Psilocybin

Psilocybin also known as 4-phosphoryloxy-N,N-dimethyltryptamine (4-phosphoryloxy-N,N-DMT), is a type of hallucinogen (classical serotonergic psychedelic) that is extracted from the genus Psilocybe mushrooms or “magic mushroom” (psilocybin-producing mushrooms) (see Figure 1) ¹, ², ³, ⁴, ⁵, ⁶, ⁷. Psychedelics are substances that exert their effects primarily by an agonist (or partial agonist) action on brain serotonin 5-hydroxytryptamine (5-HT_2A) receptors ⁸. Psilocybin binds with high affinity to brain serotonin 5-hydroxytryptamine (5-HT_2A) receptors ⁹. 5-HT serotonin receptors are densely located in areas of the brain that are responsible for the mediation of mood and anxiety disorders such as the pre-frontal cortex ¹⁰. Psychedelics affect all your senses, altering your thinking (introspection, self-consciousness, mystical experiences, altered time passage), sense of time and your mood or emotions (blissful state, euphoria, and joy) ¹¹. Psychedelics can also cause a person to hallucinate (mainly visual effects)—seeing or hearing things that do not exist or are distorted. The intensity and nature of these effects are highly influenced by the set (your personality and internal expectations of the subject), setting (environment in which the substance is used), and dosage ¹². Subjects participating in clinical trials often describe mystical experiences and improved mood while under the effects of these substances ¹³, ¹⁴. Although there is accumulating evidence that psychedelics are generally safe in humans ¹⁵, it is important to note that these substances can produce side effects and/or unpleasant experiences popularly known as “bad trips”, which involve transitory anxious and psychotic symptoms, confusion, dissociation and depersonalization ¹². Of all the psychedelic drugs, psilocybin is reported to have the most favorable safety profile ¹⁶. Despite the lack of studies investigating the comparative effectiveness of psilocybin and psychedelic drugs for the treatment of mood and anxiety disorders, the vast evidence-based data that exist for psilocybin alone suggest that psilocybin may be the most efficacious psychedelic drug for treating mood and anxiety disorders ¹⁰.

Psilocybin is considered a prodrug to psilocin ¹⁷. It is psilocin that is the main pharmacologically active substance in magic mushrooms, not psilocybin ⁹, ¹⁸. In humans, psilocybin is rapidly dephosphorylated to psilocin (4-hydroxy-N,N-dimethyltryptamine) by alkaline phosphatase in the liver ¹⁹, ²⁰ and nonspecific esterase in the intestinal mucosa ²¹.

The effects of magic mushrooms are dependent on the species of mushroom and the concentration of active metabolites in a given species, an individual’s mindset an individual’s body type (particularly weight, metabolism) and an individual’s level of tolerance ¹⁰.

The effects of psilocybin may be classified into four categories ²², ²³:

1. Perceptual
2. Cognitive
3. Emotional
4. Ego Dissolution.

More simply, psilocybin effects may be divided into psychic and somatic effects (see Table 1) ⁹. The perceptual changes are dose-dependent and could range from mental imagery, distortion, perceptual intensification, illusion, elementary hallucinations, and complex hallucinations ²³. Sense of time, location, and causal sequence can lose their usual linear cause–effect relationship ²³. Cognitive effects of psilocybin can be paradoxical and enigmatic. Certain cognitive traits associated with creativity can increase, such as divergent thinking, unlikely word associations or language patterns, expansion of semantic activation, and attribution of meaning to musical stimuli. The emotional effects are characterized by intensification of feelings, a broadening in the overall range of emotions felt over the duration of psilocybin exposure, and increased access to emotions such as unique states of euphoria characterized by involuntary grinning, uncontrollable laughter, forgiveness, connectedness, silliness, giddiness, playfulness, exuberance, or negative emotions. The majority of emotional effects of psilocybin in supportive contexts are experienced as positive or bias emotion toward constructive responses to social and environmental stimuli. There can be subtle to drastic ego dissolution experiences in which a sense of self- and ego loss occur, which are also exhibited in a dose-dependent fashion. The notion of self- and identity dissolution, sense of connection with the universe or environment, “mystical-type” experiences may reliably occur at higher doses and can be modulated by external stimuli such as music. This experience is more likely to influence long-term changes in life outlook and personality traits ²².

Psilocybin’s acute psychedelic effects are usually evident within 30 to 60 minutes after ingestion of low to moderate (2–10 g) dosing, but sometimes may not become noticeable for as long as an hour, with a gradual intensification over the first 1-2 hours ²⁴. People may think they didn’t take enough so they take more. To avoid what may be an overly intense experience from a high dose, the “start low, go slow” method is best for anyone using psilocybin mushrooms – especially for people inexperienced with them or other psychedelics.

