Little to no effect from truffles and MDMA

Why don't I feel anything from MDMA or truffles?

I barely react to psychedelics like magic mushrooms, truffles, MDMA, and amphetamines. Why is this, and is there anything I can do to ensure a good trip?

The possible causes

There can be several reasons why you experience little to no effects from psychedelics and other drugs. Let's look step by step at the possible reasons and what you can do about it while preparing for a psychedelic session.

Aphantasia

People with aphantasia naturally have difficulty conjuring up mental images. This means that they experience few or no visual images while daydreaming or remembering a scene. However, this does not necessarily mean that aphantasia makes them insensitive to psychedelic substances. During a psychedelic trip, the substances cause the brain to process visual information through a "bottom-up" mechanism. This occurs primarily by stimulating 5-HT2A receptors in visual areas, such as the primary visual cortex. This causes hallucinations that do not depend on the voluntary recall of images. Therefore, most people with aphantasia can still experience visual hallucinations during a trip, even though their ability to consciously, voluntarily recall images is impaired. For now, aphantasia only appears to have an inhibiting effect on a psychedelic trip.

Purity of the drugs

If you buy out-of-date truffles or mushrooms, the concentration of active ingredients may have decreased. Or if you buy illegal drugs and don't test for the substances and/or their concentration, you can never be certain you've ingested the amount you expected.

Insensitive receptors

Omega-3 fatty acids such as DHA and EPA contribute to the structure and fluidity of cell membranes. Optimal cell membrane composition ensures optimal functioning of receptors, including serotonin and dopamine receptors. A deficiency of these fatty acids can disrupt receptor function and diminish the experience of psychedelic substances. Recent scientific studies emphasize that a healthy intake of DHA and EPA contributes to improved neurotransmission and a more intense subjective experience.

High MAO content and habituation

Monoamine oxidase (MAO) is an enzyme naturally occurring in our bodies that plays a key role in breaking down neurotransmitters such as serotonin, dopamine, and norepinephrine. Many psychedelic substances are structurally similar to these neurotransmitters and are therefore also broken down by MAO.

In people with increased activity or a higher concentration of MAOIs, psychedelic substances are broken down more quickly. This means the substance remains active in the body for a shorter period of time and therefore has less time to produce the desired effects in the brain.

Because the psychedelic substance is metabolized more quickly, less of the active ingredient may reach the brain. This can reduce the intensity and duration of the psychedelic experience. This may explain why some people experience weaker effects after taking the same dose.

Solution:

Passionflower contains substances that have a mild inhibitory effect on the enzyme monoamine oxidase (MAO). During a psilocybin session, you can use passionflower an hour before taking it to reduce MAO enzyme activity.

Cross-tolerance

Cross-tolerance occurs when the use of one substance reduces sensitivity to another, often related, substance. This happens because both substances act on similar receptor systems in the brain, such as the serotonin 5-HT₂A receptors in many psychedelics. If these receptors have already been stimulated by a previous dose of a psychedelic, the response to a subsequent dose or to a different psychedelic may be weakened.

Influence of THC, Melatonin and Tyramine

The substances listed below may play a role in cross-tolerance to psychedelics. Higher doses of these substances increase the likelihood that the body will anticipate repeated use, potentially leading to faster metabolization of the psychedelics.

Melatonin

Melatonin is a hormone involved in regulating the sleep-wake cycle. It also influences certain receptor processes in the brain. Increased melatonin levels can alter the brain's sensitivity to other substances, potentially making psychedelics less effective.

Tyramine

Tyramine is a biogenic amine found in certain foods and in the body as a breakdown product of neurotransmitters. It can influence neurotransmitter breakdown and thus receptor sensitivity. By interacting with enzymes such as monoamine oxidase (MAO), tyramine can influence brain balance and thus alter tolerance to psychedelics.

