New research identifies how LSD and mushrooms reduce depression symptoms

‘Trip’-free depression treatments using psychoactive drugs like LSD and ‘magic’ mushrooms may have moved a significant step closer - after scientists identified a drug binding site that avoids the serotonin receptors responsible for hallucinations.

Researchers have “opened an avenue” towards developing powerful psychoactive-based drugs for depression – but without the accompanying hallucinogenic ‘trip’.

An international group of scientists discovered that the brain derived neurotrophic factor receptor TrkB binds to LSD and psilocin independently from serotonin 5-HT2A receptors responsible for psychedelic effects.

They also found that TrkB creates bonds up to 1,000 times stronger with the psychedelics than it does with conventional antidepressants.

Their paper further suggests that such strong bonding to TrkB may result in increased neuroplasticity – the mechanism thought to be responsible for reducing depression symptoms – and could potentially lead to antidepressant drugs that are far more effective than those currently available.

“Our findings support TrkB as the key target for psychedelic drug-induced plasticity (and) confirm TrkB as a common binding target for antidepressants,” the authors write in Nature Neuroscience.

“(They) 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.”

The group’s work builds upon recent studies indicating that the hallucinogenic effects of psychedelic compounds can be separated from their therapeutic properties, and the known role of TrkB in mediating neuroplasticity. Therefore, to learn more about the precise relationship between psychoactive substances and TrkB, they added psilocin and LSD to lysates of HEK293T cells transiently expressing TrkB, and observed the bonding process

Their first observation was that “radiolabelled LSD binds directly to human, rat and mouse TrkB with high affinity, which is similar to that for its canonical target 5-HT2A.” More strikingly, however, “the affinity of LSD to TrkB was up to 1,000-fold higher than that of other antidepressants such as fluoxetine and ketamine.”

The group followed up these remarkable results by giving doses of LSD or psilocin to mice depressed by stress-inducing experiments, such as repeated sessions of the forced swimming test. They found that “LSD produced a sustained antidepressant-like effect 7 days after a single administration” in wild-type mice, and “also facilitates contextual extinction of conditioned fear response 72 h after a single administration, which persists for at least 4 weeks.”

Psychedelics were also found to induce rapid TrkB trafficking into dendritic spines, while subsequent testing of neuronal cultures taken from wild type mice also revealed positive effects on brain plasticity after injection with LSD and psilocin.

The group explained that the potential of ‘trip-free’ drugs which can bypass 5-HT2A receptors and bind powerfully to TrkB may be significant – not least because they may prove more effective and faster-acting than current drugs. 

“The affinity of conventional antidepressants to TrkB, albeit pharmacologically relevant, is low,” they write.

“Brain concentrations required for selective serotonin reuptake inhibitors binding to TrkB are achieved only after long-term treatment, which may partially explain the delay in the onset of their antidepressant action.”

In contrast, “Psychedelics readily penetrate into the brain after a single dose and, as shown here, bind to TrkB with much higher affinities than antidepressants in current clinical use.

“This may contribute to the fast and potent induction of neuroplasticity and more persistent behavioral effects produced by psychedelics when compared with other antidepressants.”

As well as potentially superior to conventional antidepressants, trip-free psychedelic-based drugs could prove easier to administer on a large scale than existing depression treatments that prescribe LSD and other hallucinogens. Although these regimes have shown some promise, they require considerable specialised supervision in controlled clinical environments, and are also unsuitable for patients susceptible to psychosis or other hallucinogen-related disorders.