A study has provided new insights into how psychedelics promote plasticity in the brain – suggesting that the antidepressant effects and the hallucinatory effects may have separate mechanisms.
The findings could lead to the development of psychedelic therapeutics without hallucinations, but further research is needed.
The new animal study, published in Nature Neuroscience by Moliner et al, found that psychedelics bind to the BDNF receptor TrkB – the same receptor as current anti-depressants.
However, LSD and psilocin do so ‘with affinities 1,000-fold higher than those for other antidepressants’ such as fluoxetine and ketamine, write the authors, who add that ‘psychedelics and antidepressants bind to distinct but partially overlapping sites within the transmembrane domain of TrkB dimers.’
In this regard, the findings suggest that the TrkB TMD dimer is a ‘high-affinity primary target for psychedelics.’
The findings point towards the antidepressant effects of psychedelics in mice depending on TrkB binding ‘and promotion of endogenous BDNF signaling’. BDNF – brain-derived neurotrophic factor – is a protein related to neuron growth and brain plasticity, and, so far, research points toward people with depression having lower levels of BDNF.
Additionally, research suggests that the therapeutic effect of psychedelics is due to their ability to induce such brain plasticity.
TrkB vs 5-HT2A
Key to developing psychedelic therapeutics without hallucinations, the authors highlight that the TrkB binding of psychedelics seems to be independent of serotonin 2A receptor (5-HT2A) activation. It is the binding of serotonergic psychedelics – such as LSD – to the 5-HT2A that causes their hallucinatory effects.
‘Head twitching’ in mice is thought to be a signal of hallucinatory activity in the brain, and is dependent on psychedelic molecules binding to the 5-HT2A receptor, which the authors note is independent of TrkB binding.
They write: “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.”
Dr James Rucker, Consultant Psychiatrist and Senior Clinical Lecturer at King’s College London, stated: “This study offers an intriguing new insight into the molecular mechanism of action of psychedelics, which accumulating clinical evidence suggests have 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.
“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, this work needs to be confirmed by replication and 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 includes many other mechanisms not analysed here.”
