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 and non-toxic. Compared to illicit drugs, psychedelics cause much less harm to the end user.
The two most commonly used psychedelics are d-lysergic acid diethylamide (LSD) and psilocybin. Less common ones include mescaline, found in the North American peyote cactus ( Lophophora williamsii), and N,N-dimethyltryptamine, the principal component of the South American ceremonial sacrament ayahuasca. Researchers have also developed synthetic psychedelics.
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 to treat treatment-resistant depression.
What is the history of psychedelics?
A psychiatrist named Humphrey Osmond first used the term ‘psychedelic’ in 1957, to denote the therapeutic tendency of these drugs to ‘unmask’ repressed elements of the psyche. The word is derived from the Greek words psyche, meaning ‘mind’, and deloun, meaning ‘to manifest’.
Humans have used psilocybin and mescaline for ceremonial, 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. Ergotamine is produced by the parasitic rye fungus Claviceps purpurea. It was implicated in a mass-poisoning outbreak, believed to be from consuming spoiled rye, in the Middle Ages. These outbreaks were known as “Ignis Sacer” and “St. Anthony’s fire”, referring to the enduring effects of ergot poisoning.
The animal testing of LSD was unremarkable. But 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 (animals survived overdoses much larger than those of other substances). The threshold dose for subjective effects with LSD is approximately 50 micrograms.
Sandoz Laboratories first marketed LSD to psychiatrists under the trade name ‘Delysid’. (Sandoz has since merged with other companies to become Novartis.) Between 1947 and 1967, LSD was widely used as a therapeutic catalyst in psychotherapy. It then snared the attention of the American secret service, where it was used as an agent of ‘mind control’ under the infamous ‘MK Ultra’ programme, which was shuttered in 1973. LSD was found to be ineffective for such purposes; it only rendered civilians and troops liable to be disorganised and indifferent to authority in a cognitively destabilising environment.
The Harvard Psilocybin Project, founded by psychologist Timothy Leary, further proselytised LSD and psilocybin and led to the increasing recreational use of these substances.
At 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.
What is the experience of using psychedelic substances?
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’.
Somatic experiences may include the visceral, tactile, and interoceptive (body’s internal state) domains. Mood changes may include elation, euphoria, anxiety, and paranoia. Thought-processing changes range from changes in belief structures to the dissolution of ego boundaries, wherein the distinction between ‘self’ and the ‘other’ becomes blurred.
Entheogenic experiences include transcendental and ineffable spiritual experiences.
How do psychedelic substances work inside the body?
Classical psychedelics boost brain serotonin levels. Psilocybin’s therapeutic effects require a ‘trip’ that is mediated by the activation of serotonin receptors. A case report published in the American Journal of Psychiatry in March 2023 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.
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.
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.
Can psychedelic substances cause harm?
Death due to direct toxicity of LSD, psilocybin or mescaline has not been reported in the literature 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.
What is psychedelic-assisted psychotherapy?
Psychedelic-assisted psychotherapy has three types of sessions: preparatory, medication (1-3 sessions with moderate to high doses of a psychedelic), and integration.
In the preparatory session, the therapist engages the patient to explore their life history, educate them about what to expect during the psychedelic session, and forge a therapeutic alliance.
In the medication session, the patient is ideally accompanied by a male-female co-therapist dyad (given the potential risks of sexual abuse, which occurred with MDMA-assisted psychotherapy in the 1980s). A psychedelic drug is administered in a comfortable and well-appointed room. After ingestion, the patient is encouraged to focus their attention inward, with the option of listening to music and wearing eyeshades. Over the next 6-8 hours, the therapists listen to the patient while maintaining a neutral therapeutic stance.
In the integration session, the therapists work with the patient to interpret the contents of their psychedelic experience into meaningful long-term change, by interpreting their thoughts and ideas.
Can psychedelics be used to treat neuropsychiatric disorders?
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 and 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).
These findings were more recently replicated in a phase IIB trial, which found that a single dose of 25 mg psilocybin improved measures of depression severity, anxiety, and functioning.
Both trials had 233 participants each – a large number in trials involving treatment-resistant conditions.
In 2017, the U.S. Food and Drug Administration (FDA) designated the use of 3,4-methylenedioxymethamphetamine, a.k.a. MDMA, to be “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.
What does this mean for the use of psychedelics?
Although recent findings are encouraging, there remains uncertainty about where the psychedelic renaissance will take us. Psychedelic substances provide an intriguing avenue through which to 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.
