guidelines and in medical settings [11].
Whilst the research into this area is somewhat sparse and mostly anecdotal, there is a single double-blind, placebo-controlled clinical trial by University Hospital, Basel (NCT03604744) comparing LSD’s subjective and autonomic effects, their similarities and dose equivalence to psilocybin. However, it is important to note that this study is small with just 28 healthy participants meaning the results should be interpreted cautiously [18]. Results showed that any differences between psilocybin and LSD were dose-dependent rather than substance-dependent. However, LSD and psilocybin differently increased blood pressure and heart rate [19].
Perhaps the biggest concern with psychedelics being used as a treatment for mental illnesses is that they may induce challenging experiences in those who are already vulnerable. Relative to psilocybin/LSD alone, co-use of psilocybin/LSD with a self-reported low (but not medium-high) dose of 3,4-Methylenedioxymethamphetamine or MDMA was associated with significantly less intense total challenging experiences, grief, and fear, as well as increased self-compassion, love, and gratitude [17]. Psilocybin/LSD and medium-high dose MDMA were no more effective than psilocybin and LSD consumption alone (p=0.076) [17].
The Unanswered Questions in LSD Research
To truly understand the benefits of LSD for the treatment of mental illnesses and other illnesses including cluster headaches, it is imperative that high-quality protocols are generated. Such studies should involve hundreds of patients and ideally involve double-blinding and a placebo control group. It is most likely that disparities in the dose, dosing schedule, and clinical setting account for differences in results between clinical trials [20]
Additionally, it remains unclear what the long-term effects of LSD treatment are. A small study of 10 patients showed that LSD had lasting reductions in anxiety and no serious AEs at 12 months. However, longer-term and larger-scale studies must be undertaken due to the chronic nature of psychiatric conditions [21].
As personalised medicine gains traction, it becomes increasingly critical that psychedelic assisted therapy aligns with this trend. This is particularly imperative for harm reduction and the broader acceptance of LSD as a legitimate medicinal intervention [22]. For such a personalised approach, biomarker identification will be needed to predict individuals likely to have beneficial experiences with minimal AEs [18]. There is also a need to understand which aspects of the acute response to LSD are most useful [11], e.g., those patients who have acute mystical responses with psilocybin also have greater reductions in anxiety and depression [23-25].