Psilocybin study reports a range of 3 to 5 mg orally produce sympathomimetic effects, but not hallucinogenic effects ²⁰. Psilocybin’s hallucinogenic effects are produced within a range of 8 to 25 mg within 70 to 90 minutes ²⁰. It has been demonstrated that equimolar amounts of psilocybin and psilocin produce similar psychotropic effects in humans ⁹, ²⁵. After oral administration, most psilocybin, psilocin and glucoronidated metabolites are excreted via the kidneys, typically after about three hours ²⁶. After about 24 hour, almost all psilocybin and psilocin are excreted from the body ²⁶.

Perceptible psychological effects of psilocin correlate with plasma levels between 4 ng/mL and 6 ng/mL ²⁰. Hasler and colleagues ²⁰ estimate the bioavailability of psilocin to 52.7% after 10–20 mg psilocybin ingestion. After a rapid increase in plasma levels of psilocybin, followed by a plateau for approximately an hour, psilocybin levels wane significantly until barely detectable after 6 hours ²⁰.

Subjective effects of psilocin may last between 3 and 6 hours ⁹, after which effects subside to negligible levels ²⁴.

In clinical studies, the clinical outcome, and acute and long-term subjective effects of psilocybin administration are measured using questionnaires such as the Subjective experience (5D-ASC) ²⁷, the Beck Depression Inventory (BDI), the Profile of Mood States (POMS) [69], the State-Train Anxiety Inventory (STAI), the Mystical Experience Questionnaire and the Quick Inventory of Depressive Symptoms (QIDS). Table 2 lists additional acute and long-term, subjective effects of psilocybin administration. Table 3 lists participants’ first-hand experiences and subjective perspectives during and after psilocybin in a 2016 phenomenological study conducted by Zamaria and colleagues ³.

Psilocybin, like other psychedelics, often evokes conscious awareness of subconscious thoughts and feelings, such as repressed memories, feelings about life circumstances, fantasies, or deep fears. Therefore, if someone makes the decision to use psilocybin mushrooms, it is important for that person to be prepared to deal with unusual – and perhaps even challenging – thoughts, images, and feelings in an open and thoughtful manner. It is also best to use psilocybin (or any psychedelic) with someone is not under the influence of the substance (a “guide”) who can prevent the user from engaging in dangerous activities ²⁸.

Figure 1. Psilocybin mushrooms (Magic mushrooms)

Footnotes: Examples of Magic mushrooms (psilocybin-producing mushrooms). (a) Psilocybe cubensis (Earle) Singer also known as Stropharia cubensis. (b) Psilocybe caerulescens Murrill also known as Landslide Mushrooms or Derrumbes. (c) Psilocybe mexicana R. Heim also known as Teonanacatl, Pajaritos. (d) Psilocybe caerulipes (Peck) Sacc. also known as Blue Foot Mushroom. (e) Psilocybe stuntzii Guzmán and J. Ott also known as Blue Ringer Mushroom or Stuntz’s Blue Legs. (f) Psilocybe cyanescens Wakef. also known as Wavy Caps. (g) Psilocybe azurescens Stamets and Gartz also known as Flying Saucer Mushrooms. (h) Psilocybe pelliculosa (A.H. Sm.) Singer and A.H. Sm. (i) Psilocybe tampanensis Guzmán and Pollock also known as Magic Truffles or Philosopher’s Stone. (j) Psilocybe baeocystis Singer and A.H. Sm. (k) Psilocybe Hoogshagenii R. Heim nom. inval. also known as Little Birds of the Woods.

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Figure 2. Psilocybin

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Figure 3. Psilocin

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Figure 4. Psilocybin synthesis

Footnote: Conversion of L-tryptophan to psilocybin

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Figure 5. Psilocybin metabolism

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Figure 6. Psilocybin Mechanism of Action

Footnote: Mechanism of action of psilocin. Psilocybin binds with high affinity to serotonin (5-hydroxytryptamine) type 2A (5-HT_2A) receptors ⁹. 5-HT serotonin receptors are densely located in areas of the brain that are responsible for the mediation of mood and anxiety disorders such as the pre-frontal cortex. Molecular mechanisms of action have not yet been elucidated.

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Table 1. Psilocybin effects

Psychic Effects in Humans and Animals (in Medium Dose (12 to 20 mg orally)

Somatic Effects in Humans (Barely Noticeable or Secondary Pharmacological Effects)

Stimulation of affect/affective activation Hypnagogic experience Dreams Enhanced ability for introspection Mystical-type experience, which predicted the success of the therapy and likelihood of persisting positive benefits Illusions Synaesthesia Alterations of thought and time sense

At 8 to 12 mg oral or intramuscular injection; Mydriasis Accelerated heart frequency Slowed heart frequency Hypotension Hypertension Nausea Increased tendon reflex Decreased tendon reflex Dysmetria Tremors At 0.11 mg/kg p.o, similar effects were observed in another study. At 1.5 mg increased to 25 mg orally in three doses per day, for 21 consecutive days, another study reported no significant aberrations in the parameters above.