THC (tetrahydrocannabinol)

THC, the psychoactive component of cannabis, interacts with the endocannabinoid system. This system is closely linked to other neurotransmitter systems. When THC is used, a modulation can occur in the brain that affects the response to psychedelics. This can contribute to a reduced effectiveness of psychedelics, especially when the two substances are combined within a short period of time.

Medication

SSRIs, benzodiazepines, and antipsychotics can reduce the intensity and effectiveness of psychedelic experiences by affecting the serotonergic and other neurotransmitter systems. The most important classes are SSRIs, benzodiazepines, and antipsychotics.

SSRIs

Operation: SSRIs increase the amount of serotonin in the synapses by blocking its reuptake.
Influence on psychedelics: Many psychedelics, such as LSD and psilocybin, exert their effects through serotonin receptors (particularly the 5-HT₂A receptor). Long-term use of SSRIs can desensitize these receptors (downregulation), leading to a weakened or dulled psychedelic experience.

Benzodiazepines

Operation: Benzodiazepines, such as diazepam and alprazolam, increase the activity of the neurotransmitter GABA, which has a calming and anxiety-reducing effect.
Influence on psychedelics: Due to their sedative effects, benzodiazepines can reduce the intensity of the psychedelic experience. They can help alleviate acute anxiety or an unpleasant trip, but at the same time, their use can reduce the overall intensity of the psychedelic effects.

Antipsychotics

Operation: Many antipsychotics, such as risperidone and olanzapine, block the 5-HT₂A receptor, the same receptor on which many psychedelics base their effects.
Influence on psychedelics: Because these drugs directly interfere with the effects of psychedelics on these receptors, they can significantly weaken or even completely block the effects of psychedelics.

Some other antidepressants, such as tricyclic antidepressants or serotonin-norepinephrine reuptake inhibitors (SNRIs), can also affect the serotonergic system and thus indirectly reduce the effects of psychedelics. Furthermore, mood stabilizers and anticonvulsants can alter the excitability and dynamics of neurotransmitter systems, which can have a dampening effect on the psychedelic experience.

Less SERT

SERT plays a crucial role in serotonergic neurotransmission by transporting serotonin from the synaptic cleft back into the nerve cell. Genetic polymorphisms, such as the 5-HTTLPR variation, can lead to individuals having lower levels of SERT or less functional SERT. People with the so-called "short" variant typically have less SERT, resulting in increased extracellular serotonin levels.

Many psychedelics, such as psilocybin and LSD, exert their effects primarily through the serotonin 5-HT₂A receptors. The balance and dynamics of the serotonin system, including the activity of SERT, are important in this regard. If someone has a low SERT level, this can be affected in two ways:

Altered serotonin balance: Lower SERT activity leads to less serotonin reuptake, which can lead to higher baseline serotonin levels in the brain. This can affect how the receptors respond to a psychedelic substance.
Adjustment of receptor sensitivity: Chronically elevated extracellular serotonin levels can affect the sensitivity or number of serotonin receptors (e.g., 5-HT₂A). This can reduce the stimulation from a psychedelic.

Downregulation

Repeated stimulation of specific receptors can decrease the number or sensitivity of those receptors (downregulation). This mechanism is common with chronic amphetamine use. Downregulation causes the brain to try to avoid overstimulation with frequent use, which can make the effects of a subsequent dose of psychedelics less intense.

MTHFR and COMT

COMT

The COMT gene encodes the enzyme catechol-O-methyltransferase, which plays a key role in the breakdown of dopamine (and other catecholamines) in the prefrontal cortex. The well-known Val^158Met polymorphism results in functional differences:

People with the Val/Val variant have higher enzymatic activity, which causes dopamine to be broken down more quickly.
People with the Met/Met variant have lower COMT activity, which means relatively more dopamine remains in the synaptic cleft.

Because dopamine is involved in emotional processing, motivation, and cognitive function, these differences can influence how a psychedelic trip is experienced. For example, higher dopamine levels (as in the Met/Met variant) can lead to stronger emotional and cognitive effects, while a faster decline (as in Val/Val) can potentially produce a more "tempered" experience. This modulation of dopaminergic signaling can influence the intensity or "color" of the trip, especially when combined with the primary serotonergic effects of many psychedelics.

