Psilocybins & Ketamine
Psilocybins refer to a group of psychedelic compounds found in certain species of mushrooms, primarily from the genera Psilocybe, Panaeolus, and Gymnopilus. The primary psychoactive compounds in these mushrooms are psilocybin, psilocin, baeocystin, and norbaeocystin. Psilocybin itself is a prodrug, meaning it is biologically inactive until it is converted into its active form, psilocin, after ingestion.
Once consumed, psilocybin is rapidly dephosphorylated into psilocin by alkaline phosphatase enzymes in the liver and gut. Psilocin is structurally similar to serotonin (5-hydroxytryptamine or 5-HT) and primarily acts as an agonist at serotonin 5-HT2A receptors, with additional interactions at 5-HT1A, 5-HT2C, and other serotonin receptors.
By binding to 5-HT2A receptors in the prefrontal cortex, psilocin disrupts normal serotonin signaling, leading to increased glutamate release and enhanced neural activity, particularly in areas associated with perception, cognition, and emotion regulation. This heightened neural activity results in sensory distortions, altered thought processes, and the characteristic psychedelic experience.
A key effect of psilocin is its impact on functional connectivity in the brain. Studies using functional MRI and MEG imaging show that psilocybin disrupts the default mode network (DMN), a brain network involved in self-referential thinking, memory recall, and ego maintenance. By reducing DMN activity, psilocybin allows for increased connectivity between brain regions that do not normally communicate extensively, leading to synesthesia, novel thought patterns, and a sense of ego dissolution. This disruption is thought to be responsible for the mystical and introspective experiences often reported during psilocybin trips.
In addition to its serotonergic effects, psilocin influences dopamine release in the mesolimbic pathway, contributing to feelings of euphoria, motivation, and increased emotional sensitivity. Unlike stimulants or other classical hallucinogens such as LSD, psilocybin has a relatively low affinity for dopamine receptors, which is why it produces fewer reinforcing or addictive effects. The emotional modulation induced by psilocybin is largely due to its impact on the amygdala, reducing fear-based responses and promoting emotional openness, which is why it has shown promise in treating anxiety, depression, and PTSD.
Baeocystin and norbaeocystin, which are structurally similar to psilocybin, are also found in psychedelic mushrooms, though their pharmacological properties are less studied. Some anecdotal reports suggest they contribute to the overall psychedelic effects, but their exact role remains unclear. Unlike psilocybin and psilocin, these compounds may have a weaker affinity for serotonin receptors, producing subtler or modulated psychoactive effects.
The metabolism of psilocin occurs primarily in the liver, where it is broken down by monoamine oxidase (MAO) enzymes and excreted via urine. This metabolic pathway means that MAO inhibitors can potentiate and prolong the effects of psilocybin by slowing its breakdown. Unlike many synthetic psychedelics, psilocybin does not have a significant risk of toxicity, and its lethal dose is extremely high compared to common recreational doses.
Ketamine is a dissociative anesthetic that works primarily as an N-methyl-D-aspartate (NMDA) receptor antagonist, leading to profound alterations in consciousness, perception, and pain sensation. It is unique among anesthetics and psychoactive substances due to its ability to induce both analgesia and profound dissociation while also exhibiting rapid-acting antidepressant effects at sub-anesthetic doses.
In addition to NMDA receptor antagonism, ketamine indirectly enhances glutamate release by inhibiting presynaptic GABAergic interneurons, leading to increased activation of AMPA receptors. This upregulation of AMPA receptor activity is believed to underlie ketamine’s rapid antidepressant effects, as it promotes synaptic plasticity and the formation of new neural connections. The downstream effects include increased activity in the mammalian target of rapamycin (mTOR) signaling pathway, leading to enhanced dendritic spine growth and synaptogenesis, particularly in the prefrontal cortex and hippocampus.
Ketamine also interacts with other neurotransmitter systems. It has been shown to increase dopamine release in the mesolimbic pathway by blocking NMDA receptors on inhibitory GABAergic neurons, leading to increased dopaminergic signaling. This contributes to its euphoric and reinforcing effects, which play a role in its potential for abuse. Additionally, ketamine interacts with opioid receptors, particularly the mu and kappa subtypes, which may contribute to its analgesic and dissociative properties. However, it does not function as a traditional opioid agonist.
