The use of psychedelic drugs as a treatment for depressive disorders

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Introduction. Depressive disorders, characterized by a low mood and other symptoms, are becoming increasingly common, especially among young people. Therefore, it is important to find new, more effective methods of treating depression. Objective. To explore scientific research on new perspectives in the treatment of depressive disorders using psychedelics. Materials and Methods. Literature was reviewed to study modern methods of treating depressive disorders, as well as to analyze the frequency of ineffective modern treatment in such cases. Based on foreign studies, we also examined proposed methods of treating depressive disorders with LSD and psilocybin. Results. Research shows that psychedelic substances, such as LSD and psilocybin, can be used as fast-acting antidepressants with a long-lasting therapeutic effect comparable to existing medications. Scientists have hypothesized that the hallucinogenic effects of psychedelics can be separated, leaving only their antidepressant and stimulating properties associated with increased neuroplasticity  the brain's ability to change and form new connections between neurons under the influence of new experiences. Research also shows that psychedelics affect brain-derived neurotrophic factor and its receptor TrkB, which contributes to enhanced neuroplasticity. Conclusions. Thus, there is a possibility of developing compounds or their combinations that retain the antidepressant properties of psychedelics without the hallucinogenic effect. Understanding the mechanisms of action of psychedelics opens up new perspectives for more effective and safe use of these drugs in medical practice.

Keywords: depression; psilocybin; psilocin; lysergic acid diethylamide (LSD.                                            

Research of this kind holds immense significance as understanding the mechanisms of action of psychedelics is fundamental for developing more effective and safe methods of utilizing these complex substances in medical practice.

 

Conclusion: According to scientific research, LSD and psilocybin can be used in the treatment of depression as fast-acting antidepressants with a prolonged therapeutic effect. They are capable of restoring disrupted chemical processes in the brain related to the emotional state of depressive patients. Previous studies have shown that psychedelics exhibit similar efficacy compared to other antidepressants. However, for a more comprehensive understanding of their mechanism of action and, most importantly, long-term safety, further research and clinical trials are necessary. Despite this, the existing data arouse interest and suggest the potential use of psychedelics in depression treatment.

World Health Organization (WHO) data shows that over 260 million people worldwide suffer from clinical depression, with 15-33% of patients experiencing treatment-resistant depression, meaning that they do not respond to current medications. In this context, it is clear that new treatment methods are needed for those who do not find adequate relief from currently available drugs. Recent studies confirm that psychedelic substances can play a role in combating depressive symptoms. One such substance attracting attention is psilocybin, which has been actively researched as a potential treatment for depression, along with lysergic acid diethylamide (LSD).

 

Research Objective: Analysis of literature data on the use of psilocybin and lysergic acid diethylamide (LSD) as alternatives to available antidepressants for treating depression.

Materials and Methods: Review of scientific literature and analysis of research studies.

Results:

Studies have shown that psychedelic substances, such as LSD (lysergic acid diethylamide) and psilocybin (psilocin metabolite), can actually act as fast-acting antidepressants, with a long-lasting therapeutic effect. They have a significant impact on the brain and can help patients with depression restore disrupted chemical processes related to their emotional state.

 

Previous clinical research results indicate that the use of psychedelics has potentially equal effectiveness compared to existing medication. They possess substantial therapeutic potential and can maintain positive treatment outcomes for an extended period.

 

These key findings indicate that both psilocybin and LSD have potential in treating depression, particularly in patients who struggle to achieve positive outcomes with standard treatment. However, more extensive and controlled clinical trials are needed to better understand the efficacy, safety, and optimal dosage of these substances. Overall, literature data on these substances offer an intriguing area for future research and can assist in determining their role in clinical practice.

 

Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is a natural psychedelic prodrug narcotic compound produced by over 200 species of mushrooms. It is an alkaloid from the tryptamine family, a phosphorylated derivative of psilocin.

LSD (Lysergic acid diethylamide-25, LSD, from German Lysergsäurediethylamid - diethylamide of d-lysergic acid) is a semi-synthetic psychoactive narcotic substance from the lysergamide family.

 

"Traditionally, the acute hallucinogenic effects of psychedelics through the activation of the serotonin receptor (5-HT2A) have limited their active clinical utilization, as it requires special medical monitoring during prolonged sessions in a controlled clinical setting. Additionally, concerns exist that psychedelics may cause long-term perception disorders induced by hallucinogens, or irreversible cases of psychosis in susceptible population groups (which is why patients with bipolar disorder or schizophrenia in the family history have been excluded from trials of psychedelic drugs for depression)" - noted researchers.

Based on the publications of the article in 2023, scientists from the University of Helsinki (Finland) conducted experiments on mice and found that psychoactive narcotic substances, such as LSD and psilocybin, can induce antidepressant effects through specific receptor interactions. Exploring this mechanism provides an opportunity to develop new medications that can be applied in depression treatment in humans without the negative side effect of hallucinations. The study was published in the journal NatureNeuroscience.

In accordance with the latest article in the journal Science, the psychedelic action is associated with a selective activation of intracellular 5-HT2AR receptors within neurons of the cerebral cortex. These receptors can be located on the cell surface as well as in their cytoplasm. Not all molecules can activate these intracellular receptors, as it depends on their hydrophobicity and solubility in water. This property is what allows molecules like dimethyltryptamine (DMT), a psychoactive substance naturally present in the brain, to activate intracellular 5-HT2AR receptors that do not respond solely to serotonin.

 

Neuroplasticity is the brain's ability to restructure itself and form new connections between neurons in response to damage, exposure to new stimuli, and so forth. Neuroplasticity is crucial for learning, stress response, and overall is essential for the proper functioning of the nervous system. The degree of neuroplasticity can be unique to each individual and may vary throughout life. Factors such as age, genetics, environment, and lifestyle can influence its expression.

 

Enhancing neuroplasticity is precisely linked to the action of psychedelics (such as DMT) on serotonin receptors (5-HT2AR) within neurons. This effect has been confirmed in experiments on rodents, noting an antidepressant effect, as well as in microscopic brain tissue studies.

 

Thus, scientists have again found evidence that compounds or their combinations preserving the antidepressant effects of psychedelics without the hallucinogenic effects can be identified. 

 

"The brain-derived neurotrophic factor (BDNF) and its TrkB (tropomyosin receptor kinase B coded by the human Ntrk2 gene) are central mediators of neuroplasticity and the therapeutic action of antidepressants. Recent discoveries have shown that antidepressants, including traditional ones like fluoxetine and imipramine, as well as the fast-acting ketamine, directly bind to TrkB and enhance the BDNF signal transmission. BDNF and TrkB also participate in the action of psychedelics as downstream effectors of 5-HT2A serotonin receptor activation. We decided to investigate whether direct binding to the TrkB protein can mediate the neuroplastic effects underlying the therapeutic potential," explained the scientists.

 

The experiments were conducted on laboratory mice aged 17-19 weeks and in vitro on HEK293T cell culture from human embryonic kidney cells temporarily synthesizing the TrkB protein, as well as on N2a cells and mature neuron culture. The substances for study included ketamine hydrochloride, R, R-HNK, LSD, psilocin, lisuride hydrogen maleate, cabergoline, ketanserin, and M100907. For in vitro investigations, they were dissolved in dimethyl sulfoxide and diluted in a ratio of 1 to 1000, and for in vivo experiments on rodents, drugs were diluted in sterile 0.9% sodium chloride and administered intraperitoneally.

 

The researchers concluded that in neurons, LSD and psilocin (the metabolite of psilocybin) bind to the TrkB receptor 1000 times better than classic antidepressants, such as fluoxetine and ketamine. This enhances the brain-derived neurotrophic factor action on TrkB, which in turn increases synaptic transmission between neurons, indicating a process of neuroplasticity.

 

The study showed that under stress, a single dose of LSD had a persistent antidepressant-like effect in mice. According to the scientists, this effect is due to the binding of the narcotic substance to TrkB, irrespective of serotonin receptors. Therefore, LSD also induced a hallucinogenic effect in animals in the form of head twitching. However, this was associated with the activation of serotonin receptors and not TrkB.

 

"Our data confirm that TrkB is the common primary target for antidepressants, and suggest that TrkB allosteric modulators lacking 5-HT2A serotonin receptor activity can preserve the antidepressant effect of psychedelics without the hallucinogenic effects," the researchers summarized.

 

About the authors

Kseniya Gennadievna Egovtseva

Federal State Budgetary Educational Institution of Higher Education "St. Petersburg State Pediatric Medical University".

Email: ksyu.egovtseva.93@mail.ru

Student

Russian Federation, 194100 ,Russia ,St. Petersburg,Litovskaya street 2

Vladimir Vasilievich Rusanovsky

Federal State Budgetary Educational Institution of Higher Education "St. Petersburg State Pediatric Medical University".

Author for correspondence.
Email: rusvv2058@mail.ru
ORCID iD: 0000-0002-0432-7946
SPIN-code: 7010-4530

MD, Professor of the Department of Pharmacology with a course in Clinical Pharmacology and Pharmacoeconomics

Russian Federation, 194100 ,Russia ,St. Petersburg,Litovskaya street 2

Anastasia Olegovna Zvereva

Federal State Budgetary Educational Institution of Higher Education "St. Petersburg State Pediatric Medical University".

Email: Nasternych99@mail.ru

Student

Russian Federation, 194100 ,Russia ,St. Petersburg,Litovskaya street 2

Maria Andreyevna Zhdanova

Federal State Budgetary Educational Institution of Higher Education "St. Petersburg State Pediatric Medical University".

Email: Maryz1999z@mail.ru

Student

Russian Federation, 194100 ,Russia ,St. Petersburg,Litovskaya street 2

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