Psilocybin structure, pharmacodynamics and effects Flashcards
What is psilocybin chemical structure
Psilocybin is a naturally occurring psychedelic compound found in certain species of mushrooms. It is structurally similar to serotonin.
Tryptamine Backbone: Psilocybin is a member of the tryptamine family. It has a structure based on the tryptamine molecule, which is a derivative of the amino acid tryptophan.
Phosphorylated Group: Psilocybin is unique due to a phosphate group attached to its molecular structure. This phosphorus-containing group is part of what makes psilocybin distinct from other tryptamines.
What is the Functional Groups of psilocybin?
4-hydroxy (4-HO) Group: It has a hydroxyl group (-OH) attached to the fourth carbon of the indole ring, similar to the structure of the neurotransmitter serotonin.
N,N-dimethyl Group: Attached to the nitrogen (N) atom of the tryptamine structure, it has two methyl groups (–CH₃)
Metabolism to Psilocin
In the body, psilocybin is quickly dephosphorylated to psilocin (4-HO-DMT), which is the compound that actually exerts the psychedelic effects. Psilocin has a very similar structure but without the phosphate group.
How are ‘magic mushrooms consumed’?
- Most typically they are consumed by eating the raw or dried fruiting bodied of the fungi.
- Dried mushrooms can also be smoked.
- Synthetic psilocybin is taken orally in capsules
Do mushrooms that produce psilocybin also generate other psychoactive compounds in addition to psilocybin?
- Psilocin: This is the active metabolite of psilocybin. Once psilocybin is ingested, it is quickly converted into psilocin in the body, which is primarily responsible for the psychedelic effects.
- Baeocystin and Norbaeocystin: These are analogs of psilocybin and are present in smaller amounts in many psilocybin-producing mushrooms. Baeocystin is similar to psilocybin but with a methyl group in place of psilocybin’s ethyl group. Norbaeocystin is a demethylated derivative of baeocystin. The psychoactive properties of these compounds are less understood, but they are believed to contribute to the overall psychoactive effects of the mushrooms.
- Tryptophan Derivatives: Some psilocybin-producing mushrooms may also contain other compounds derived from tryptophan, the amino acid that serves as the starting point for the synthesis of psilocybin and related compounds.
The combined effect of these compounds, along with psilocybin and psilocin, contributes to the overall psychedelic experience associated with these mushrooms. However, the precise role and psychoactive potency of some of these minor compounds are not as well studied as psilocybin and psilocin.
What is the Entourage Effect in reference to psilocybin?
The “entourage effect” is a term that originates from the study of cannabis and refers to the idea that various compounds within a plant work together synergistically to produce a particular effect. In the context of psilocybin mushrooms, the entourage effect would suggest that the combination of various psychoactive and non-psychoactive compounds found in these mushrooms (like psilocybin, psilocin, baeocystin, norbaeocystin, and others) work together to produce the overall psychedelic experience.
Synergistic Interaction: It’s hypothesized that the different compounds in psilocybin mushrooms may interact synergistically, meaning that their combined effect is greater than the sum of their individual effects.
Modulation of Effects: The presence of various compounds could potentially modulate the intensity, duration, and quality of the psychedelic experience. For example, minor compounds like baeocystin might subtly alter the effects of psilocybin and psilocin.
Complexity of Experience: The entourage effect might explain why the effects of psychedelic mushrooms can vary between different species or even different batches of the same species. The specific concentration and ratio of compounds could influence the nuances of the experience.
What happens after oral ingestion of psilocybin?
After ingestion, psilocybin is rapidly converted to psilocin by liver enzymes. It is psilocin that reaches the brain and is responsible for producing the neuropsychological effects.
How is dosage calculated for ingestion?
Clinical research studies have administered doses based mg/kg (dose based on weight).
Determine the Dose per Kilogram:
First, you need to decide on the appropriate mg/kg dose. In clinical research, common doses of psilocybin range from about 0.1 to 0.4 mg/kg. The specific dose within this range depends on factors like the purpose of the treatment, the setting, and the individual’s health and experience with psychedelics.
Formula - Individual dose = body weight (kg) x Dose (mg)
Convert to Mushroom Weight (if using whole mushrooms instead of pure psilocybin):
Since psilocybin content in mushrooms varies, a rough average is used for conversion. A common estimate is that dried psilocybin mushrooms contain about 1% psilocybin by weight.
Convert the psilocybin dose to mushroom weight by dividing the dose in milligrams by 0.01 (or multiply by 100).