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Table 2. Psilocybin additional acute and long-term subjective effects

	Effect
1	Positive changes in personality and increased altruism. This may, in turn, have wider benefits to society and the global environment.
2	Enhanced feelings of connectedness
3	Enhanced-nature relatedness
4	Pro-environmental behavior
5	Decreased violent and criminal behavior
6	Reduced suicidal ideation
7	Protection against suicidality and psychological distress (lifetime psilocybin-use)
8	Tempered politically authoritarian views
9	Increase in personality domain of openness
10	Ego dissolution. Reduction of egotistical attitudes, narcissism and induces greater prosocial behavior.
11	Sustained/persisting improvement in attitudes and behavior. One study reports substantial decreases in depressive and anxious symptoms persisting up to 6 months after a single active treatment. In another study, participants report positive persisting effects in areas of mood, behavior, and attitudes after up to 14 months after psilocybin therapy.
12	Improved psychological flexibility and feelings of personal meaningfulness, and subsequent improved psychological outlook. Ability to reframe how a patient views their medical conditions, themselves, their lives and relationships with others.
13	Increase in one’s subjective sense of wellbeing.
14	Quantum change (meaningful personal transformations)
15	Enhancement of “meaning responses”
16	Increased meditation depth
17	Increased incidence of positive self-dissolution

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Table 3. Psilocybin Treatment Subjective Experiences

	Subjective, First-Hand Accounts of Experience with Psilocybin Treatment
1	-Transcendental experience -“Mystical” -“Divine” -“Otherworldly experience” -“Felt like I saw God” -“Deep spiritual experience” -“Connection to something spiritual” -“Connection and spirituality with God” -“Continuity and oneness with God” -“Bliss, heaven, nirvana” -“Mystical and transcendental experience akin to a deep or profound state of meditation or an egoless state” -“Amazement”
2	Changes in outlook -“Major shift in attention and perspective of the world” -“Notable and intense change in perspective of the world” -“Noticeable intricacies in environment” -“Clarity” -“Inspiration for behavioral change” -“Reduction in being too concerned about things, in general. Not neglectful, but hopeful”. -“Acceptance of concern with aging and death”.
3	-Unity consciousness and ego dissolution -“Perception of life as a deeper, richer experience” -“Greater connection to nature, to other people, and to all living things” -“At one with the universe and all of existence” -“Every particle of existence felt like an extension of myself” -“Increased “connectedness” and “acceptance”” -“Feeling of being able to explore oneself more with others” -“Intense, beautiful feeling of love and joy and gratitude for everything”
4	Peace and Happiness -“Incredible, profound calmness and stillness” -“Happiness and contentment” -“Persistent happiness and joy”
5	-Increased introspection -“Greater capacity to motivate and examine oneself” -“Greater understanding of self” -Self-assessment -“Looking at oneself with much more objectivity” -“Reception of thoughts from a wise place” -“Greater insight” -“Greater self-awareness” -“Greater ability to understand what will bring happiness” -“Greater sense of purpose and direction” -“Persisting feeling of self-awareness and insight” -“Greater trust in one’s feelings and experiences” -“Access to deeper parts of oneself” -“Greater connection to core values” -“Feeling more “grounded” -“Persisting insight” -“Awareness of emotions and thoughts and better ability to articulate one’s thoughts and emotions to others. -“Deep appreciation and sense of gratitude”
6	Physical/Mental -Improvement of mental wellbeing -Increase in patience- Reduction in depressive thoughts -Reduction in anxiety -“Lighter, limber, more energetic” -Persistent reduction in psychological distress (anxiety, worry, and sadness) -“Expedited self-development” -“Healthy and beneficial behavioural changes” -“Ability to understand and deliberately divert focus from/mitigate depressive thoughts”

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Table 4. Factors that affect therapeutic or clinical outcome of psilocybin administration

