The Use of Psychedelics as a Treatment for Depressive Disorders

📖 What’s This Paper About?

This paper explores the use of psychedelics, specifically psilocybin and LSD (lysergic acid diethylamide), as potential treatments for depression. The authors from Saint Petersburg State Pediatric Medical University analyze scientific research showing that these substances may offer rapid and lasting antidepressant effects, especially for those with treatment-resistant depression.

Why This Matters

According to the World Health Organization, over 260 million people worldwide suffer from clinical depression, with 15-33% experiencing treatment-resistant forms. This highlights an urgent need for alternative treatments for patients who don’t respond to conventional medications.

• Conventional antidepressants are ineffective for many patients
• Psychedelics show promise for rapid and lasting effects
• New understanding of mechanisms may lead to non-hallucinogenic treatments

Top 5 Takeaways

2. Neuroplasticity as a Key Mechanism

Psychedelics enhance neuroplasticity—the brain’s ability to reorganize and form new neural connections—which may underlie their therapeutic effects in treating depression.

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The Bigger Picture

This research represents a paradigm shift in understanding depression treatment. By identifying the specific mechanisms through which psychedelics produce antidepressant effects, scientists may develop new medications that retain therapeutic benefits without hallucinogenic properties. This could revolutionize treatment for the millions suffering from depression, especially those who don’t respond to current options.

Final Thought

While psychedelics remain controversial, their potential to address treatment-resistant depression through unique neurological pathways offers hope for new therapeutic approaches that could transform mental healthcare.

THE USE OF PSYCHEDELICS AS A TREATMENT FOR DEPRESSIVE DISORDERS

Egovtseva K.G., Zvereva A.O., Zhdanova M.A.

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Saint Petersburg State Pediatric Medical University

Scientific supervisor: Professor, Doctor of Medical Sciences Rusanovsky V.V.

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

Introduction

Data from the World Health Organization (WHO) indicate that over 260 million people worldwide suffer from clinical depression, with 15-33% of patients experiencing resistant forms of depression that do not respond to existing medications. In this context, it becomes clear that new treatment methods need to be developed for those who cannot receive adequate help from currently available drugs. Recent studies confirm that psychedelic substances may play a certain role in combating depressive symptoms. One such drug that has received attention is psilocybin – a substance that has been actively studied in recent years as a potential treatment for depression, as well as lysergic acid diethylamide (LSD).

Objective

Analysis of literature data on the use of psilocybin and lysergic acid diethylamide (LSD) as an alternative to available antidepressants for the treatment of depression.

Materials and Methods

Review of scientific literature and analysis of scientific research.

Research Results

Studies have shown that psychedelic substances such as LSD (lysergic acid diethylamide) and psilocybin (a metabolite of psilocin) can actually be fast-acting antidepressants while having 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.

Results from previous clinical studies show that the use of psychedelics has potentially equal effectiveness to existing medications. They possess significant therapeutic potential and can maintain positive treatment results for a long time.

These key findings indicate that both psilocybin and LSD have potential in treating depression, especially in patients who fail to achieve positive results from standard treatment. However, more extensive and controlled clinical studies are needed to better understand the effectiveness, safety, and optimal dosage of these substances. Overall, the literature data on these substances provide an interesting area for future research and may help determine their role in clinical practice.

Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is a natural psychedelic pro-drug narcotic compound produced by more than 200 species of fungi. It is an alkaloid from the tryptamine family; a phosphorylated derivative of psilocin.

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

“Until now, the acute hallucinogenic effects of psychedelics through serotonin receptor (5-HT2A) activation have limited their active clinical use, as this requires special medical supervision during prolonged sessions in a controlled clinical environment. In addition, there are concerns that psychedelics may cause prolonged perceptual disorder induced by hallucinogens, or irreversible cases of psychosis in susceptible populations (because of this, patients with bipolar disorder or schizophrenia in family history have already been excluded from trials of psychedelic drugs for depression),” the scientists noted.

According to publications from a 2023 article, scientists from the University of Helsinki (Finland) conducted experiments on mice and found that psychoactive narcotic substances, such as LSD and psilocybin, can cause antidepressant effects through connection with specific receptors. Studying this mechanism provides an opportunity to create new drugs that can be used in treating depression in humans without the negative side effect of hallucinations.

