How Promising is Psilocybin for Depression?

Learn about psilocybin in this article. It is a hallucinogenic compound of certain mushrooms grown in Mexico, Central America, and the United States.

What is Psilocybin?

Psilocybin is a hallucinogenic compound found in certain types of mushrooms grown in Mexico, Central America, and the United States.¹

Street Names

According to the Drug Enforcement Administration (DEA), magic mushrooms, mushrooms, and shrooms are common street names for psilocybin mushrooms.

Different Forms of Psilocybin Mushrooms

Over one hundred species of mushrooms of the genus Psilocybe (and some species of other genera) produce psilocybin. Examples of such species, including their nicknames, are listed below:²

Psilocybe cubensis (the most common cultivated species) ³
Psilocybe caerulescens – Landslide Mushroom, Derrumbes
Psilocybe mexicana – Teonanacatl, Pajaritos
Psilocybe carulipes – Blue Foot Mushroom
Psilocybe stuntzii – Blue Ringer Mushroom, Stuntz’s Blue Legs
Psilocybe cyanescens – Wavy Caps
Psilocybe azurescens – Flying Saucer Mushrooms
Psilocybe tampanensis – Magic Truffles, Philosopher’s Stone

They are often eaten whole, with or without food, but can also be heated in water to produce a “tea” or, if dried, powdered and consumed in capsules.⁴

Is it Legal?

Psilocybin is not legal in the United States, as it is a Schedule I substance under the Controlled Substances Act of 1970. Schedule I is for substances with a high potential for abuse, lack of therapeutic approval, and that cannot be used safely in medicine.

However, a 2017 review concluded that existing evidence does not support placement more restrictively than Schedule IV and stipulated that the original placement of psilocybin was the result of a substantial overestimation of the risk of harm and abuse potential. Even so, removal from Schedule I can only occur if a medicinal product containing a Schedule I substance is approved for therapeutic use as a drug by the Food and Drug Administration (FDA). ⁴

How does Psilocybin Work?

The Effect on the Brain

Psilocybin is a classic psychedelic drug. Classic psychedelic drugs interact with serotonin and dopamine receptors (and their subtypes) in the brain.⁵

Serotonin (5-hydroxytryptamine, 5-HT) is a small molecule that functions as a neurotransmitter in the central nervous system. There are seven different serotonin receptor classes, designated 5-HT1 through 5-HT7. Subtypes within each class are designated by an additional letter (e.g., 5-HT1A or 5-HT1B).

How Brain Chemicals Are Affected

Serotonin receptors mediate emotions and moods (e.g., anxiety and aggression), cognition, sex, learning memory, appetite, and other biological, neurological, and neuropsychiatric processes. Multiple recreational and pharmaceutical drugs, such as antipsychotics, antidepressants, antiemetics, antimigraine agents, and hallucinogens, target these receptors.⁶

Psilocybin is not the main pharmacologically active substance in magic mushrooms. Psilocybin is metabolized into psilocin, meaning it is a prodrug to psilocin. Psilocin is a high-affinity agonist at serotonin 5-HT2A receptors. An agonist is a compound that can bind to and cause the activation of a receptor.⁷ This 5-HT2A agonism induces ‘frontal hyper-frontality’ which produces a “mystical-like” hallucinatory effect.

Other psychological effects may include:⁸

Hallucinations (visual and auditory)
Synesthesia
Altered perception of time
Altered body image
Increased introspection
Derealization

The Effect on the Body

5-HT2A agonism is also associated with mydriasis (dilation of the pupils), increased heart rate and blood pressure, and feelings of nausea.⁸In the liver, psilocybin is extensively converted to psilocin within thirty minutes.⁹

The DEA reports the following physical effects of psilocybin:

- - Nausea
  - Vomiting
  - Muscle weakness
  - Lack of coordination

Effects of Psilocybin Mushrooms

Psychedelic Experience

The effects of psilocybin mushrooms depend on the species of mushroom used (e.g., the concentration of active metabolites in the species) and on the user’s mindset, body type (e.g., weight, metabolism), and level of tolerance. A medium dose (12-20 mg) may produce several psychic effects. The effects can be classified into four categories:

Perceptual
Cognitive
Emotional
Ego Dissolution

Most users experience a “stereotyped” timeline of effects: for a few hours after ingestion, the user is in a psychedelic state. This state comprises sensory hallucinations and an experience described by many as a religious or spiritual transcendental experience. Then, after the initial effects of the drug have worn off, many individuals experience an afterglow effect characterized by an elevated mood, which may last for several weeks. This effect is what leads people to rate the experience as one of the most personally meaningful experiences of their life.

Risks

Because psilocybin induces changes in perception and affects normal cognitive processing, the risk of injury/accidents linked to inappropriate/inadequate behaviors is increased. In addition, flashbacks or hallucinogen persisting perception disorder (HPPD) may occur.¹⁰

Many varieties of poisonous mushrooms may be incorrectly identified as psilocybin mushrooms. Psilocybin mushrooms are not known to cause major organ toxicity or death, but misidentification can lead to the ingestion of toxic species with potentially fatal outcomes.

