A psychedelic high

The world is on the cusp of a tussle between the need to urgently provide new treatments options for depression and the importance of thoroughly evaluating them before approval. With these words, Vidita Vaidya, a neuroscientist and professor at Mumbai’s Tata Institute of Fundamental Research, captured the essence of the global discourse on the use of controversial substances called psychedelics (a class of hallucinogens) in treating mental health problems. Vaidya was speaking at a science conference in Gurugram, Haryana, on February 24, 2024. “India, too, needs clinical trials to understand how these substances work and their potential risks,” she said.

Psychedelics are drugs that induce states of altered perception, behaviour, consciousness and thought, often with increased awareness of the senses. Though they belong to the same class—psychotropic—as other drugs for mental health problems, they seem to work better (see ‘A class of its own’). Since about 30 per cent of the patients do not respond to current medications, as per a 2019 paper in BMC Psychiatry, psychedelics are increasingly being explored in some countries as alternate therapy for depression, anxiety, post-traumatic stress disorder (PTSD) and other mental health problems. As Vaidya notes, there is burning need for new treatments for depression, which is pushing governments to move quickly. So far, Australia, Canada, Denmark, Israel and a few states in the US (Oregon and Colorado) have allowed use of psychedelics for medicinal use.

Subject of study

About 100 substances are known to have psychedelic properties, as per UN’s “World Drug Report 2023”. Of these, about five are the subject of global research in the past two decades: lysergic acid diethylamide (LSD); 3,4-methyle-nedioxy-N-methamphetamine (MDMA); N, N-dimethyltryptamine (DMT); ketamine and psilocybin.

Psychedelics are categorised into two broad categories: classical and nonclassical depending upon their mode of action. Classical psychedelics are thought to trigger hallucinations by activating a receptor called serotonin 5-HT, which is widely present in the human body, from the gastrointestinal tract to platelets to the nervous system. Nonclassical psychedelics bind to varied receptors. While LSD, psilocybin and DMT are called classical psychedelics, ketamine and MDMA are labelled nonclassical. Of the five psychedelics under research focus, MDMA has completed phase 3 trials (for PTSD) and ketamine (for treatment-resistant depression). The rest are being evaluated in phases 1 and 2 (substance that show potential in preclinical studies undergo three phases of clinical trials, lasting months to years, to assess efficacy, dosage, safety and side effects).

For now, scientists have some understanding of how psychedelics function. They believe these substances induce neuroplasticity— capacity of the neurons and neural networks in the brain to rewire and change their behaviour in response to new stimulation. For instance, humans experience neuroplasticity when they learn something new—be it a game, language or a musical instrument. The other theory is that these substances decrease connectivity within the differential mode network, a grouping of interconnected brain regions. “This allows people to suddenly shift the reference to self. It changes your perception from you being the centre to suddenly being a part of the large world,” Vaidya tells Down To Earth (DTE). Researchers are yet to work out these mechanisms in detail, partly due to the global crackdown that brought research on psychedelics to a standstill from the 1970s to the 2000s (see ‘Story so far’). The crackdown started with the US administration introducing a legislation to prohibit psychedelics in 1970. The UN followed suit in 1971 and introduced a treaty, the United Nations Convention on Psychotropic Substances, that divided psychedelics into four categories, based on their addictive potential and medical applications. The Convention, however, allowed their use for scientific and limited medical purposes after authorisation by governments. Some 180 nations, including India, ratified the treaty. In 1985, India legislated the Narcotic Drugs and Psychotropic Substances (NDPS) Act, which prohibits the use of narcotic and psychotropic substances, except for medical or scientific purposes. The Act lists all psychotropic drugs under one schedule. State drug controllers are tasked with providing licences to manufactures of psychotropic substances and monitor them. The tight restrictions impeded scientific investigations.

The second wave

By the turn of century, things began looking up, again due to actions initiated by the US. In 2000, a group of researchers from Johns Hopkins University, US, received a regulatory approval to resume research with psychedelics in healthy volunteers who had no previous experience with psychedelics, setting off a second wave of psychedelic research and clinical trials. This was further propelled by two US-based non-profits— Multidisciplinary Association for Psychedelic Studies (MAPS) and Heffter Research Institute. Both these organisations have been credited for bringing psychedelics back under the umbrella of legally sanctioned research, according to a 2020 paper in Frontiers in Psychology.

But this legitimising has generated industry’s interest in psychedelic drugs. “MAPS started as a non-profit and then became a public benefit company, but now it has gotten more in the direction of traditional pharma,” Nese Devenot, senior lecturer at Johns Hopkins University, US, tells DTE. MAPS’ presence is clearly visible on the sector. In six of the 40 clinical trials listed on ClinicalTrials.gov, a registry of global clinical trials maintained by the US National Library of Medicine, MAPS is either a collaborator or a sponsor. Lykos Therapeutics, founded by MAPS, which is involved in the development of novel therapies and therapeutic approaches to treat mental health conditions, is a sponsor in 19 of the 40 trials and a collaborator in two.

Researchers are circumspect about clinical trials sponsored by industry because there is a major conflict of interest, Lekhansh Shukla, assistant professor at the Centre for Addiction Medicine, National Institute of Mental Health & Neurosciences (NIMHANS), tells DTE. “People’s shares and the existence of a particular company depend on the outcome of that clinical trial,” he explains. The studies run by MAPS are likely to have influenced Australian regulators to approve MDMA for PTSD.

The Australian case

In 2023, Australia’s regulator, the Therapeutic Goods Administration (TGA), brought down MDMA (for PTSD) and psilocybin (for treatment-resistant depression) from the country’s schedule 9 (highest level of prohibition) to schedule 8 (which allows the two psychedelics to be prescribed by authorised practitioners for the designated conditions). The rationale behind this move was that the clinical trial for MDMA-assisted therapy for PTSD suggests a good efficacy and might be suitable for patients unresponsive to standard treatment, Suresh Sundram, head of department of psychiatry at Australia’s Monash University, tells DTE. “There is lesser quality data for psilocybin for treatment-resistant depression but they believe there’s enough positive evidence from the clinical trial,” he says.

Australia’s decision has attracted other criticisms. Shukla suspects that the move was more a result of lobbying than scientific evidence. Anees Bahji, clinical assistant professor at the University of Calgary, Canada, has a similar view. “While Australia’s decision reflects a broader global trend of reevaluating the therapeutic potential of psychedelics, it is essential to note that this step does not necessarily imply strong scientific evidence supporting their benefits,” he tells DTE. What’s worse, TGA is not collecting data on how patients respond to MDMA and psilocybin treatment.

“Unfortunately, this is not a centralised process. So from a clinical perspective, we would not really know what the outcomes are,” Sundram says. Such database will be important to record safety concerns.

Possible side effects

Sundram points out that both the substances could potentially cause a very uncommon condition called hallucinatory perceptual persistence disorder, in which symptoms experienced during acute hallucinogen intoxication reemerge even after drug cessation. Roshan Bhad, additional professor of psychiatry at National Drug Dependence Treatment Centre, All India Institute Of Medical Sciences, Delhi, says that he has seen cases of psychosis due to unregulated consumption of MDMA and LSD.

The Indian government is not likely to start clinical trials any time soon, but it could take cognisance of developments in the West, Bhad says. If the USFDA approves a drug, then the Drug Controller General of India, who heads the Central Drugs Standard Control Organisation, may conduct an initial study or try to grant a fast-track approval if large-scale evidence supports its use, he says.

This was first published in the 1-15 May, 2024 print edition of Down To Earth

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