What if “magic mushrooms” could help treat depression without causing visions or “cosmic travel”? Faced with classic antidepressants which still leave many patients suffering, psilocybin is attracting the attention of psychiatrists. But its psychedelic effect remains a major obstacle in the clinic.
In trials, one or two doses of psilocybin, given in a very supervised medical setting, have already provided a lasting reduction in depressive symptoms, sometimes for 6 to 12 months. However, for the many patients suffering from
treatment-resistant depressionthe cost, the duration of the sessions and the risk of a “bad trip” strongly limit access to this type of therapy. Hence an intriguing question: can we keep the antidepressant effect without the hallucinations?
Psilocybin, promise for depression but beware of tripping!
About 15% of people with depression receive no benefit from antidepressants, and 30 to 40% respond only partially. Psilocybin is one of the rare molecules capable, in a single supervised session, of helping these patients. It acts on serotonin receptors, including the famous 5-HT2A, considered to be the main trigger of hallucinations. Psilocybin is a psychotropic drug present in certain mushrooms. This hallucinogenic substance, whose effects are comparable to certain drugs, modifies the perceptions of those who consume it and can cause visual and auditory distortions.
This “trip” is not trivial: it requires several hours of therapist presence, a dedicated room, psychological preparation and excludes people vulnerable to psychosis, such as those suffering from schizophrenia spectrum disorders or having a family history of psychosis. For public health systems, this risk-cost combination poses a real diffusion problem.
Discovery of the non-hallucinogenic receptor, 5-HT1B
The work at Dartmouth is changing perspective. “When we think of psilocybin, we think of acute effects like hallucinations, attributed to the activation of a specific neuroreceptor. We thought that the beneficial effects reported in the treatment of depression and anxiety might be linked to other receptors“, explains Sixtine Fleury Guarini, first author of the study and doctoral student in the laboratory of Katherine Nautiyal, associate professor of psychological and cognitive sciences and lead author of the study.
The prolonged antidepressant effects of psilocybin are often associated with a specific brain receptor: 5-HT2A, which is also most strongly linked to hallucinations. However, psilocin, the “active” form of psilocybin (the part that binds to brain receptors after consumption), interacts with numerous sites in the serotonergic system, a network of neurotransmitters involved in particular in the regulation of mood, sleep, appetite and social behavior.
With Katherine Nautiyal, she tested the role of
5-HT1B receptoralready targeted by several anti-migraine and non-hallucinogenic drugs. By blocking or removing this receptor and then injecting psilocybin, the team observed that the effects positive behavioral effects on depression and anxiety were no longer improvedwhile the classic “trip” sign in mice remained present. “Our study shows that there is probably another target,” says Nautiyal, pointing out that psilocybin profiles “show that these drugs bind to almost all serotonin receptors“. In other words, 5-HT1B seems essential for antidepressant effects, but not for hallucinations.
Towards psilocybin without hallucinations against depression?
If these results in animals are confirmed in humans, they would open the way to “psilocybin analogue” medications banking on the 5-HT1B receptor and on specific mood circuits, without plunging the patient into a psychedelic state. Imaging work carried out in humans already shows that psilocybin lastingly reorganizes the connectivity between the hippocampus and the default mode network, a change proposed as a marker of its therapeutic effects.
This research is still at the preclinical stage, with variable effects depending on the sex of the animals and the type of stress used, a sign of a complex and multi-receptor mechanism. “These substances could open up new perspectives for clinical therapy and medicines,” summarizes Fleury, before adding: “It’s important to find better treatments that are more effective and efficient for people, but it’s just as important to do it safely“.