Formula - Mushroom weight (g) = Individuals dose (mg) / 0.01
Example Calculation:
Assume a dose of 0.2 mg/kg and an individual weighing 70 kg.
Individual’s Dose (mg) = 70 kg × 0.2 mg/kg = 14 mg of psilocybin.
To convert this to dried mushroom weight: 14 mg / 0.01 = 1.4 grams of dried mushrooms.
Types of dosages?
Microdose: Generally ranges from 0.1 to 0.5 grams of dried mushrooms. This dose is intended to be sub-perceptual, meaning it doesn’t induce significant psychedelic effects.
Low Dose: Around 0.5 to 2 grams of dried mushrooms. This dose may lead to mild perceptual changes and emotional effects.
Moderate Dose: Typically between 2 to 3.5 grams of dried mushrooms. This is often considered a standard recreational dose, leading to a more intense psychedelic experience.
High Dose: Above 3.5 grams of dried mushrooms. High doses can lead to very intense experiences, including profound changes in perception, deep introspection, and possible ego dissolution.
What are some examples of psychoactive mushroom species and examples of their effects?
Each species can vary in terms of potency, the nature of the psychedelic experience it induces, and other characteristics. Here are a few well-known examples:
- Psilocybe Cubensis
Common Names: Golden Teacher, Mexican Mushroom, Cubes
Effects: Known for providing a balanced psychedelic experience with visual hallucinations and profound changes in thought and mood. The intensity can range from mild to strong depending on the dose.
Popularity: One of the most widely known and cultivated species due to its relatively high psilocybin content and ease of growth. - Psilocybe Semilanceata
Common Names: Liberty Cap
Effects: Noted for producing strong, vivid visual hallucinations and a powerful spiritual experience. It’s generally considered more potent than P. Cubensis on a per gram basis.
Habitat: Commonly found in nature, especially in grassy areas, and has a distinctive conical cap. - Psilocybe Azurescens
Common Names: Flying Saucer Mushroom, Blue Runners, Blue Angels
Effects: Known to be one of the strongest psilocybin mushrooms, with high levels of psilocybin and psilocin. Users report extremely powerful visual hallucinations and profound insights, along with strong euphoria.
Habitat: Grows naturally in a small area of the West Coast of the United States and is more challenging to cultivate. - Psilocybe Cyanescens
Common Names: Wavy Caps
Effects: Similar to P. Azurescens in potency but may produce a more intense neurological experience, including synesthesia (blending of sensory experiences, like “hearing” colors).
Habitat: Often found in wood chips and mulched garden beds in the wild. - Psilocybe Mexicana
Common Names: Teonanácatl, Pajaritos
Effects: Traditionally used in Native American religious ceremonies, it’s known for inducing a lighter, more euphoric experience, often with less intense visual hallucinations compared to stronger species.
Cultivation: It’s one of the species used to produce psilocybin truffles or “sclerotia,” which are compact masses of hardened mycelium.
How does micro-dosing work?
Microdoses range from 5-10% of a regular dose, and produce sub-perceptual effects, free from visual distortions. Usually a dose of 1-2 mg
A common regimen consists of taking a microdose once every three days for a period of a month. Reposts have shown improved mood, enhanced creativity, and boosted energy and focus.
What is the onset and duration of psychoactive effects after orally administering pure psilocybin?
Psychoactive effects appear above 20 - 90 min after oral administration of pure psilocybin. They last for at least 3 - 6 hours
What happens when psilocin reaches the brain, and what are the functions of the serotonergic system it affects?
Once psilocin reaches the brain, it binds to several different subtypes of serotonin (5-HT) receptors resulting in a number of different effects.
The serotonergic system is windspread in the brain and gastrointestinal tract, and is involved in regulating many aspects of our human experience such as mood, appetite, sexual behaviour, cognitive and memory function, pain, sleep, body temperature and reward system.
How can the interaction between psilocin (the active metabolite of psilocybin) and specific serotonin receptors in the brain leads to its psychedelic effects?
- 5-HT2A Receptor and Psilocin
Mechanism: Psilocin primarily binds to the 5-HT2A receptor, a subtype of serotonin receptors. This binding is crucial for the psychedelic effects of psilocin.
– Example: When psilocin binds to the 5-HT2A receptors in the brain, it can lead to altered perceptions, visual hallucinations, and changes in thought processes. - Ketanserin as an Antagonist
Function: Ketanserin is a 5-HT2A receptor antagonist, which means it blocks these receptors.