	Factor
1	Extra-pharmacological elements (as with any drug). These include age factors, body weight, body size, 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), experimental setting, social interaction, cultural influences, medical history, placebo design and response to placebo, and drug instrumentalization (instruments used to administer drugs).
2	Mindset -Patient attitude and expectations (psychological flexibility/ outlook) -Preconceptions of treatment -Affective processes
3	Setting -Use of music and/or art -Use of religious and spiritual imagery -Engagement with nature -Use of a purpose-built facility
4	Psychological support -Intensive clinical care/contact -Supportive and reassuring interaction with therapists/sitters. -Reliable induction of “mystical experience” by clinician/therapist. Mystical experiences after psilocybin administration directly correlate with therapeutic outcome and persisting positive subjective effects.
5	Specific types of psychological experiences
6	Treatment type -Some patients may require personalized/individualized treatment which may involve combination therapy with other drugs. Drug interactions may likely affect psilocybin treatment. -Treatments with mushroom extracts as opposed to pure isolated psilocybin may also have different outcomes.
7	Type of mood or anxiety disorder
8	Degree of suicidality (ideation and actual attempts) in a patient. It is recommended that such patients who will be less likely to benefit from such treatment should be excluded from psychedelic therapy.
9	Patients with a family history of psychotic disorders. It is recommended that such patients who will be less likely to benefit from such treatment should be excluded from psychedelic therapy. Psychedelics may augment/compound symptoms of psychoses.
10	Patients who score high on neuroticism, a Big Five higher-order personality trait. It is recommended that such patients who will be less likely to benefit from such treatment should be excluded from psychedelic therapy.
11	Patients with history or current diagnosis of bipolar disorder and schizophrenia. It is recommended that such patients who will be less likely to benefit from such treatment should be excluded from psychedelic therapy.
12	Patients at high risk for developing psychosis, even though psilocybin does not cause lasting anxiety, depression or psychosis. It is recommended that such patients who will be less likely to benefit from such treatment should be excluded from psychedelic therapy.
13	Patients on other psychedelic/anti-psychotic/anti-depressant medications such as selective serotonin re-uptake inhibitors (SSRIs), haloperidol, tricyclic anti-depressants, lithium, and monoamine oxidase inhibitors.

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Are Psilocybin mushrooms addictive?

Psilocybin is not considered to be addictive nor does it cause compulsive use ²⁹. One reason is that the intense experience, which can be physically and mentally challenging, may cause people using psilocybin to limit their frequency of use ²⁸. Another reason is that the human body quickly builds tolerance to psilocybin, such that people require much higher doses after only a few days of repeated use, making it extremely difficult to have any effect after more than four days of repeated usage ²⁸. And because of the similar brain receptors involved in their effects, cross- tolerance occurs with LSD and psilocybin, which means that if someone takes LSD one day, the effects of taking psilocybin the next day will be diminished ²⁸.

Are Psilocybin mushrooms illegal?

In nearly all cases, yes. Psilocybin and psilocin are listed in Schedule 1 of the Controlled Substances Act, making it illegal to cultivate or possess psilocybin-producing mushrooms for either
personal consumption or distribution. However, they can be used for scientific research under tightly-controlled conditions with a special license from the U.S. Drug Enforcement Administration (DEA). While laws vary by specific substance, the U.S. Drug Enforcement Administration (DEA) lists most psychedelic and dissociative drugs on the U.S. schedule of controlled substances here (https://www.deadiversion.usdoj.gov/schedules).

Because federal law does not list the various species of mushrooms containing psilocybin themselves, some people arrested for criminal possession, cultivation or distribution of mushrooms have claimed innocence. One such case in Florida in 1978 led to a state Supreme Court ruling that the legislature needed to specifically list psilocybin-containing mushrooms as illegal ³⁰. The decision’s precedent led to arguments in subsequent cases in several other states ³¹. In 2005, an appeals court in New Mexico ruled that growing psilocybin mushrooms for personal consumption could not be considered “manufacturing a controlled substance” under state law ²⁸. Regardless, in most cases psilocybin, and psilocybin-containing mushrooms are illegal federally and statewide, with cultivation, possession and sale offenses being grounds for arrest ²⁸.

How does psilocybin work?

Psilocin reacts agonistically with serotonin (5-hydroxytryptamine) type 2A (5-HT_2A) receptors to produce a “mystical-like” hallucinatory effect ⁹, ²³ due to induced frontal hyper-frontality ⁹, which in turn mediates its anti-depressant and anti-anxiety effects (see Figure 5) ³, ⁵. One possible anti-depressant mechanism of action of psilocybin is via deactivation or normalization of the hyperactivity of the medial prefrontal cortex (mPFC) ³², ³³, ³⁴. During depression, the medial prefrontal cortex (mPFC) is typically hyperactive ³⁵.

Anti-depressant properties of psilocybin are mediated via modulation of the prefrontal and limbic brain regions, with the inclusion of the amygdala ³⁶. The amygdala plays an essential role in perception and emotion-processing networks ³⁴. In cases of depression, an individual typically loses responsiveness to emotional stimuli ³⁷. It is also suggested that the hyper-frontal metabolic pattern produced after psilocybin administration and 5-HT_2A receptor activation is comparable to metabolic patterns produced in acute psychotic episodes in chronic schizophrenics ¹⁹.