The subjective effects of ketamine are dose-dependent. At low doses, users experience mild dissociation, altered perception of time and space, and euphoria. Moderate doses induce stronger dissociation, out-of-body experiences, and reduced sensory awareness, often referred to as the "K-hole" when taken at high doses. At anesthetic doses, ketamine induces unconsciousness while preserving airway reflexes, which is why it is commonly used in medical settings for anesthesia, particularly in emergency medicine and pediatric surgery.
Ketamine is metabolized in the liver primarily by cytochrome P450 enzymes, converting it into norketamine, its main active metabolite. Norketamine has weaker NMDA receptor antagonism but still contributes to the overall pharmacological effects. The elimination half-life of ketamine is relatively short, ranging from two to three hours, though its psychological effects can persist longer depending on the dose.
Beyond its dissociative and anesthetic properties, ketamine has gained significant attention for its rapid and sustained antidepressant effects, particularly in treatment-resistant depression. Unlike traditional antidepressants, which take weeks to produce effects, ketamine can relieve depressive symptoms within hours. This rapid response is attributed to its ability to enhance synaptic plasticity and restore neural connectivity in brain regions associated with mood regulation, particularly the prefrontal cortex.
The combination of psilocybin and ketamine would create a unique interaction between two profoundly mind-altering substances with distinct but potentially synergistic mechanisms.
Neurochemically, the interaction between serotonin and glutamate systems could result in unique cognitive effects. Psilocybin increases glutamate release in the prefrontal cortex by activating 5-HT2A receptors, while ketamine indirectly enhances AMPA receptor activity by blocking NMDA receptors and increasing extracellular glutamate. This could lead to a hyperplastic state where neurons are highly responsive, potentially strengthening neuroplasticity and memory formation associated with the psychedelic experience. The combination might also result in more fluid and unpredictable thought patterns, with increased dreamlike or surreal elements in the trip.
Emotionally, the interaction between psilocybin’s serotonergic modulation and ketamine’s dissociative effects could vary depending on dosage. At lower doses, ketamine might blunt the emotional intensity of psilocybin, leading to a more neutral, detached psychedelic state. This could be beneficial for individuals who experience anxiety on psychedelics, as ketamine’s dissociative properties might reduce overwhelming emotional responses. However, at higher doses, the combination could become overwhelming, with rapid shifts between deep emotional introspection and complete detachment, potentially leading to confusion, fear, or disorientation. The unpredictability of such a state could make it difficult to integrate the experience afterward.
Physiologically, both substances affect heart rate and blood pressure, with ketamine typically increasing them slightly and psilocybin having variable cardiovascular effects depending on the user’s state. While neither drug is known for extreme cardiovascular stress in healthy individuals, their combined effects might be more pronounced, particularly in those with preexisting conditions.
Additionally, ketamine’s ability to cause nausea and psilocybin’s tendency to induce gastrointestinal discomfort could make the experience physically uncomfortable if not properly prepared for.
Currently, there is limited research specifically examining the combined use of psilocybin and ketamine. However, individual studies on each substance provide insights into their potential interactions.
A study published in Frontiers in Pharmacology explored the effects of low doses of psilocybin and ketamine on motivation and attention in animal models. The findings suggested that both substances, when administered separately, enhanced motivation and attentional performance, indicating potential therapeutic benefits. However, the study did not investigate the effects of combining these substances.
Another study examined the impact of psilocybin and ketamine on brain neurotransmitter levels. Both substances were found to increase extracellular levels of dopamine, serotonin, glutamate, and GABA in the frontal cortex of rats. These changes in neurotransmitter levels could have implications for mood and cognition, but the study did not assess the effects of using both substances concurrently.
Given the lack of direct research on the combination of psilocybin and ketamine, any conclusions about their combined effects remain speculative. Combining psychoactive substances can lead to unpredictable interactions and potential risks.
This combination requires a lot of experience with substances separately, compliance with minimum dosages, rare repetition and a meaningful approach.
Last edited by a moderator: