Psychedelics are a group of drugs that alter perception, mood, and thought-processing while a person is still clearly conscious. Usually, the person’s insight also remains unimpaired. Psychedelics are non-addictive, non-toxic and compared to illicit drugs, they are less harmful to the end user. In India, the Narcotic Drugs and Psychotropic Substances Act 1985 prohibits the use of psychedelic substances. Ketamine, a dissociative anaesthetic with psychedelic properties, is used under strict medical supervision, for anaesthesia and treatment-resistant depression.

A psychiatrist named Humphrey Osmond first used the term ‘psychedelic’ in 1957. The word is derived from the Greek words psyche, meaning ‘mind’, and deloun, meaning ‘to manifest’. Humans have used psilocybin and mescaline for ceremonies, healing, and spiritual rituals for millennia. Temples built for mushroom ‘deities’ in indigenous cultures in Mexico and Guatemala date back to 7000 BC. Records of the Greek ‘Eleusinian Mysteries’ indicate that psychedelics were used in ceremonial rituals.

The modern-day use of psychedelics is commonly associated with the German chemist Arthur Heffter isolating mescaline from the peyote cactus in 1897. In 1938, while investigating compounds related to ergotamine (one of the ergot alkaloids), the Swiss chemist Albert Hofmann first synthesised LSD. When Hofmann accidentally contaminated himself with a small dose of LSD, he experienced what was likely the world’s first ‘acid trip’. On a hunch, he resynthesised LSD in 1943 and, with further testing, found LSD to be extremely potent and physiologically relatively safe.

Between 1947 and 1967, LSD was widely used as a therapeutic catalyst in psychotherapy. The Harvard Psilocybin Project, founded by psychologist Timothy Leary, further proselytised LSD and psilocybin which led to the increasing recreational use of these substances. Around this time, medical concerns and the Vietnam War prompted the conservative Richard Nixon administration to criminalise the use of psychedelics and other psychoactive drugs. This “war on drugs” stopped all medical use and pushed recreational use underground. Media campaigns in the 1960s and 1970s further stigmatised the use of all psychoactive drugs.

Users of psychedelic substances report changes in perception, somatic experience, mood, thought-processing, and entheogenic experiences. Perceptual distortions most commonly include the visual domain. An intriguing phenomenon called synaesthesia may occur, where the sensory modalities cross and the user may ‘hear colour’ or ‘see sounds’.

About half of the ingested psilocybin is absorbed via the digestive tract. In the body, psilocybin is converted to psilocin, which is then metabolised in the liver. LSD is completely absorbed in the digestive tract and then metabolised in the liver. Classical psychedelics boost brain serotonin levels. Psilocybin’s therapeutic effects require a ‘trip’ that is mediated by the activation of serotonin receptors. A recent case report published in the American Journal of Psychiatry demonstrated that robust and sustained antidepressant effects can occur even in the absence of psilocybin’s psychedelic effects. This finding, if replicated in larger trials, will have major implications for people with treatment-resistant depression. They can then get better without having to endure a trip.

Modern neuroimaging suggests that psychedelics are neither stimulants nor depressants of brain activity. Instead, they increase the cross-talk between different brain networks, and this correlates with the subjective effects of psychedelics.

Death due to direct toxicity of LSD, psilocybin or mescaline has not been reported despite 50-plus years of recreational use. An overdose requires cardiac monitoring and supportive management in a low-stimulus and reassuring environment.

Synthetic psychedelics (such as 25I-NBOMe) have been associated with acute cardiac, central nervous system, and limb ischaemia, as well as serotonin syndrome. There have also been reports of death attributed directly to synthetic psychedelic use.

The psychological effects of psychedelics depend on the interaction between the drug and the user’s mindset (together called a set), and the environmental setting. People with a personal or family history of psychosis are strongly discouraged from experimenting with psychedelics.

There is also no evidence that psychedelics cause physiological or psychological dependence — nor has any withdrawal syndrome been identified. Tension headaches are common in the 24 hours after use and are offset by the use of simple analgesics. This said, brief and self-limiting psychotic episodes can occur when a user is intoxicated with psychedelics, particularly LSD. They are more common among first-time users and among those with a personal or family history of psychiatric illness. Users describe these experiences as a ‘bad trip’ and they are more likely to occur in unfavourable environments.

In November 2022, the results from a phase II psilocybin trial were published in the New England Journal of Medicine. The trial found that a single 25-mg dose of psilocybin reduced depression scores over three weeks in people with treatment-resistant depression. Adverse events included headache, nausea, and dizziness which occurred in 77% of the participants. Suicidal ideation, suicidal behaviour, and self-injury occurred in all dose groups (1 mg, 10 mg, and 25 mg).

In 2017, the U.S. Food and Drug Administration (FDA) designated the use of 3,4-methylenedioxymethamphetamine, also known as MDMA, to be the “breakthrough therapy” in the treatment of post-traumatic stress disorder (PTSD). Under its “expanded access” program, the FDA has allowed a small number of people — particularly those seriously ill with PTSD and who haven’t responded to other treatment — to use MDMA.

Recently, the U.S. non-profit Multidisciplinary Association for Psychedelic Studies (MAPS) also announced positive results from its observational study on MDMA-assisted therapy for patients with PTSD, echoing the findings of its phase-III MDMA trial, published in Nature Medicine in May 2021. In 2018, the FDA had granted “breakthrough therapy” status to psilocybin for treatment-resistant depression as well.

Although recent findings are encouraging, there remains uncertainty about where the psychedelic renaissance will take us. Psychedelic substances provide an intriguing avenue through which one can probe the broader constructs of creativity, spirituality, and consciousness, aside from their therapeutic effects.

While not a panacea, psychedelic substances have certainly reinvigorated clinical and research interests, and have added to psychiatry’s ever-expanding therapeutic armamentarium. If larger phase III trials establish their safety and therapeutic efficacy, the FDA and other regulatory bodies may clear these agents for routine clinical use.

Dr. Alok Kulkarni is a senior geriatric psychiatrist and neurophysician at the Manas Institute of Mental Health and Neurosciences, Hubli.