MTHFR

The MTHFR gene (methylenetetrahydrofolate reductase) plays a crucial role in folate and methylation metabolism. This enzyme is essential for the production of 5-methyltetrahydrofolate, the active form of folate required for methylation processes in the body. This methylation, in turn, is important for the synthesis of neurotransmitters such as serotonin.

Polymorphisms such as the C677T variant can reduce MTHFR activity, leading to reduced folate availability and disrupted methylation status.
This can result in less efficient serotonin synthesis and metabolism.

Since many psychedelics (e.g., psilocybin and LSD) exert their effects through serotonin receptors (such as the 5-HT2A receptor), reduced MTHFR activity could affect serotonergic balance. Theoretically, this could alter the intensity, duration, or even the quality of the psychedelic experience.

Possible interaction between COMT and MTHFR

Variations in COMT and MTHFR can interact. A combination of a "slow" COMT variant (Met/Met) with an MTHFR variant that reduces methylation capacity could lead to altered balances of both dopamine and serotonin. Since both neurotransmitters are important for mood, cognition, and perception, such an interaction could result in a psychedelic trip that is different in intensity than in someone without these genetic variations.

Influence of the liver

The liver plays an important role in the processing and intensity of a psychedelic trip. This is because the liver is involved in the metabolism (breakdown and conversion) of psychedelic substances via enzymes in the cytochrome P450 system.

Metabolism

Psilocybin → PsilocinThe liver converts psilocybin (the inactive form) into psilocin, the substance that actually produces the psychedelic effects. Impaired liver function can delay this conversion, causing the peak of the trip to occur later or last longer.
LSD It is largely metabolized in the liver. Individual variations in liver enzymes can affect the duration and intensity of the trip.
DMT and MAOIsDMT is normally broken down rapidly by MAO enzymes in the liver. MAOIs (such as those in ayahuasca) block this process, allowing DMT to remain active and enabling a long-lasting psychedelic experience.

P450 enzymes

Some people have genetic variants of CYP enzymes (such as CYP2D6 or CYP3A4), which causes them to metabolize psychedelics faster or slower.
Inhibitors or inducers of these enzymes (e.g., grapefruit juice, certain medications, or herbs such as St. John's wort) can affect the intensity or duration of a trip.

Liver health

Poor liver function (for example, due to liver disease or heavy alcohol consumption) can slow the breakdown of psychedelics, leading to an unpredictable or prolonged trip.
Overloaded liver: If the liver already has to process a lot of other substances (for example due to medication use or poor nutrition), the metabolism of psychedelics can be affected.

Conclusion

There is no single cause for a diminished response to psychedelic substances; multiple factors can play a role. Both internal factors (genetic predisposition, receptor sensitivity, liver metabolism) and external factors (purity of the substance, interactions with other substances and medications) influence the final experience. Therefore, the reason why a standard dose does not produce the desired effects can vary from person to person.

Recommendations

Check the purity and freshness of the substance: Make sure your truffles, mushrooms, or MDMA come from a reputable source and, if possible, have them tested for composition.
Please consider any interactions: Avoid concomitant use of other substances such as THC, melatonin or tyramine, which can weaken the effects of psychedelics.
Consider diet and supplements: An optimal intake of omega-3 fatty acids can contribute to better receptor function. A healthy diet also generally supports neurotransmission.
Be aware of medication use: If you are taking medications such as SSRIs, benzodiazepines, or antipsychotics, discuss with a doctor how they may affect your psychedelic experience.
Pay attention to your body and genetic factors: Although genetic predisposition (such as variations in SERT, COMT, or MTHFR) isn't easy to change, being aware of it can help you have realistic expectations. If in doubt, it's advisable to consult a specialist.
Caution with MAO inhibitors: Use passion flower or other MAO inhibitors only with the correct knowledge and preferably under expert advice, to avoid unforeseen effects.

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