No to little effect of truffles and MDMA

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

I have almost no reaction to psychedelics like magic mushrooms, truffles, MDMA and amphetamines. Why is this and can I do something about it to get a good trip though?

The possible causes

There could be several reasons if you have no to little effects from psychedelics and other drugs. Let's take a step-by-step look at what reasons this may have and what you can possibly do about it while preparing for a psychedelic session

Afantasy

People with aphasia naturally have difficulty recalling mental images. This means that while daydreaming or remembering a scene, they experience little or no visual images. However, this does not necessarily mean that aphasia makes them insensitive to psychedelic substances. During a psychedelic trip, substances cause the brain to process visual information via a 'bottom-up' effect. This happens mainly through the stimulation of 5-HT₂A receptors in visual areas, such as the primary visual cortex. This creates hallucinations that do not rely on the voluntary recall of images. This allows most people with aphasia to still experience visual hallucinations during a trip, even though their ability to recall images in a conscious, voluntary way is impaired. For the time being, aphasia seems to be able to only inhibit a psychedelic trip.

Drug purity

If you buy outdated truffles or magic mushrooms, the concentration of active substances may have dropped. Or if you buy illegal drugs and you do not test for the substances and/or concentration of these substances, you can never be sure if you have 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. An optimal composition of cell membranes ensures that receptors, including serotonin and dopamine receptors, function optimally. A deficiency of these fatty acids can disrupt receptor function and reduce the experience of psychedelic substances. Recent scientific studies highlight 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 that occurs naturally in our bodies and plays an important 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 greater amount of MAO, psychedelic substances are broken down faster. This means that the substance remains active in the body for less time and thus has less time to produce the desired effects in the brain.

Because the psychedelic substance is metabolised faster, less of the active substance may reach the brain. This may 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 mildly inhibit the enzyme monoamine oxidase (MAO). In a session with psilocybin, you can use passionflower an hour before taking it to lower 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 another psychedelic may be weakened.

Influence of THC, Melatonin and Tyramine

The substances below may possibly play a role in cross-tolerance to psychedelics. With higher intakes of the substances below, you increase the likelihood that the body will start anticipating repeated intakes and may also break down psychedelics faster as a result.

Melatonin

Melatonin is a hormone involved in regulating the sleep-wake cycle. It also affects certain receptor processes in the brain. Elevated melatonin levels can alter the brain's sensitivity to other substances, possibly causing psychedelics to work less well.

Tyramine

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

THC (tetrahydrocannabinol)

THC, the psychoactive component of cannabis, acts on the endocannabinoid system. This system is closely intertwined with other neurotransmitter systems. When using THC, a modulation can occur in the brain that affects the response to psychedelics. This can contribute to reduced effectiveness of psychedelics, especially when both drugs are combined in a short period of time.

Medication

SSRIs, benzodiazepines and antipsychotics can reduce the intensity and effectiveness of psychedelic experiences due to their influence on the serotonergic and other neurotransmitter systems. The main groups are SSRIs, benzodiazepines and antipsychotics.

SSRIs

Operation: SSRIs increase the amount of serotonin in synapses by blocking its reuptake.
Influence on psychedelics: Many psychedelics, such as LSD and psilocybin, exert their effects via serotonin receptors (especially the 5-HT₂A receptor). Long-term use of SSRIs can cause these receptors to become less sensitive (downregulation), leading to a weakened or blurred 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 dampen the intensity of the psychedelic experience. They can help relieve 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 action.
Influence on psychedelics: Because these drugs directly counteract the action 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-noradrenaline reuptake inhibitors (SNRIs), may also affect the serotonergic system, thereby indirectly reducing the effects of psychedelics. Furthermore, mood stabilisers and anticonvulsants can alter the excitability and dynamics of neurotransmitter systems, which can have a dampening effect on the experience of psychedelics.

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 cause people to have a lower amount or less functionally active SERT. People with the so-called 'short' variant typically have less SERT, resulting in increased levels of extracellular serotonin.