It is also reported that psilocybin binds with high affinity to the 5-HT_2A serotonergic receptor subtype, but with low affinity to the 5-HT_1A serotonergic receptor subtype ⁹. The interaction of psilocybin and psilocin with 5-HT_2A receptors to produce psychotomimetic effects has been confirmed in experiments with ketanserin, a 5-HT_2A antagonist that attenuates the effects of psilocybin ⁹, ²⁷. In addition to interaction with 5-HT_2A receptors, it is also suggested that the psychopharmacological action of psilocybin may also be mediated by non-5HT2 receptors ³⁸, ²¹, ³⁴. Psilocybin and psilocin also interact with the 5-HT_1D and 5-HT_2C receptor subtypes ⁹.

Psilocybin is reported to result in significant changes in brain dynamics and functional connectivity between areas of the brain ³⁶, ³⁹, ⁴⁰, ⁴¹. Psilocybin-induced alteration in brain connectivity involves the disintegration of associative networks and integration of sensory function networks ¹⁹. It is suggested that this dissociation may mediate the subjective effects of psilocybin use and a state of unconstrained cognition ¹⁹. On the same tangent, a possible mechanism of action behind psilocybin’s psychotomimetic effects are via interactions with feedback loops between the cortex and thalamus ⁹. Psilocybin administration produces general cortical activation ¹⁹. This is confirmed by increased levels of the cerebral metabolic rate of glucose in the prefrontal cortex, anterior cingulate, temporal cortex, and putamen ⁴². This increase in the prefrontal cortex, anterior cingulate, temporal cortex, and putamen activity is positively correlated with hallucinatory “ego dissolution” ¹⁹. The metabolic rate of glucose also increased in distinct right-hemispheric frontotemporal cortical regions ⁴³.

Serotonin 5-HT_2A receptors are distributed in multiple areas of the brain that play a role in psychosis and psychotic symptoms, such as the cerebral cortex (prefrontal cortex) and periphery ²⁷, striatum, ventral tegmental area, and thalamus ⁴⁴.

In addition to the presence of serotonergic cell bodies, dopaminergic cell bodies are also distributed in the ventral tegmental area ⁴⁵, an area of the brain that plays a role in reward-processed, and regulation of emotion and cognitive behaviors ⁴⁶. Although the neuropharmacological mechanisms of action of psilocybin are not definitively elucidated, there is evidence that, in addition to interaction with the serotonergic system, psilocybin also seems to interact, though not directly, with the mesolimbic dopaminergic pathway that plays a significant role in the brain’s reward system ⁴⁵. This proposed indirect mechanism of action is suggested by psilocybin’s low addictive or abuse potential ⁴⁵. It has also been hypothesized that there is a positive correlation between depression and dopamine deficiency in the mesolimbic pathways ⁴⁷.

It is also hypothesized that schizophrenia and possibly other mood and anxiety disorders is characterized by dysregulation or disbalance of serotonin and dopamine ⁴⁸. In acute psychoses, one study even concludes that5-HT_2A and 5-HT_1A serotonergic receptors play an important role in the modulation of striatal dopamine release. This suggests that psilocybin may have significant potential in the treatment of schizophrenia and possibly other psychiatric disorders ⁴⁸. In another study, psilocybin was indirectly responsible for an increase in endogenous dopamine via a decrease in 11C-raclopride binding potential bilaterally in the caudate nucleus (19%) and putamen (20%) ⁴⁹.

A 2021 study by Grandjean and colleagues ⁵⁰ investigated the effects of psilocybin on functional connectivity across the entire brain region in mice. One possible mechanism of action by which psilocybin produces anti-depressant effects is via interaction with or alteration of the default-mode network ⁵¹. Using resting-state functional MRI (fMRI), psilocybin was shown to decrease functional connectivity within dopamine (DA)-associated striatal networks, in addition to demonstrating alteration (increase) of functional connectivity between serotonin (5-HT) associated networks and cortical areas ⁵⁰. This study confirms the interaction of psilocybin with the mesolimbic dopaminergic pathway to produce neural and psychological effects ⁵⁰. Data presented in another mice study suggest that psilocin, an active metabolite of psilocybin, has been shown to increase the concentrations of both extracellular dopamine and serotonin (5-HT) in the mesoaccumbens and/or mesocortical pathway ⁵². This presents yet another possible mechanism of anti-depressant action of psilocybin/psilocin, that is, the ability to increase dopamine, a neurotransmitter that is responsible for the regulation of emotions and even an individual’s physical well-being ⁵³. Concentrations of both extracellular dopamine and serotonin (5-HT) in the ventral tegmental area (VTA) were not affected ⁵². This further suggests that, in addition to the ventral tegmental area (VTA), the brain’s reward circuity may also be influenced by other regions of the brain.