Effect of Blocking: By blocking the 5-HT2A receptors, ketanserin prevents psilocin from binding to them. This effectively diminishes or nullifies the psychedelic effects that psilocin would normally induce.
– Example: If someone takes ketanserin before or during the use of psilocybin, they might experience significantly reduced or no psychedelic effects, as the primary action site of psilocin is blocked. - Other Serotonergic Receptors
Lower Affinity Binding: Psilocin also binds to other serotonin receptor subtypes like 5-HT2C, 5-HT1A, and 5-HT1B, but with lower affinity compared to 5-HT2A.
Less Impact on Consciousness: These receptors are less involved in the consciousness-altering effects of psilocybin. This means that while they may contribute to the overall experience, they are not as central to the psychedelic effects as the 5-HT2A receptor.
– Example: Binding of psilocin to these other receptors might influence mood, anxiety, and various cognitive processes, but these effects are more subtle and less pronounced compared to the vivid perceptual and cognitive alterations mediated by the 5-HT2A receptor.
What is the role of ketanserin in relation to the effects of psilocybin?
Ketanserin (antagonist) = Blocks effect of psilocybin.
How does psilocybin affect the dopamine system?
Interaction with Dopamine System
Indirect Influence: Psilocybin and its active metabolite, psilocin, indirectly affect the dopamine system. While they don’t bind strongly to dopamine receptors like they do with serotonin receptors, their activity in the brain can lead to changes in dopamine release and transmission.
Dopamine Release: Psilocybin can increase the release of dopamine in certain areas of the brain. This is thought to contribute to the mood-altering effects of psilocybin.
Examples of Dopamine-Related Effects
Mood Changes: Dopamine is closely associated with mood and reward. The elevated mood or feelings of euphoria that some users experience under the influence of psilocybin could be partly due to increased dopamine activity.
Altered Thought Patterns: Dopamine plays a role in cognitive processes. Changes in thought patterns, such as non-linear thinking or enhanced creativity reported during psilocybin use, might be influenced by altered dopamine transmission.
What is temporal synesthesia?
Simply - A phenomenon where one sensation is experienced by a second sensory pathway. One may see colours while listening to music, or hear sounds when while smelling a fragrance.
Temporal synesthesia, also known as time-space synesthesia, is a neurological phenomenon where individuals perceive time as a spatial construct. In this form of synesthesia, people experience time units like hours, days, weeks, or years as occupying specific spatial positions or shapes around their body or in an external space.
Characteristics of Temporal Synesthesia:
– Spatial Representation of Time: Individuals with temporal synesthesia may visualize units of time in spatial arrangements. For example, a year might be seen as a circle surrounding the individual, with months or days at fixed points around the circle.
– Automatic and Involuntary: Like other forms of synesthesia, these experiences are automatic and not a result of conscious effort or imagination.
Impact on Perception and Cognition:
– Temporal synesthesia can influence how individuals perceive the passage of time and can sometimes aid in memory and organization, as the spatial representation of time can serve as a mental calendar.
– It can also lead to unique perspectives on planning and time management, as individuals with this form of synesthesia might “see” their schedules and deadlines in a spatial layout.
What is meant by depersonalisation in the context of psilocybin use?
Depersonalisation -detached observer.
This refers to a disconnection or detachment from one’s sense of self or identity. For example, during a psilocybin experience, an individual might feel as though they are observing themselves from an outside perspective, losing the usual sense of personal identity.
What is meant by derealisation in the context of psilocybin use?
This is often described as the feeling that the external world is unreal.
Some go as far as to say that the ego has dissolved to merge with a larger consciousness that is beyond bodies, thoughts or identities. This can be pleasurable, aweing and can cause deep positive emotions. It can also be frightening and agitating.
What are serotonin 2A (5-HT2A) receptors?
They are G-protein coupled receptors located postsynaptically to serotonergic neurons.
Where are 5-HT2A receptors highly expressed in the brain?
They are highly expressed in the cortex and in regions associated with the default mode network (DMN).
How is ketanserin used in research involving 5-HT2A receptors?
Ketanserin, an antagonist of 5-HT2A receptors, can be labeled with radioactive ions to visualize these receptors in the brain during imaging studies.
What is the research significance of ketanserin in relation to 5-HT2A receptors?
It is used to block the effects of drugs like psilocybin by binding to 5-HT2A receptors, thereby diminishing their subjective effects.
What conditions are associated with increased densities and functioning of 5-HT2A receptors?
Anxiety and stress in humans have been linked to increased densities and functioning of 5-HT2A receptors.