Many psychedelics, such as psilocybin and LSD, exert their effects mainly through the serotonin-5-HT₂A receptors. The balance and dynamics in the serotonin system, including the activity of SERT, are important here. If someone has a lower number of SERT, this can affect them in two ways:

Altered serotonin balance: Lower SERT activity leads to less reuptake of serotonin, which can lead to higher base serotonin levels in the brain. This can affect how receptors respond to a psychedelic substance.
Adaptation of receptor sensitivity: Chronic elevated extracellular serotonin levels can cause serotonin receptors (e.g. 5-HT₂A) to become altered in sensitivity or number (downregulation). As a result, stimulation by a psychedelic drug may be weaker.

Downregulation

Repeated stimulation of specific receptors may reduce the number or sensitivity of those receptors (downregualtion). This mechanism happens a lot in the chronic use of amphetamines. Downregualtion means that with frequent use, the brain tries to avoid over-stimulation, which can make the effects of a new dose of psychedelics less intense.

MTHFR and COMT

COMT

The COMT gene encodes for the enzyme catechol-O-methyltransferase, which plays an important role in the breakdown of dopamine (and other catecholamines) in the prefrontal cortex. The 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 faster.
People with the Met/Met variant have lower COMT activity, leaving relatively more dopamine in the synaptic cleft.

Because dopamine is involved in emotional processing, motivation and cognitive functions, these differences can affect 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 breakdown (as in Val/Val) can potentially give a more "tempered" experience. This modulation of dopaminergic signalling can affect the intensity or "colour" of the trip, especially when combined with the primary serotonergic effects of many psychedelics.

MTHFR

The methylenetetrahydrofolate reductase (MTHFR) gene 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. In turn, this methylation is important for the synthesis of neurotransmitters such as serotonin.

Polymorphisms such as the C677T variant can decrease the activity of MTHFR, leading to reduced folate availability and impaired 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 may affect each other. A combination of a "slow" COMT variant (Met/Met) with an MTHFR variant that reduces methylation capacity could together lead to an altered balance 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 from 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 metabolisation (breakdown and conversion) of psychedelic substances via enzymes in the cytochrome P450 system.

Metabolisation

Psilocybin → Psilocin: The liver converts psilocybin (the inactive form) into psilocin, the substance that actually causes the psychedelic effects. Impaired liver function can slow down this conversion, causing the peak of the trip to come later or last longer.
LSD is largely metabolised in the liver. Individual variations in liver enzymes can affect the duration and intensity of the trip.
DMT and MAOIs: DMT is normally quickly broken down by MAO enzymes in the liver. MAOIs (as in ayahuasca) block this process, keeping DMT active and allowing for a prolonged psychedelic experience.

P450 enzymes

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

Liver Health

Poor liver function (e.g. due to liver disease or heavy alcohol consumption) can slow down 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 (e.g. due to drug use or poor diet), the metabolisation of psychedelics may be affected.

Conclusion

There is no single cause for an impaired response to psychedelic substances; several factors can play a role together. Both internal (genetic predisposition, receptor sensitivity, liver metabolism) and external factors (purity of the substance, interactions with other substances and medication) influence the final experience. As a result, why a standard dose may not produce the desired effects may be different for each individual.

Recommendations

Check the purity and freshness of the substance: Make sure your truffles, shrooms or MDMA come from a reliable source and, if possible, have them tested for composition.
Take into account any interactions: Avoid simultaneous use of other substances such as THC, melatonin or tyramine that can weaken the effects of psychedelics.
Consider nutrition and supplements: Optimal intake of omega-3 fatty acids can help improve receptor function. Healthy diet also generally supports neurotransmission.
Be aware of medication use: If you take medications such as SSRIs, benzodiazepines or antipsychotics, discuss with a doctor how they might affect your psychedelic experience.
Pay attention to your body and genetic factors: Although genetic predisposition (such as variations in SERT, COMT or MTHFR) is not easily changed, awareness of this can help you have realistic expectations. When in doubt, it is advisable to consult a specialist.
Caution with MAOIs: Use passionflower or other MAOIs only with proper knowledge and preferably under expert advice, to avoid unforeseen effects.

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