Serotonin (5-hydroxytryptamine) type 2A (5-HT_2A) receptors activation and subsequent activation of postsynaptic glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors by psilocybin is associated with increased glutamate concentration. Glutamate is responsible for normal, healthy brain functioning ⁵⁴.

Psilocybin treatment, in some cases with psychological support, also resulted in increased responsiveness to positive emotional stimuli in the right amygdala ³⁷, ⁵⁵ and decreased or normalization of responsiveness to negative or neutral emotional stimuli ⁵⁶, ³⁴, ⁵⁷, ⁵⁸, ⁵⁹, ⁶⁰. Psilocybin was also shown to attenuate amygdala activation in response to threat-related visual stimuli ⁵⁸ and reduced threat-induced modulation of the primary visual cortex by the amygdala ⁵⁸. The amygdala modulates the primary visual cortex via top-down connectivity ⁵⁸.

In contrast, other selective serotonin reuptake inhibitors (SSRIs) may produce anti-depressant effects by attenuating the hyper-responsiveness of the amygdala to fearful emotional stimuli, thereby inhibiting negative emotions ³⁷. Hyperactivity of the amygdala to fearful emotional stimuli is typically characteristic of depression ⁶¹. SSRIs mitigate this hyperactivity to emotional stimuli ⁶¹ whereas psilocybin is suggested to increase amygdala activation to positive emotional stimuli ⁶¹, ⁶². In another study, psilocybin treatment also reduced anhedonia (the inability to feel pleasure) ⁶³.

Barrett and colleagues ⁵⁶ also suggest that psilocybin may even influence brain plasticity as confirmed by the persisting positive effect and increased amygdala response to positive emotional stimuli up to one month post psilocybin treatment.

Unlike indoleamine LSD and other hallucinogens that that bind to dopamine D2 receptors to produce the typical dopaminergic “psychotic” experiences, psilocybin and psilocin have no affinity for dopamine D2 receptors ⁹, ²³, ⁶⁴, despite the existence of a functional interaction between the serotoninergic and central dopaminergic systems ⁹. This functional interaction between the serotoninergic and central dopaminergic systems has been demonstrated in experiments with haloperidol, a D2 receptor antagonist that attenuates the psychotomimetic effects of psilocybin ⁹.

A study by Carhart-Harris ⁵¹ investigated the effects of psilocybin on cerebral blood flow and blood-oxygen-level-dependent resting-state functional connectivity (RSFC) via functional magnetic resonance imaging (fMRI). Post psilocybin treatment, authors reported decreased amygdala cerebral blood flow associated with reduced symptoms of depression, and increased resting-state functional connectivity within the default-mode network ⁶⁵, increased resting-state functional connectivity in the ventromedial prefrontal cortex-bilateral interior lateral parietal cortex, and decreased resting-state functional connectivity in the parahippocampal–prefrontal cortex ⁵¹. Alteration of the default mode network is characteristic of mood and anxiety disorders ⁶⁶ and another possible mechanism of action by which psilocybin produces anti-depressant effects is via interaction with the default-mode network ⁵¹, via disruption of functional connectivity between the medial temporal lobe (MTL) and the default-mode network ⁶⁷.

Another functional magnetic resonance imaging (fMRI) study ⁶² reports a decreased functional connectivity between the amygdala and the ventromedial prefrontal cortex (vmPFC) in response to fearful and neutral (but not happy) faces after psilocybin treatment. The ventromedial prefrontal cortex (vmPFC) is responsible for emotional processing, action, cognitive behaviour and goal-orientation, and demonstrates top-down inhibitory control on the amygdala ⁶². It is suggested then that psilocybin treating, which decreases functional connectivity between amygdala and the ventromedial prefrontal cortex (vmPFC) in response to fearful and neutral (but not happy) faces, also decreases the top-down inhibitory control that the ventromedial prefrontal cortex (vmPFC) has on the amygdala, and ultimately results in increased amygdala activity ⁶². In medication-naïve individuals, decreased functional connectivity between the amygdala and the left rostral prefrontal cortex (left rPFC) is characteristic of major depressive disorder ⁶⁸.

Also characteristic of depression and schizophrenia is an alteration of serotonergic signalling ⁶⁹. Therefore, drugs that target serotonergic receptors in the prefront cortex may be of clinical importance ⁶⁹.

What are uses of psilocybin?

Mushrooms used non-medically are usually taken orally either by eating dried caps and stems, or steeped in hot water and drunk as a tea, with a common dose around 1 to 2.5 grams, though
potency may vary regardless of the amount ⁷⁰. Dried mushrooms are typically more potent than fresh ones. Risk of fatal overdose is virtually nonexistent with psilocybin mushrooms; however, risky behaviors sometimes occur while people are under the influence.

