Psychedelic Research

From Albert Hofmann's bicycle ride in 1943 through prohibition to today's clinical trials: how psilocybin, LSD and MDMA act on the brain, what the evidence for treating depression and PTSD shows, and the risks.

First wave

On 19 April 1943 the Swiss chemist Albert Hofmann at Sandoz deliberately took a small dose of LSD, which he had first synthesised in 1938, and experienced intense perceptual changes during his bicycle ride home — later celebrated as "Bicycle Day". In the 1950s and 60s, LSD and psilocybin (identified in mushrooms by Hofmann in 1958) were studied extensively as research tools and treatments for alcoholism and other conditions, but many studies lacked proper controls. Amid recreational use and the counterculture, they were banned; in the US, the Controlled Substances Act of 1970 placed them in Schedule I, and most research stopped.

How they act on the brain

Classic psychedelics — psilocybin (converted in the body to psilocin), LSD, DMT and mescaline — are agonists at the serotonin 5-HT2A receptor, abundant on cortical pyramidal neurons. Brain imaging shows reduced integrity of the default mode network and increased communication between normally segregated networks. In cell and animal studies, they promote rapid growth of dendritic spines and synapses ("psychoplastogens"). Theories link their effects to temporarily relaxing the brain's strong prior beliefs.

The renaissance

From the 2000s, carefully controlled studies resumed. In 2006 Roland Griffiths and colleagues at Johns Hopkins showed psilocybin could produce experiences participants rated as among the most meaningful of their lives. Trials followed for depression, cancer-related distress, smoking and alcohol use disorder. The US FDA granted breakthrough therapy designation to psilocybin for treatment-resistant depression (2018) and major depression (2019). A 2022 phase 2 trial of psilocybin in treatment-resistant depression found a significant benefit at a high dose — along with some adverse effects. In July 2023 Australia allowed authorised psychiatrists to prescribe psilocybin and MDMA for specific conditions; the US state of Oregon opened supervised psilocybin services in 2023.

MDMA and setbacks

MDMA, which mainly releases serotonin and promotes feelings of closeness, was tested in MDMA-assisted therapy for PTSD with positive phase 3 results, but in August 2024 the FDA declined approval, citing concerns about trial design, blinding (participants can usually tell if they got the drug) and safety data.

Risks and caveats

Psychedelics can cause frightening experiences, risky behaviour, raised blood pressure and, rarely, prolonged psychosis or lasting perceptual changes; they're generally avoided in people with a personal or family history of psychosis or bipolar disorder. Effects in trials come with extensive preparation, supervision and therapy — not the same as recreational use.