What have postmortem studies revealed about 5-HT2A receptors in depressed and suicidal individuals?
Postmortem studies have shown greater expression of 5-HT2A receptors in the brains of depressed and suicidal individuals.
How have animal studies contributed to understanding 5-HT2A receptors?
Knockout or downregulation of 5-HT2A receptors in mice has been shown to result in decreased anxiety levels.
What is the relationship between SSRIs and 5-HT2A receptors?
Antidepressant medications like SSRIs are associated with reduced levels of 5-HT2A receptors.
How do psilocybin and SSRIs modulate serotonergic activity?
Psilocybin activates 5-HT2A receptors, while SSRIs primarily affect serotonin reuptake.
What is the role of the 5-HT1 receptor subtype in serotonin regulation?
The 5-HT1 receptor subtype acts as an autoreceptor that inhibits serotonin release when stimulated, providing negative feedback to control serotonin levels in the synapse.
How do antidepressants affect 5-HT1 receptors with chronic use?
Chronic use of antidepressants desensitizes 5-HT1 receptors, which restores serotonin release and reduces limbic responsiveness, leading to emotional blunting.
What is the effect of psilocybin on emotional processing and consciousness?
Psilocybin activates 5-HT2A receptors, facilitating emotional processing, disrupting normal consciousness, and increasing sensitivity to the environment.
How do serotonin receptors influence other neurotransmitters when activated?
Serotonin receptors, when activated, modulate the release of neurotransmitters such as dopamine, GABA, acetylcholine, norepinephrine, and glutamate, impacting various neurological processes.
What role does glutamate play in the central nervous system?
Glutamate is the primary excitatory neurotransmitter in the brain, crucial for rapid transmission of information.
How does psilocybin affect glutamate levels and what implications does this have?
Psilocybin, as a 5-HT2A agonist, increases glutamate activity in the prefrontal cortex (PFC), influencing prefrontal network activity and contributing to its psychedelic effects.
What changes in cerebral blood flow and glutamate levels are observed with psilocybin use?
Psilocybin increases cerebral blood flow and glutamate concentrations in the medial prefrontal cortex (mPFC), while decreasing them in the hippocampus. This correlates with experiences of ego dissolution.
How does psilocybin affect GABA levels in the brain?
Psilocybin also increases GABA, an inhibitory neurotransmitter, in the medial prefrontal cortex (mPFC).
What are the theories explaining the reduction in glutamate and cerebral blood flow in the hippocampus during psilocybin administration?
One theory suggests that psilocybin’s agonism of 5-HT2A receptors on GABAergic interneurons inhibits glutamate release. Another theory proposes that psilocin (psilocybin’s active form) activates 5-HT1A receptors in the hippocampus, which also modulates serotonin function.
Why is understanding psilocybin’s effects important for psychiatric research?
Understanding how psilocybin interacts with complex brain systems and neurotransmitter networks can provide insights into psychiatric disorders and potentially improve treatment protocols.
What methods were used in the study by Dr. Robin Carhart-Harris to measure brain changes during psilocybin use?
Arterial spin labeling (ASL) perfusion and blood-oxygen level-dependent (BOLD) fMRI were used to monitor physiological changes in the brain.
How quickly did participants experience subjective effects after psilocin infusion, and why was this significant?
Participants experienced subjective effects within five seconds of psilocin infusion, allowing researchers to correlate these effects with measured brain activity in real-time.
What were the unexpected results of the study regarding brain activity under psilocybin influence?
Contrary to expectations, the study found decreased blood flow and BOLD signal in subcortical and cortical regions rather than increased activity.
Which brain regions showed the most significant decreases in blood flow during psilocybin use?
The thalamus and anterior and posterior cingulate cortex (ACC/PCC) exhibited the most notable decreases in blood flow.
What was observed regarding connectivity between the medial prefrontal cortex (mPFC) and the PCC during the study?
There was decreased connectivity between the medial prefrontal cortex (mPFC) and the posterior cingulate cortex (PCC) during psilocybin use.
How did changes in cerebral blood flow (CBF) correlate with subjective effects reported by participants?
Greater decreases in CBF in the anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC) correlated with more intense subjective effects reported by participants.
How did the BOLD fMRI scans of 15 participants differ from the ASL perfusion study in terms of brain activity under psilocybin influence?
The BOLD fMRI scans showed similar decreases in cerebral blood flow (CBF) as ASL, with additional decreases in regions like higher order visual areas not observed in ASL.