Abusing psilocybin may increase the risk of having a “bad trip,” an undesired physical and emotional experience characterized by altered visual perception, extreme distress, fear, lack of coordination, derealization, depersonalization, paresthesia, heightened fright, panic attacks, traumatic flashbacks, paranoia, delirium, short-term psychosis, and other symptomology characteristics of schizophrenia.

Thus, the risks of psilocybin include dangerous behavior in unprepared, unsupervised users, and exacerbation of mental illness in those with or predisposed to psychotic disorders.

Psilocybin-Assisted Treatment for Depression

The past decade has seen a significant increase in research directed at psilocybin treatment of a variety of ailments, including anxiety/depression, addiction, obsessive-compulsive disorder, and cluster headache.¹¹

Trials

The table below lists recent trials, publications, and achievements relating to psilocybin-assisted treatment for depression:

Institute or Organization	Publications/Areas of Study/Clinical Trials
Center for Psychedelic and Consciousness Research (John Hopkins University, USA) Founded in 2019	Effects of psilocybin-assisted therapy for major depressive disorder: A randomized clinical trial.
Usona Institute (Wisconsin, USA).	2018—U.S. Food and Drug Administration (USFDA) approval for a psilocybin treatment for major depressive disorder (MDD)
Compass Pathways Ltd. (London, UK).	2018—U.S. Food and Drug Administration (USFDA) approval of “breakthrough therapy” status in 2018 for a psilocybin treatment they developed for treatment-resistant depression
Cybin, Corp. (Toronto, ON, Canada)Founded in 2019.	A psilocybin drug targeting MDD (in phase 2a and phase 2b of clinical trial).
Heffter Research Institute (founded and Incorporated in New Mexico, USA 1993).	Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial.
Department of Psychiatry (Yale University, USA).	The Yale Manual for Psilocybin-Assisted Therapy of Depression

Note: “Breakthrough therapy” status means that the FDA believes that the preliminary clinical evidence of psilocybin as a treatment for depression may demonstrate a substantial improvement over available therapy on a “clinically significant endpoint. The designation is made to speed up the development and review of psilocybin treatment. ¹²

In addition, two trials (clinical trial numbers: NCT03380442, NCT03715127) investigating the clinical indication of psilocybin for depression (one by the Helsinki University in Finland and one by the University of Zurich in Switzerland) are set to finish in September and October 2021.

Effects

Existing research has found it is very likely that the psychedelic experience itself is important for the antidepressant effects of psilocybin.

A plethora of factors affects the therapeutic/clinical outcome of psilocybin administration, including:

Age, body weight, muscle mass, genetics, drug tolerance, drug interactions, drug purity, dosage, gender, recreational consumption and inexperience with recreational drug use, past experiences with drug use, mindset, setting (context in which drug is used), cultural influences, and medical history
Mindset (e.g., patient attitude and expectations, preconceptions of treatment)
Setting (e.g., use of music/art, of religious/spiritual imagery, or a purpose-built facility)
Psychological support (e.g., intensive clinical care/contact)
Specific types of psychological experiences
Treatment type (e.g., personalized treatment, combination therapy with other drugs)
Type of mood or anxiety disorder
Degree of suicidality
Family history of psychotic disorders
A high score on neuroticism
History or current diagnosis of bipolar disorder and schizophrenia
High risk for developing psychosis
On other psychedelics/anti-psychotic/anti-depressant medications (e.g., selective serotonin reuptake inhibitors (SSRIs), haloperidol, tricyclic anti-depressants, lithium, and monoamine oxidase inhibitors)

Before and After Treatment

Research participants have reported their experience and subjective perspective during and after psilocybin treatment as:

Transcendental experience
Enhanced feelings of connectedness
Sustained improvement in attitudes and behavior
Perception of life as a deeper, richer experience
Increased sense of wellbeing
Reduction in depressive thoughts and anxiety

According to a study by the John Hopkins University of Medicine, higher doses of psilocybin (20–30 mg/70 kg) directly correlate to positive persisting effects on behavior, attitude, mood, and general outlook on life up to fourteen months after follow-up.

Mixing Mushrooms with Other Drugs

In general, simultaneous use of alcohol and other drugs may exacerbate the psychological and physical risks of psilocybin. A 2011 evaluation found that the most harmful instances of magic mushroom use tended to involve the combination of other drugs including alcohol with mushrooms.

Fortunately, mushrooms do not stick around the body for long. Psilocybin and psilocin are excreted (that is, via the kidneys), and about 2/3rds of excretion occurs in the first three hours. After twenty-four hours, the compounds are undetectable in the urine.

Psilocybin Myth and Misunderstandings

To reiterate, the characterization of psilocybin as a substance with high abuse potential is based largely on social lore, sensationalized media coverage, and misinformation and misunderstanding about the actual risk of dependence and harm during the 1960s.

Although scientific evidence confirms that there has been abuse and supports regulation as a controlled substance, the actual risk of dependence and harm associated with psilocybin has been estimated to be among the lowest of all major substances of abuse and dependence – lower than caffeine, cannabis, and nicotine. If there is one thing to take away from this article, it’s that there are thousands of years of anecdotal evidence (in addition to modern-day studies) which confirm that psilocybin has an incredibly favorable safety profile.