Research conducted in the mid-20th century found that carefully monitored and controlled use of psilocybin may be beneficial for many psychiatric disorders, personal and spiritual development, and creative enhancement ⁷¹. However, after psilocybin was banned in 1970, clinical research to evaluate its medical safety and efficacy of psychedelics was effectively halted until the late 90s and early 2000s ⁷².

There are dozens of studies taking place to evaluate the medical safety and effectiveness of psychedelics, including psilocybin. Much of the earlier research did not stand up to today’s standards, as they often lacked a placebo control group or double-blinding procedures (in which neither the subject of the research nor the investigators knew whether the subject received psilocybin or placebo). Nevertheless, their promising findings have been revisited and spurred a resurgence of new, more rigorous research on the potential benefits of psychedelics as a treatment for cluster headache ⁷³, anxiety, addiction to alcohol and other drugs ⁷⁴, depression ⁷⁵, obsessive-compulsive disorder (OCD) ⁷⁶, as well as neuroimaging experiments furthering the understanding of psychedelic effects on the brain ⁷⁷.

Because of the expensive and labyrinthian approval process for research with Schedule 1 drugs, as well as the political influence of the war on drugs, research evaluating psilocybin’s beneficial uses does not receive funding from academic or government institutions and this has left many unanswered questions regarding the pharmacology and toxicology of psilocybin ⁷⁸.

Psilocybin side effects

The risks associated with psychedelic drugs are mostly psychological, not physical. Physically, psilocybin mushrooms are considered to be one of the least toxic drugs known ²⁸. Although lethal doses have been determined from experiments in several animal models ⁷⁹, recorded cases of death exclusively attributed to usual doses of psilocybin mushrooms in humans are extremely rare ⁸⁰.

Physical effects of psilocybin mushrooms are minor but varied and can be unique from person to person. The most consistent reactions of psilocybin mushrooms, such as dilated pupils (mydriasis), elevated blood pressure (hypertension) and increased heart rate (tachycardia), are usually mild, and considered side effects of emotional intensification. However, these along with other reported symptoms like nausea, increased perspiration, numbing and tremors, can sometimes make psychological symptoms like anxiety, panic attacks, paranoia, and mood swings seem worse ⁸¹. Long-term physical effects of psilocybin mushrooms are directly attributed to the pharmacology of psilocybin are rare, and research suggests they may also be due to latent psychological disorders ²⁸.

However, predicting what kind of experience a person will have after taking psilocybin is difficult, so experts recommend that people with a personal or family history of mental illness should be aware of their vulnerability to potential latent psychological issues emerging or being triggered.

Comprehensive reviews of the thousands of sessions using psilocybin and other psychedelics in legal clinical research settings during the 1950s and 60s have consistently found extremely low incidences of acute and chronic problems among individuals lacking pre-existing severe psychopathology. Recent reviews of the clinical literature also suggest that chronic problematic effects, when they do occur, are most often linked to psychological instability present prior to use ⁸².

Hallucinogen Persisting Perception Disorder (HPPD), sometimes mistakenly referred to as “flashbacks”, is a condition unique to psychedelics, involving perceptual changes lasting weeks or months following the use of a drug like psilocybin. Though exact prevalence is unknown, Hallucinogen Persisting Perception Disorder (HPPD) is considered relatively rare, with no physical changes or neurological damage associated as the cause ⁸³.

Is psilocybin safe?

Due to the lack of quality control regulations under prohibition and the risk of consuming things growing in nature, there is potential for people attempting to pick psilocybin mushrooms in the wild to accidentally take poisonous mushrooms instead ²⁸. Similarly, though also very unlikely, poisonous mushrooms are sometimes misrepresented and sold as psilocybin, and these do come with more physical risks, including fatal overdose ²⁸.

There is no safe level of drug use. Use of any drug always carries some risk. It’s important to be careful when taking any type of drug. While more research is needed, the reported incidence of serious adverse events from professionally supervised use of specific psychedelic drugs, such as in clinical trials, is relatively low ⁸⁴, ⁸⁵, ⁸⁶, ⁸⁷. However, many past clinical studies on these drugs have not adequately assessed or reported on adverse events ⁸⁸.

Psilocybin is a Schedule 1 controlled substance as defined by the United Nations 1971 Convention on Psychotropic Substances. By this definition, psilocybin is considered to have a high abuse potential and is currently not accepted medically ¹⁰. In uncontrolled settings such as in recreation, abuse of psilocybin may lead to what is referred to as a “bad trip” ¹⁰. This is an undesired or even traumatic physical and emotional experiences characterized by altered visual perception, extreme distress, fear, lack of coordination, derealization, depersonalization, paraesthesiae, heightened fright, panic-attacks, traumatic flashbacks, paranoia, delirium, short-term psychosis and other symptomology characteristics of schizophrenia ⁸⁹, ⁹⁰, ⁹¹, ⁹². This undesired physical experience may also be accompanied by nausea, vomiting, dilated pupils (mydriasis), headache, chills and drowsiness ⁸⁹. Some symptoms may even persist. A “bad trip” is typically treated with benzodiazepines ¹⁰.