The study was published in the journal Nature Neuroscience.

According to the latest article in Science, psychedelic action is associated with selective activation of only intracellular 5-HT2AR, which are found in neurons of the cerebral cortex. These receptors can be located both on the cell surface and in their cytoplasm. Not all molecules can activate these intracellular receptors, as it depends on their hydrophobicity and water solubility. It is because of this property that dimethyltryptamine (DMT) molecules, which is a psychoactive substance that naturally occurs in the brain, can activate intracellular 5-HT2AR that do not respond only to serotonin.

Neuroplasticity is the brain’s ability to restructure itself and form new connections between neurons when damaged, when exposed to new stimuli, and so on. Neuroplasticity underlies learning, response to stress, and is generally very important for the normal functioning of the nervous system.

The degree of neuroplasticity can be unique to each person and can vary throughout life. Factors such as age, genetics, environment, and lifestyle can influence its manifestation.

The enhancement of neuroplasticity is precisely related to the action of psychedelics (such as DMT) on serotonin receptors (5-HT2AR) inside neurons. The effect on animal behavior was confirmed in experiments on rodents (an antidepressant effect was noted), as well as in microscopic studies of their brain tissues.

Consequently, scientists have again found confirmation that it is possible to find compounds or their combinations that preserve the antidepressant effects of psychedelics and are devoid of hallucinogenic properties.

“Brain-derived neurotrophic factor (protein, BDNF) and its TrkB (tropomyosin tyrosine kinase receptor, encoded in humans by the 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 fast-acting ketamine, directly bind to TrkB and enhance BDNF signaling. BDNF and TrkB are also involved in the action of psychedelics as downstream effectors of serotonin receptor 5-HT2A12 activation. We decided to study whether direct binding to the TrkB protein can mediate the neuroplastic effects underlying the therapeutic potential,” the scientists explained.

Experiments were conducted on laboratory mice aged 17-19 weeks and in vitro — on a culture of HEK293T cells from human embryonic kidney temporarily synthesizing TrkB protein, as well as N2a cells and a mature culture of neurons. Substances for study included: ketamine hydrochloride, R,R-HNK, LSD, psilocin, lysuride hydrogen maleate, cabergoline, ketanserin, and M100907. For in vitro studies, 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 scientists concluded that in neurons, LSD and psilocin (a metabolite of psilocybin) bind to the TrkB receptor 1000 times better than classical antidepressants — fluoxetine and ketamine. This enhanced the effect of brain-derived neurotrophic factor on TrkB, which in turn increased synaptic transmission between neurons, indicating a process of neuroplasticity.

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

“Our data confirm that TrkB is a common primary target for antidepressants and suggest that allosteric modulators of TrkB, devoid of serotonin receptor 5-HT2A activity, may preserve the antidepressant effect of psychedelics without hallucinogenic effects,” the researchers concluded.

Studies of this type are of great importance, as understanding the mechanisms of action of psychedelics is the basis for developing more effective and safer methods of using these complex drugs in medical practice.

Conclusion

According to scientific research, LSD and psilocybin can be used to treat 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 depressed patients. Previously conducted studies have shown that psychedelics have similar effectiveness compared to other antidepressants. However, for a more complete understanding of their mechanism of action, and most importantly safety in the long term, additional research and clinical trials are needed. Despite this, the available data generate interest and point to the potential use of psychedelics in the treatment of depression.

References

This is informational, not medical advice.

Sources

Sources

1. https://naked-science.ru/article/biology/psihodeliki-poboroli-depressiyu

2. https://www.nature.com/articles/s41593-023-01316-5

3. F. Holze, A. M. Becker, K. E. Kolaczynska, U. Duthaler, and M. E. Liechti, "Pharmacokinetics and Pharmacodynamics of Oral Psilocybin Administration in Healthy Participants," Clin. Pharmacol. Ther., no. January 2023, 2022, doi: 10.1002/cpt.2821.

4. R. A. Al-Naggar, H. Alshaikhli, and G. Erlam, "Effectiveness of psilocybin on depression: A qualitative study," Electron. J. Gen. Med., vol. 18, no. 3, 2021, doi: 10.29333/ejgm/10862.