There has long been interest in the potential therapeutic effects of synthetic and natural psychedelics, such as lysergic acid diethylamide (LSD) and psilocybin – the active compound in magic mushrooms – in the treatment of depression. But it remains a controversial topic. Doctors and therapists are concerned about the risks of self-experimentation with psychedelics in the absence of supervision and supportive psychotherapy. The therapeutic context is very important, as unsupervised use can lead to the notorious ’bad trip’, in which users experience intense anxiety and hallucinations. 

Inconsistencies 

In addition to the health risks of psychedelics, natural products such as psilocybin are often inconsistent. This makes it difficult to obtain approval from agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Furthermore, they evaluate the safety and efficacy of drugs, not the circumstances of use. How should these agencies deal with a drug that requires special monitoring, therapy, and a specific environment for a safe effect? 

Therefore, there is a need for substances with the antidepressant effects of psychedelics that are lacking the hallucinogenic side effects. Research from the University of Helsinki on the mechanisms of action of LSD and psilocybin provides a starting point.  

Synaptic plasticity 

In an in vitro experiment using mouse, rat, and human cells, the researchers showed that LSD and psilocybin bind to the TrkB receptor. This receptor is found in brain cells and plays a crucial role in neuronal growth and changing the strength of the connection between two neurons, known as synaptic plasticity. 

The protein BDNF (brain-derived neurotrophic factor) activates this process by binding to TrkB and inducing dimerization; two TrkB receptors join to form a functional complex. In mouse brain slices, researchers observed that LSD phosphorylates the TrkB receptor in the presence of BDNF. This suggests increased dimerization. This reaction leads to an increase in synaptic plasticity, which is considered an essential component of the therapeutic effect of both conventional antidepressants and psychedelics. 

Remarkably, LSD has a 1,000 times higher affinity for the TrkB receptor than common antidepressants such as fluoxetine and imipramine. This makes LSD a promising candidate for further research into its therapeutic use in depression and other mood disorders. 

No hallucinogenic effects 

The above findings are consistent with previous research. An important new result is that LSD and psilocybin’s antidepressant actions are independent from their hallucinogenic effects. An indicator of hallucinogenic effects in rodents is a rapid side-to-side head movement, which researchers refer to as the ’head-twitch’ response. This behavior is triggered by psychedelics binding to the serotonin 5-HT2A receptor. LSD and psilocybin activate both TrkB and 5-HT2A, but studies in living mice show that these psychedelics’ antidepressant effects persist when 5-HT2A is blocked. 

This suggests that as far as the ’head-twitch’ response is a reliable translation of hallucinogenic effects in humans, the antidepressant effects depend only on activating TrkB and not 5-HT2A. These findings open the door to the development of TrkB-activating compounds as potential antidepressants for the treatment of depression and other mood disorders.  

Rafael Moliner, et al., Psychedelics promote plasticity by directly binding to BDNF receptor TrkB, Nature Neuroscience (2023) [Open Access]