Mushroom toxicity is also a risk associated with some species of psilocybin mushrooms ¹⁰. Though rare and typically accidental, mushroom poisoning is also a risk, and may lead to minor gastrointestinal illness such as gastroenteritis, erythromelalgia, rhabdomyolysis, intestinal fibrosis, hypertension, hyperreflexia, liver failure, renal failure, convulsions, bradycardia, and tachycardia ⁸⁹, ⁹³. Mushroom poison may also require medical intervention or emergency hospitalization ⁸⁹, ⁹⁰. In general, alcohol and other drugs may worsen the psychological and physical risks of psilocybin abuse ¹⁰. On the same tangent, individuals with a personal or family history of severe psychotic and psychiatric disorders are discouraged from using psilocybin, and by extension, other psychedelics ⁹⁴.

In general, psilocybin is reported to have the most favourable safety profile of all psychedelic drugs ¹⁶, ⁹⁵, ⁹⁶. Thousands of years of anecdotal evidence in addition to modern-day scientific studies confirm that psilocybin has low physiological toxicity, low abuse or addictive ability, safe psychological responses, no associated persisting adverse physiological or psychological effects during or after use ⁹⁷, ⁹, ⁹⁸, ⁹⁹. Psilocybin overdose is very rare ²⁸, ¹⁰⁰. One such report of psilocybin overdose and subsequent fatality was specifically due to cardiac arrest, some 2 to 3 hours after psilocybin ingestion, in a 24-year-old female who, 10 years prior, had a heart transplant due to end-stage rheumatic heart disease ¹⁰¹.

In patients with mental or psychiatric disorders, suicidal ideation and auto-mutilation are possible risks of magic mushroom ingestion and have been documented in the literature ¹⁰². Another risk is the possibility of exacerbating psychotic symptoms ¹⁰³. As a result, having psychotic disorders such as schizophrenic tendencies is a contraindication for undergoing psychedelic-assisted psychotherapy, particularly psilocybin-assisted psychotherapy ¹⁰⁴.

It is also reported that repeated psilocybin use will build high tolerability but will not lead to physical dependence ⁹, ³⁴, ¹⁰⁵. Cross-tolerance with other psychedelics such as LSD and mescaline is also a possibility ³⁸, ¹⁰⁶. Discontinued psilocybin use does not typically cause adverse physical effects or symptomology related to drug withdrawal ¹⁰. There is also a chance that psychological withdrawal may occur ¹⁰.

The Registry of Toxic Effects of Chemical Substances (RTECS) has assigned psilocybin a therapeutic index of 641, associated with a relatively better safety profile in comparison to nicotine and aspirin, with values of 21 and 199, respectively ⁹⁸. Essentially, this means that psilocybin has very low chronic toxicity, moderate acute toxicity, negligible public health and criminal effects ⁹². To date, there is no standard value for a lethal dose at neither the recreational nor medicinal levels in humans ⁹⁹.

Risks associated with psilocybin may be prevented or alleviated with the implementation of a medically supervised setting, preparatory counseling to induce the right patient mindset, and adequate professional clinical psychological and physiological support ¹⁰⁷. Due to the low physiological toxicity, low abuse/addictive liability, safe psychological responses, no associated persisting adverse physiological or psychological effects during or after use, it is hypothesized that the lethal dose of psilocybin is far greater than the effective dose ¹⁰⁸, ¹⁰⁹, ¹¹⁰, ²⁶.

How risky are Psilocybin mushrooms compared to other drugs?

Psilocybin is considered to have extremely low toxicity, and cases of death have been extremely rare. But beginning in the 1960s and continuing today, sensationalized media coverage of psychedelic-related deaths misattributed the role of psychedelics like psilocybin in causing suicide or accidental death ²⁸.

Recent results from epidemiological studies have actually shown lower rates of mental health disorders and suicide among people who have used psychedelics like psilocybin ¹¹¹, ¹¹², ¹¹³.

The risks from psilocybin are dependent on set (your personality and internal expectations of the subject), setting (environment in which the substance is used) and the dose and differ from other types of drugs, including alcohol, benzodiazepines, and opiates, which produce relatively predictable physical and psychological effects ²⁸. The consequences of negative or challenging experiences can be minimized by education and awareness of psilocybin’s effects, with particular attention paid to issues around set and setting prior to the experience.

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