Psychedelic Substances and Psychiatric Disorders: What the Research Shows

Treatment-resistant depression, substance use disorders, anxiety disorders: for some psychiatric conditions, existing therapies do not always suffice. It is precisely from this unmet therapeutic need that neuropharmacology research has, in recent years, been living what researchers call the “psychedelic renaissance”: a renewed interest in psychedelic substances — molecules that act on perception, consciousness and mood — as a possible therapeutic tool, always in combination with psychotherapy.

This is the focus of the research conducted by Professor Danilo De Gregorio, who studies the mechanisms of action of these substances on brain circuits in animal models of mood disorders and substance use disorders. On 18 May 2026, De Gregorio will inaugurate his laboratory at Vita-Salute San Raffaele University and San Raffaele Hospital in Milan, dedicated to the memory of Professor Daniela Parolaro, a leading Italian pharmacologist in addiction research.

From the 1950s to the psychedelic renaissance

Discussing these compounds in medicine may seem like a novelty, but research in this field has much deeper roots. LSD, one of the best-known synthetic psychedelics, was first synthesised in 1938 by Swiss chemist Albert Hofmann, who personally experienced its effects on consciousness and perception before beginning to study them systematically.

Between the 1950s and 1960s, substances such as LSD and psilocybin — a molecule derived from hallucinogenic mushrooms — featured in numerous psychiatric research programmes. In the 1970s, however, these substances were classified as drugs of abuse and progressively excluded from university laboratories and clinical psychiatry.

The situation began to change in the early 2000s, when scientists in the United States, Canada and subsequently the United Kingdom resumed their study. «Not all psychedelic substances act on the reward and gratification circuits involved in addiction,» De Gregorio explains. «Psilocybin, for example, does not affect these networks, whereas ketamine can — a dissociative anaesthetic approved in Italy in 2023 for cases of treatment-resistant depression, where patients have not responded to at least two courses of standard antidepressant therapy.»

How ketamine and psilocybin act on the brain

Psychedelic substances such as psilocybin and ketamine differ from conventional antidepressants in their effect on brain plasticity. The most widely used antidepressant drugs, such as selective serotonin reuptake inhibitors, typically require around four weeks to produce a clinically meaningful improvement.

Ketamine, by contrast, acts rapidly and — when accompanied by psychotherapy — is indicated for suicidal symptoms in patients with treatment-resistant depression. The molecule promotes glutamate release, one of the brain’s principal neurotransmitters, inducing rapid changes in the connections between neurons.

For many researchers, this represents one of the most significant advances introduced in psychiatry in recent decades. «Ketamine’s effects appear within two hours and are sustained over time, though patients still require periodic administrations,» notes De Gregorio.

Psilocybin follows a different pharmacological pathway: it acts primarily on the serotoninergic receptor 5HT2A located in the cerebral cortex. The most recent studies suggest that this substance too promotes neuroplasticity processes, but without significantly affecting the reward and gratification circuits.

Psychedelics and mental health: what clinical trials show

In recent years, clinical trials on psychedelic substances have multiplied worldwide. «There are now trials on the use of these substances for depression, anxiety and substance use disorders,» says De Gregorio. «In June 2025, New Zealand authorised the therapeutic use of psilocybin for treatment-resistant depression, while in July 2025 the University of Chieti launched the first Italian clinical study on the same indication.»

One of the principal challenges in clinical research concerns the design of randomised controlled trials, considered the gold standard for evaluating the efficacy and safety of a treatment. In these studies, the drug is compared with a placebo in randomly selected patient groups.

With psychedelic substances, however, the effects on mood and perception are often so rapid and distinctive that patients and clinicians can readily identify who has received the drug and who the placebo. This can influence results and make it harder to distinguish the actual treatment effect from participants’ expectations. A perfect placebo and complete blinding in psychedelic clinical trials are probably impossible to achieve. Nevertheless, the risk of bias can be reduced.

The use of carefully selected active placebos, more rigorous experimental designs with appropriate doses and comparators, psychedelic-naïve patient samples, careful management and measurement of expectations, rigorous assessment of blinding maintenance, and modern statistical tools can make psychedelic studies more reliable — even if they will never be fully “blinded”.

Open questions in psychedelic research

Despite the advances of recent years, many questions about the biological mechanisms of psychedelic substances remain unanswered. While their effects on brain plasticity are established, the precise way in which these changes connect to the therapeutic benefits observed in clinical studies is not yet fully understood.

De Gregorio’s laboratory aims to explore these aspects through electrophysiology, behavioural pharmacology and optogenetics — a technology that allows specific neural circuits to be activated or silenced using light pulses.

«While research on depression and anxiety disorders is more advanced, there is still a long way to go on alcohol and other substance use disorders,» adds De Gregorio. «Partly for historical and cultural reasons: in the past, all psychedelic substances were assumed to cause addiction, which meant they were not studied as potential therapeutic tools for treating addictions.»

Fentanyl, new addictions and the future challenges of research

Beyond the effects of psychedelics on substance use disorders, De Gregorio intends to investigate the biological mechanisms of fentanyl addiction, a synthetic opioid now at the centre of one of the most serious international public health emergencies, with a growing presence in Europe as well.

«In the United States, the opioid crisis arose primarily from the widespread use of prescription painkillers, dispensed for years with very little restriction,» De Gregorio explains. «In Italy, there is no current emergency. According to the most recent data, in 2024 there were 71 seizures of fentanyl-based medicines in Italy, and the phenomenon is linked mainly to recreational use and illicit trafficking.»

In Canada, the United Kingdom and the United States, new synthetic substances similar to fentanyl are also spreading, often undetected by standard toxicological tests. They act on mu-opioid receptors, causing cardiorespiratory depression and increasing the risk of respiratory arrest. «In our laboratory we would also like to study these molecules, with the aim of clarifying their biological mechanisms and contributing, in time, to the development of more targeted clinical interventions,» concludes De Gregorio.