Recent studies have shown that the hallucinogenic and antidepressant effects of psychedelic drugs like LSD and psilocin are driven by separate mechanisms. European researchers led by the University of Helsinki in Finland found that these drugs may have the potential to be used as antidepressants and plasticity-promoting agents without triggering the psychedelic trips that they are commonly known for.

Psychedelics’ Strong Bond to Receptor TrkB

The researchers discovered that LSD and psilocin are strongly bound to the receptor TrkB (neurotrophic receptor tyrosine kinase) 1,000 times stronger than other antidepressants like fluoxetine and ketamine. This association boosts brain-derived neurotrophic factor (BDNF), a protein that controls plasticity and learning in the brain, making it easier for mice to create new neural pathways and unlearn a conditioned fear response.

Dissociation between Hallucinogenic and Antidepressant Effects

By conditioning mice to fear foot shocks and then attempting to reverse this conditioning through retraining, the researchers found that mice given psychedelics were better at overcoming their fear than the control group. However, this behavioral effect was lost in mice with a mutation that affected the binding of psychedelics to the TrkB receptor. This suggests that TrkB mediates the plasticity-related and antidepressant-like effects of LSD at the network and behavioral levels but is not involved in its hallucinogenic-like action.

Psychedelics’ Limited Clinical Application

The hallucinogenic effects of psychedelics limit their clinical application, as their administration is restricted to clinical settings that often require intensive monitoring. These data open an avenue for the structure-based design of high-affinity TrkB-selective ligands with fast and long-lasting antidepressant action, potentially devoid of hallucinogenic-like activity.

Psychedelics such as MDMA, psilocin, and LSD have been used in a few preliminary clinical trials as treatments for depression and post-traumatic stress disorder. These drugs are thought to increase neuroplasticity and may help people unlearn unhelpful behaviors and develop fresh ways of seeing the world when combined with therapy.

In February, Australia became the first country in the world to allow psychiatrists to prescribe psilocybin (which is converted into psilocin in the body) and MDMA for the treatment of mental illnesses that are resistant to other forms of treatment.

The separation of the mechanisms that drive the hallucinogenic and antidepressant effects of psychedelics is a significant breakthrough for the potential use of these drugs as treatments without triggering the psychedelic trips that they are commonly known for. The dissociation between the hallucinogenic and antidepressant effects of LSD and psilocin may pave the way for the development of new, high-affinity TrkB-selective ligands with fast and long-lasting antidepressant action, devoid of hallucinogenic-like activity. This could benefit individuals with depression and post-traumatic stress disorder who are resistant to other forms of treatment.

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