Researchers have recently shown that separate mechanisms drive the hallucinogenic and antidepressant effects of psychedelics like LSD and psilocin, potentially paving the way to use these 'party drugs' as treatments that don't trigger psychedelic trips.
"The antidepressant and plasticity-promoting effects of psychedelics may be dissociable from their hallucinogenic effects," the researchers write in their published paper.
These psychedelic drugs have shown promise as treatments for depression and post-traumatic stress disorder in a few preliminary clinical trials. If these drugs could be re-engineered to switch off their hallucinogenic effects, they may be more readily accepted and easier to use as treatments.
Using cells in a dish, European researchers led by the University of Helsinki in Finland found that LSD and psilocin strongly bound to the receptor TrkB (neurotrophic receptor tyrosine kinase). This bond was 1,000 times stronger than that of other antidepressants, such as fluoxetine and ketamine.
This association boosted brain-derived neurotrophic factor (BDNF), a protein that controls plasticity and learning in the brain.
By enhancing BDNF, psychedelics made it easier for mice to create new neural pathways, and unlearn a conditioned fear response.
In the study, researchers tested this by conditioning mice to fear foot shocks, and then attempting to reverse this conditioning through retraining. Mice given psychedelics were better at overcoming their fear than the control group.
This behavioral effect was lost in mice with a mutation that affected the binding of psychedelics to the TrkB receptor.
Mice on psychedelics seemed to hallucinate – as indicated by little head twitches – regardless of this mutation, suggesting that something other than the TrkB receptor was triggering hallucinations.
The hallucinogenic effects of psychedelics are known to be mediated by the activation of serotonin receptors in the brain. When researchers blocked this pathway using a serotonin antagonist, the head twitching stopped.
"Taken together, these results strongly suggest 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," the researchers write.
"The hallucinogenic effects of psychedelics limit their widespread clinical application, as their administration is restricted to clinical settings that often require intensive monitoring," they explain.
"These data … open an avenue for structure-based design of high-affinity TrkB-selective ligands with fast and long-lasting antidepressant action, but potentially devoid of hallucinogenic-like activity."
Over the past decade, there has been an increase in the number of clinical trials using MDMA, psilocin, and LSD to treat psychiatric disorders such as anorexia, post-traumatic stress disorder, and depression.
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 treatment-resistant mental illnesses.
This paper was published in Nature Neuroscience.