Psychedelics: A "Trip" to Heal Our Minds?
Used by humans for millennia but prohibited in modern societies, psychedelics are experiencing a rebirth today, carrying with them the hope of revolutionary treatments for mental disorders.
Psychedelics are psychoactive molecules inducing an alteration of consciousness. Coined by British psychiatrist Humphry Osmond, the term translates literally to "mind manifesting." These compounds mainly belong to three major chemical families: tryptamines, phenethylamines, and lysergamides. They can be of natural or synthetic origin (manufactured in a laboratory).
Illustration of the different families of psychedelic compounds according to their chemical structures and origins
(from Kelmendi et al. Current Biology. 2022)
Journey to the Depths of Consciousness
"Psychedelic" is a broad term with a debated classification, encompassing various substances. Classic psychedelics like psilocybin, LSD, or DMT possess hallucinogenic properties and are structurally close to serotonin. Serotonin is a neurotransmitter, a brain hormone, involved in regulating emotions, sleep, and appetite. Classic psychedelics exert their hallucinogenic effects by binding to the serotonin 5-HT2A receptor. Other psychoactive substances are also grouped under the term "atypical," such as MDMA (ecstasy), ibogaine, or ketamine. These substances respectively induce increased empathy, visual and sensory distortions, and a dissociative state.
Psychedelic substances have been used for spiritual and medical purposes for millennia by the Maya, Aztecs, Greeks, and indigenous peoples of America. In the 1960s, psychedelics played a crucial role in the emergence of counterculture in the United States, especially through the "hippie" movement. Today, strictly regulated and prohibited in most countries, psychedelics could return to the spotlight due to their therapeutic potential.
A Panacea for Mental Health?
Psychiatric disorders currently affect one in eight people worldwide. Available treatments are effective for only a certain number of patients. Approximately one-third of patients with depression are resistant to antidepressants. Innovation in this therapeutic field is a key research challenge. Psychedelics represent immense hope within the scientific and medical community, especially regarding their potential therapeutic benefits in mood and anxiety disorders.
Indeed, since the 2010s, several studies with rigorous methodological standards have highlighted the potential therapeutic effects of psychedelics. High doses of psilocybin, for example, have been reported to reduce anxious and depressive symptoms and improve optimism in 80% of patients with advanced cancer. In patients with depression, studies have shown a marked decrease in depressive symptoms in response to psilocybin. Additionally, esketamine, a ketamine derivative, has recently been approved for use in conjunction with an antidepressant to enhance its efficacy. MDMA, on the other hand, holds enormous promise in the treatment of post-traumatic stress disorder, with several clinical trials demonstrating its effectiveness. Finally, ibogaine, the active substance in iboga, a plant native to Africa, could prove effective in addiction treatment, despite potential cardiac risks.
All these results are promising and suggest the advent of a potential new era of pharmacological treatments in psychiatry. If their effectiveness is proven, psychedelics could offer several advantages: a low number of administrations, rapid therapeutic effects, few side effects, and a very low toxicological and addictive profile. Some clinical trials are underway to determine their effectiveness on a larger number of patients. Regarding the safety of their use, the main risks are the "bad trip" and possible long-term sequelae such as persistent hallucinations.
How Do Psychedelics Work?
Various research works indicate that psychedelics induce their hallucinogenic effects via the serotonin 5-HT2A receptor. They are agonists of this receptor because, similar to endogenous serotonin (produced by the brain), they bind to and activate this receptor. The 5-HT2A receptors are particularly expressed in the prefrontal cortex, a brain area involved in cognitive tasks and decision-making. Specifically, the prefrontal cortex plays a crucial role in emotion control by regulating structures involved in anxiety (such as the amygdala) or mood (such as the dorsal raphe, where the majority of serotonin-producing neurons are located).
Illustration of the human brain with the prefrontal cortex, the amygdala and the dorsal raphe nucleus
Psychedelics induce short- and long-term effects, ranging from the cellular level to neuronal networks. When a classic psychedelic is administered, it binds to the 5-HT2A receptor on the surface of certain neurons. This binding induces several mechanisms inside the cell, including an increase in the activity of these neurons. This increased activity allows for enhanced communication between neurons. On a larger scale, changes in the activity of certain neurons regulate other areas of the brain, especially those involved in emotion processing.
Psychedelics are also substances that promote neuroplasticity by regulating the expression of specific genes. Neuroplasticity refers to a process of structural and functional transformations of neurons in response to various stimuli. Several studies report that psychedelics can modify the morphology of neurons or increase their branching. The neuroplasticity processes induced by psychedelics could allow for a rearrangement of neuronal connections, underpinning their therapeutic effects. One hypothesis is that these neuronal rearrangements could facilitate the abandonment of certain beliefs or thought patterns responsible for maladaptive behavior.
Diagram representing the mechanisms of action of psychedelics and their short-term and long-term effects
Closely linked to their effects on the brain, the psychological effects of psychedelics could also explain their therapeutic effects. In particular, these substances can reduce the integration of negative stimuli, rumination, promote social interactions, and restore a physiological response to rewards, often altered in psychiatric disorders. Furthermore, psychedelics have the property of dissolving the ego, which could, according to some researchers, be the key to their therapeutic action. Several studies show that a positive experience of ego dissolution induced by psychedelics is correlated with better therapeutic outcomes. These studies highlight a crucial question within the scientific community: is the "trip" essential for the therapeutic effects of psychedelics? Indeed, some researchers have demonstrated in animals the antidepressant and anxiolytic properties of psychedelic-derived compounds lacking hallucinogenic effects. Clinical trials of these non-hallucinogenic compounds are currently ongoing.
The road is still long before psychedelics can one day integrate into our pharmacopoeia. Nevertheless, the results are promising, and psychedelics are now the subject of immense hope in the fields of mental health and psychiatry.
Sources:
2. Kelmendi et al. Psychedelics. Current Biology. 2022
3. Kwan et al. The neural basis of psychedelic action. Nature Neuroscience. 2022
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