The first hallucinogen synthesized was LSD (1938) by a Swiss chemist Albert Hoffman. LSD was being marketed as an adjunctive psychotherapy medication as early as 1947 by Sandoz. In 1960, the study of psilocybin began as an adjuvant agent for psychotherapy started by Harvard psychologist Timothy Leary. The concept is an old one but now the studies are better designed. All this investigation came to a halt after the Controlled Substances Act was passed in 1970. The past decade has seen a resurgence in the study of the potential benefits of psychedelic compounds. The DEA currently classifies these agents as Schedule I substances.
The psychedelics are currently classified into four classes based on their pharmacological profiles and chemical structures.
Classic psychedelics: Serotonin 2A (5-HT2A) receptor agonists (LSD, psilocybin, and ayahuasca) covered in this article
Empathogens or entactogens: mixed serotonin and dopamine reuptake inhibitors and releasers (MDMA).
Dissociative anesthetic agents: (N-methyl-D-aspartate [NMDA] antagonists e.g. ketamine
Atypical hallucinogens: affecting multiple neurotransmitter systems
Psilocybin: is derived from tryptamine precursors and found in a variety of mushroom species natively used in Central and South America to facilitate spiritual experiences. Psilocybin is metabolized to psilocin which inhibits the serotonin transporter. It also has binding affinities to multiple serotonin receptors (5-HT2A, 5-HT2C, 5-HT1A, and 5-HT1B). It has been investigated in the treatment of refractory mood disorders and obsessive-compulsive disorder, anxiety at end-of-life, and alcohol and tobacco use disorders. In the past RCT has shown positive effects in improvement of mood and even with a six-month follow-up. It has been studied with comorbid cancer-related anxiety using RCTs suggesting lasting efficacy. It was designated “breakthrough therapy” status by the FDA in 2018 for treatment-resistant depression. Multiple trials are ongoing at this time without enough data to support use in clinical practice currently. It can cause increased fear, anxiety, depression, and paranoia.
LSD: This is an ergot derivative that is known for its ability to induce powerful psychedelic and spiritual experiences. The effects of LSD are mediated via partial agonism at the 5-HT2A receptor, binding to the 5-HT2C, 5-HT1A, and 5-HT2 B receptors and binding at D2 receptors. It also causes glutamate release in the frontal cortex. LSD has been studied for pain syndromes, mood disorders, anxiety, and alcohol use disorder. This agent has been studied outside of the United States by Swiss and German researchers using RCTs. The results are less impressive than psilocybin. The evidence is currently limited and needs further study.
Ayahuasca: This is a decoction of two different plants in the amazon basin (Banisreriopsis caapi and Psychotria viridis). It is used for traditional practices by indigenous groups in the north-western Amazon region. The preparation simultaneously inhibits monoamine oxidase A (MAO-A), preventing degradation of a serotonin and a norepinephrine transporter. It also serves as an agonist of the 5-HT1A, 5-HT2A, 5-HT2C, and 5-HT2B. This agent is associated with auditory and visual hallucinations, altered spatial orientation, altered sensorium, and euphoria. This is agent is being studied outside the United States for antidepressant refractory depression. In small samples, it has been found to been shown to improve mood with impressive statistical significance (p<0.0005). The studies are limited by small samples, lack of standardization of the concoction administered, and lack of placebo.
MDMA: This agent has structural similarities to amphetamine and mescaline. Despite a lack of evidence, some psychotherapists began using MDMA to enhance the outcome of psychotherapy sessions. It was associated with feelings of emotional well-being and called “penicillin of the soul”. It subsequently became a street drug being illicitly produced and called “ecstasy”.
The effects are mediated by multiple mechanisms including monoamine release, serotonin, and norepinephrine transporter reuptake inhibition, monoamine oxidase inhibition, a partial agonist of the serotonin receptors (5-HT2A, 5-HT1A, and 5-HT2C receptors.). This agent has been studied in healthy volunteers as well as PTSD patients using RCTs for MDMA assisted psychotherapy. There were statistically significant changes in the MDMA treated group revealing a decline in symptoms (p=0.0005). The studies used and the Clinician-Administered PTSD Scale (CAPS) a gold standard for this disease state. The FDA has approved clinical trials in 2016 for PTSD. In 2017 MDMA also was given “breakthrough therapy” status by the FDA.
In Summary: The psychedelic drugs are in various stages of investigation currently. The number of sites doing research is limited by these drugs being classified as Schedule I. These agents are currently not ready for prime time. They need further study, and if approved by the FDA may come under the Risk Evaluation and Mitigation Strategy (REMS). With the FDA approval of intranasal esketamine for depression and the off-label use of intravenous ketamine infusions this group of agents may offer hope in the future to relieve the suffering of our patients.