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Psychedelics act against depression by stimulating connections between neurons

Antidepressant effect occurs independently of the mechanism that alters perception of reality

Psilocybe zapotecorum, a hallucinogenic mushroom from which psilocine is extracted

Alan Rockefeller / Wikimedia Commons

Studies conducted over recent years, still with modest numbers of participants, suggest that psychedelic substances, known for altering perceptions of reality and causing hallucinations, have a fast, powerful antidepressive effect. An international paper published on June 5 in the journal Nature Neuroscience is helping to throw some light on how they act to alleviate depression. The study, in which three Brazilian researchers participated, also indicates that the effect against depression would be independent of that which causes distortion of reality, possibly leading, in principle, to the development of more effective medications free from hallucinogenic effects to treat the condition, which afflicts some 300 million people around the globe.

In experiments with cells and laboratory animals, the group, coordinated by neuroscientist Eero Castrén of the University of Helsinki in Finland, found that psychedelics prepare the neurons to better respond to a protein that stimulates the formation of new connections with other cells, and the strengthening of those already in place: the brain-derived neurotrophic factor (BDNF). Compounds such as lysergic acid diethylamide (LSD), and psilocin, extracted from mushrooms of the Psilocybe genus, bond to a protein in the neuronal membrane known as the tropomyosin-related kinase B receptor (TrkB), which is activated by BDNF. Produced in the brain itself, BDNF, on connecting to and activating TrkB, triggers a cascade of chemical commands that lead the neural cells to multiply or create extensions and points of contact with other neurons. This phenomenon, known as neuroplasticity, is associated with the brain’s capacity to learn and store information, and to an improvement in depression symptoms.

In the experiments described in Nature Neuroscience, rat neurons cultivated in the laboratory and treated with LSD or psilocin developed more branches and connections with other cells in the presence of BDNF than those receiving an inert compound. This cell arborization effect was lost when the tests were conducted on genetically mutated neurons which deformed the TrkB receptor stem to which the psychedelic substances connect.

Biochemists, pharmacologists, and physicians already suspected that neuroplasticity might be the responsible factor for the antidepressant action of many medications, including those that increase levels of the neurotransmitter serotonin, such as fluoxetine and the like. One of the reasons for doubts around whether the effect of these compounds did not arise merely from the availability of serotonin or other neurotransmitters is that their levels rise very rapidly after commencement of treatment, but the symptoms of depression only start to subside weeks later. “We imagined that in addition to increased serotonin levels, there were other factors involved,” reports Brazilian pharmacologist Cassiano Ricardo Diniz, coauthor of the study. Diniz participated in the experiments that demonstrated the antidepressant action of the psychedelics via TrkB during his research season at the Castrén laboratory in Finland. “Evidence obtained by other groups suggested that the antidepressant effect of several medications was attained via BDNF, but we thought that the action occurred indirectly, due to the increased levels of this neurotrophic factor, and not because the antidepressants were binding to the molecule that facilitates its action.”

What was observed in the case of LSD and psilocin — the form of psilocybin that reaches the brain — had already been observed by the Castrén group in other types of antidepressants. Experiments conducted by Brazilian pharmacologist Plínio Casarotto, a member of the Finnish team, and published in 2021 in the journal Cell, demonstrated that fluoxetine, in the category of serotonin reuptake inhibitors; imipramine, a tricyclic antidepressant; and ketamine, an anaesthetic with antidepressant action, promoted neuroplasticity by binding to TrkB and facilitating the action of BDNF. “Antidepressants alone do not activate this receptor but put it into a state susceptible to activation by BDNF,” says Casarotto, another of the study’s coauthors.

The confirmed difference now is that psychedelics present a greater tendency to interact with the TrkB receptor than fluoxetine, impramine, and ketamine. Moreover, LSD and psilocin connect to a slightly different receptor section from other antidepressants and render its structure stable for longer, as well as making it more favorable to BDNF binding. “The minimal difference in the orientation of the protein, and permanence in this state for some nanoseconds more, has enormous consequences for the action of BDNF,” adds Casarotto. “The time and manner in which psychedelics connect to TrkB may go some way to explaining why their effects appear to kick in more quickly and are more powerful and lasting than conventional antidepressants.” Classic antidepressants have a very low level of affinity to TrkB, and for this reason, according to the researchers, high levels would be required to achieve the concentration that induces neuroplasticity, which may cause more pronounced side effects.

Tests on mice enabled the researchers to confirm these findings and obtain indications that interaction with the serotonin receptor would be responsible for the hallucinogenic effects of these compounds. Rodents with a mutation that deformed TrkB — and prevented LSD and psilocin from binding to this receptor — did not respond to the behavioral tests evaluating symptoms similar to those of a depressive condition in human beings. They did, however, present neck torsion similar to the way dogs act when they try to dry themselves — an action attributed to hallucination. This effect disappeared when the rodents received a compound preventing LSD and psilocin from connecting to the serotonin receptor. “We demonstrated that the serotonin receptor appears to be very important for the hallucinogenic effect of psychedelics, but not for antidepressant action,” says Brazilian biologist Caroline Biojone, of the University of Helsinki team.

The findings of this study, say the authors, pave the way for the design of compounds with an equivalent structure to that of psychedelics, which have a high level of affinity with TrkB and quick-starting, long-lasting antidepressant action, but without the hallucinogenic effects. “The data strongly suggest this possibility, but more studies are required to reproduce the results,” states psychiatrist Jaime Hallak, of the University of São Paulo’s Ribeirão Preto School of Medicine (FMRP-USP), who did not participate in the research.

According to psychiatrist Acioly Lacerda, of the Federal University of São Paulo (UNIFESP), the development of an antidepressant having only the characteristics desired in psychedelics would reduce the risk of chemical dependence and potentially cut treatment costs. Currently, psychedelics are used in some countries to treat depression under experimental conditions only in clinical trials requiring prior approval from ethics committees and regulators. “The pathway to a new medication with these characteristics is long, and has high levels of failure,” notes Lacerda. “More than 90% of the molecules tested to treat psychiatric illnesses are not approved in the final clinical trials phase,” he concludes.

1. Study of the relevance of p75 receptor activation in the effect of antidepressants on memory extinction (nº 18/04250-5); Grant Mechanism Postdoctoral Fellowship; Supervisor Leonardo Resstel Barbosa Moraes (USP-RP); Beneficiary Cassiano Ricardo Alves Faria Diniz; Investment R$309,872.87.
2. Study of the relevance of p75 receptor activation in the effect of fluoxetine on memory extinction (nº 18/18500-3); Grant Mechanism Fellowship Abroad; Principal Investigator Leonardo Resstel Barbosa Moraes (USP-RP); Supervisor Eero Castrén (University of Helsinki); Beneficiary Cassiano Ricardo Alves Faria Diniz; Investment R$275,440.61.

Scientific articles
MOLINER, R. et al. Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. Nature Neuroscience. june 5, 2023.
CASAROTTO, P. et al. Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell. mar. 4, 2021.