Psilocybin is a 5HT-2A (serotonin 2A) receptor agonist, which seems to play a role in both the hallucinogenic and therapeutic impacts. Studies in treatment-resistant depression patients show increased functional connectivity during emotional processing tasks, particularly in the amygdala and the prefrontal cortex. This is similar to the neural plasticity induced by psychedelics in general. 

All of these processes/regions have been implicated in the antidepressant action of typical antidepressants like SSRIs, which may explain why psilocybin has observed antidepressant properties.

Therapeutic mechanisms of psilocybin

In 2021 the FDA approved the use of 3,4-methylenedioxymethamphetamine (MDMA) for the treatment of PTSD. The compound was studied as a treatment as studies suggest it acts by binding to the presynaptic serotonin transporters inducing a release of serotonin. The trials conducted administered three doses of MDMA paired with manualized therapy during an eighteen-week treatment plan. The results of the study showed significantly reduced symptoms of depression as well as regulated amygdalar serotonergic function in comparison to the control (placebo) group. Each study conducted showed similar results which led to the approval for the regulated use of MDMA to treat PTSD symptoms.

Treatment of PTSD using MDMA (Ecstasy)

A micro-dose is considered to be 1/20 to 1/10 of an active dose of a psychedelic. Taking micro-doses of psychedelics like LSD, psilocybin, and ketamine is thought to be helpful for treating depression since taking small doses is not enough to feel the full psychoactive effects, but enough to feel its stimulating and positive effects.

Clinical uses of Microdosing Psychedelics

Psychedelics, in particular LSD and psilocybin, have been investigated as potential treatments for depressive symptoms. There is evidence for short-, medium-, and long-term usefulness in both micro-dosing and regular studies. In addition to the potential cognitive stimulation (LSD) or emotional well-being effects (psilocybin), these treatments are generally well-tolerated in clinical and general populations. In addition, MDMA has received breakthrough treatment status with the FDA for the treatment of PTSD.

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Psychedelics (or hallucinogens) are a class of psychoactive substances (Psychoplastogens) that produce changes in perception, mood, and cognitive processes, such as altering thinking, sense of time, and emotions. They can also cause a person to see or hear things that do not exist or are distorted. They can be naturally occurring or synthetic. Examples include:
- Lysergic acid diethylamide (LSD)
- Dimethyltryptamine (DMT)
- 3-[2-(Dimethylamino)ethyl]-1H-indol-4-yl dihydrogen phosphate (Psilocybin)
- Mescaline
- Peyote


Psychedelic Drugs

Microdosing is the administration of a psychedelic drug/medication at one-tenth of the dose that would cause hallucinogenic effects.

Microdosing

The study of the use of extracts and compounds obtained from mushrooms as medicines or health-promoting agents. Mycotherapy, also known as fungal or mushroom therapy, is a branch of natural medicine exploring the therapeutic properties and potential health benefits of various mushrooms. The practice of using mushrooms for medicinal purposes has been observed in different cultures throughout history, and it continues to gain recognition and scientific interest in modern times.

Mycotherapy

- Monoamine hypothesis
- Monoamine Oxidase (MAO)
- Reserpine
- Tricyclics
- Selective serotonin reuptake inhibitors (SSRIs)

Drug Treatments for Depressive Disorders

Kuypers, K. P. C.. (2020). The therapeutic potential of microdosing psychedelics in depression. Therapeutic Advances in Psychopharmacology, 10, 204512532095056. https://doi.org/10.1177/2045125320950567

The therapeutic potential of microdosing psychedelics in depression

Galvão-Coelho, N. L., Marx, W., Gonzalez, M., Sinclair, J., De Manincor, M., Perkins, D., & Sarris, J.. (2021). Classic serotonergic psychedelics for mood and depressive symptoms: a meta-analysis of mood disorder patients and healthy participants. Psychopharmacology, 238(2), 341–354. https://doi.org/10.1007/s00213-020-05719-1

Classic serotonergic psychedelics for mood and depressive symptoms

Louie, A. K., Beresin, E. V., Coverdale, J., Balon, R., Guerrero, A. P. S., Morreale, M. K., Aggarwal, R., & Brenner, A. M.. (2020). Are Psychedelics Something New in Teaching Psychopharmacology?. Academic Psychiatry, 44(5), 511–514. https://doi.org/10.1007/s40596-020-01294-x

Are Psychedelics Something New in Teaching Psychopharmacology?

