Recreational to medical? Psychedelics hold antidepressant effects, study finds

08 Jun 2023 --- A team of 33 researchers across eight countries has found psychedelics to have an antidepressant effect on the brain more rapidly and with longer-lasting results than antidepressant drugs. But, a psychiatrist says that though the study findings are intriguing, they might not reflect the actual mechanisms underpinning antidepressant responses in the human brain to psychedelics. 

Psilocin, a hallucinogenic compound from magic mushrooms, was found to directly bind TrkB (Tropomyosin receptor kinase B) – a receptor for brain-derived neurotrophic factor (BDNF) that regulates growth and survival of cells – with affinities 1,000 times higher than antidepressant drugs.

According to the study published in Nature, psychedelics and antidepressants bind to distinct but partially overlapping sites within the transmembrane domain of TrkB dimers. 

“Commonly used antidepressants take weeks for their effects on [one’s] mood to appear and need to be administered daily for extended periods to avoid relapse. Psychedelics can produce fast and enduring antidepressant responses with a single dose when administered in a controlled clinical setting with the supervision of trained professionals,” Rafael Moliner, lead author of the study, tells NutritionInsight.

“This makes them a promising alternative to currently approved antidepressant treatments. However, their hallucinogenic action can limit their therapeutic reach, as there are concerns that psychedelics may trigger irreversible psychotic events in patients with a family history of bipolar disorder or schizophrenia.”

The findings indicate that psychedelics produce their effects through two independent pathways, each mediated by a different receptor. “Intriguing insights”
Dr. James Rucker, consultant psychiatrist & senior clinical lecturer at King’s College London, says: “This study offers an intriguing new insight into the molecular mechanism of action of psychedelics, which accumulating clinical evidence suggests antidepressant properties.”

“The authors have shown interesting evidence in cultured neurons and rodents that the antidepressant effect and subjective effect may in fact be mediated by separate mechanisms.” 

Essentially all drugs with antidepressant effects bind to the TrkB receptor and induce neuroplasticity, which is critical for their therapeutic action, Moliner explains.

“Our findings indicate that psychedelics produce their effects through two independent pathways, each mediated by a different receptor. The therapeutic pathway is mediated by TrkB and the hallucinogenic pathway is mediated by 5-HT2A.”

This means that it is possible to rationally design new compounds inspired by psychedelics that target TrkB with high affinity but do not interact with 5-HT2A, retaining the fast and enduring antidepressant action of psychedelics while being safer and devoid of hallucinations. These compounds could then reach a much higher number of patients than psychedelics.

“We have found that psychedelics bind to TrkB with 1000 times higher affinity than other antidepressants in current clinical use (like the commonly used fluoxetine or fast-acting ketamine),” continues Moliner. 

“In our recent study, we show how psychedelics bind in a different but slightly overlapping binding site in the transmembrane domain of TrkB than the site previously found for fluoxetine.” 

These differences might partly explain why psychedelics have faster and longer-lasting antidepressant effects and their more potent effects on neuroplasticity compared to other antidepressants, he details. 

“Our data confirm TrkB as a common primary target for antidepressants and suggest that high-affinity TrkB positive allosteric modulators lacking 5-HT2A activity may retain the antidepressant potential of psychedelics without hallucinogenic effects,” the study reads.

Needs replicationThe high costs of intensive medical care and support required during lengthy psychedelic sessions are an obstacle, Moliner says.
There are many open questions in psychedelic research. It will be essential to study whether results obtained using mice and neurons in a dish also apply to humans. 

Moliner stressed the growing need to find reliable biomarkers associated with neuroplasticity, as currently there is a lack of well-validated methods to assess plasticity in the human brain directly. 

“It will also be important to explore whether the combination of psychedelics with a 5-HT2A antagonist – to block the hallucinations – in the clinic can be effective. A recent pioneering case report suggests this would be possible, as a patient with depression treated with a combination of the psychedelic psilocybin with a 5-HT2A antagonist showed a rapid and enduring antidepressant response without the hallucinations.”

However, he stresses that the high costs of intensive medical care and support required during lengthy psychedelic sessions are also an obstacle. 

“For these reasons, there is growing interest in designing new treatments that could retain the fast and long-lasting antidepressant effects of psychedelics, but without their hallucinogenic effects,” Moliner says.

Meanwhile, Rucker notes that the work needs to be confirmed through replication. If confirmed, this may allow the development of new antidepressants that target the antidepressant mechanism without the disorientating subjective effects of classical psychedelics that currently limit their use to carefully controlled medical settings.

“However, the findings here may not reflect the actual mechanisms underpinning antidepressant response in the human brain. It is likely that the overall mechanism of action of psychedelics and antidepressants include many other mechanisms not analyzed here,” Rucker concludes.

By Beatrice Wihlander