Potential clinical uses for psychedelics

Serotonergic psychedelics have been shown to increase dendritic arborization, spinogenesis, and synaptogenesis, particularly in the prefrontal cortex. This seems to operate in a similar neural pathway to BDNF (TrkB and mTOR receptors), and it is mediated by the serotonin 2A receptors. This is one potential antidepressant  mechanism of psychedelic drugs.

Psychedelics and Neuroplasticity

Psilocybin is a 5HT-2A (serotonin 2A) receptor agonist that is a naturally-occurring psychedelic compound. It is derived from over 200 species of fungi, many from the genus Psilocybe. A purified bioactive compound derived from medicinal mushrooms.

Psilocybin

A meta-analysis of randomized trials investigating the use of lysergic acid diethylamide (LSD) for alcohol use disorder (AUD) demonstrated substantial and statistically significant improvements in LSD's effectiveness compared to control conditions. Furthermore, clinical studies indicate promising anti-addiction effects of LSD and related classic psychedelics in the treatment of alcohol and other substance use disorders.

Reduction in Alcohol Use Disorder and consumption after psychedelic use

Impact of Microdosing clinical study -- Why necessary and how useful?
 -- Why Necessary?

It has often been claimed that psychedelics have therapeutic value in treating many types of mental health conditions such as depression. It is seen that psychedelics like LSD or psilocybin have shown subtle but positive effects on cognitive processing. Howeverm there are other side effects that are also present in the dosing of these drugs if not carefully dosed, and in lower doses. 

Fungi are one of the main natural sources of psychedelic compounds such as psilocybin. Research suggests that psychedelics may have positive health effects on those suffering from both chronic mental and physical illnesses.

Mushrooms in Medicine

- A risk of taking SSRIs
- Many over-the-counter drugs may synergize with the drugs to push synaptic serotonin levels too high
- Symptoms include confusion, muscle spasms, and fever

Serotonin Syndrome

Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs used to treat conditions like depression, which is often associated with low serotonin levels. Unlike agonists or antagonists that bind to receptors, SSRIs work by blocking the reuptake process. This action prevents unused serotonin from being reabsorbed by the presynaptic neuron, allowing it to remain in the synaptic cleft for a longer period. The extended presence of serotonin enhances its interaction with postsynaptic receptors, thereby strengthening its overall effect. Common examples of SSRIs include Prozac, Paxil, and Zoloft.

SSRIs and SNRIs

Tricyclic (or heterocyclic) antidepressants inhibit the reuptake of serotonin and/or norepinephrine, and are thus called due to their three (or more)-ring chemical structure. Some examples include:

- Amitriptyline (Elavil) 
- Nortriptyline (Aventyl)
- Maprotiline hydrochloride (Ludiomil)
- Desipramine hydrochloride (Norpramin)
- Clomipramine (Anafranil)

A similar drug is Bupropion (Wellbutrin), which is an aminoketone that weakly blocks norepinephrine, serotonin, and dopamine reuptake.

Tricyclic Antidepressants

MAOIs inhibit the breakdown of the enzyme that breaks down monoamine neurotransmitters. Some MAOIs have antidepressant effects, including:

- Phenelzine (Nardil)
- Isocarboxazid (Marplan)
- Tranylcypromine (Parnate)

Monoamine Oxidase Inhibitors (MAOIs)

Ketamine, a rapid-acting anesthetic and NMDA receptor antagonist, has been investigated for use in treatment-resistant  depression. When infused in sub-anesthetic doses over a short period (e.g. 40 minutes), ketamine has been shown to have rapid antidepressant effects that can last for up to 4 weeks in some patients.

Using ketamine for treatment-resistant depression

Caffeine has been shown to increase the antidepressant effects of repeated transcranial magnetic stimulation in humans and the antidepressant-like effects of SSRIs, SNRIs, and atypical antipsychotics in mouse models. The proposed mechanism for this is that caffeine's adenosine receptor antagonism increases downstream production of serotonin, dopamine, and norepinephrine.

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