No to little effect of truffles and MDMA

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

I hardly react to psychedelic substances like mushrooms, truffles, MDMA and amphetamines. How is this possible and is there anything I can do to have a good trip?

The possible causes

There can be several reasons why you may not experience any or only minimal effects from psychedelics and other drugs. Let’s look at step by step what these reasons could be and what you can do about them during the preparation for a psychedelic session.

Fantasy

People with imagination naturally have difficulty in evoking mental images. This means that they hardly or not at all experience visual images during daydreaming or when recalling a scene. However, this does not necessarily mean that they are insensitive to psychedelic substances due to imagination. During a psychedelic trip, the substances ensure that the brain processes visual information through a ‘bottom-up’ effect. This mainly occurs through the stimulation of 5‑HT₂A receptors in visual areas, such as the primary visual cortex. This results in hallucinations that are not dependent on the voluntary summoning of images. As a result, most people with imagination can still experience visual hallucinations during a trip, even though their ability to consciously summon images is reduced. For now, imagination seems to only have a inhibitory effect on a psychedelic trip.

Purity of the drugs

If you buy aged truffles or mushrooms, the concentration of active substances may have decreased. Or if you buy illegal drugs and your test does not detect the substances and/or concentration of these substances, you will never know for sure whether you have received the amount of the substance you expected.

Sensitive receptors

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

High levels of MAO and habituation

Monoamine oxidase (MAO) is an enzyme that naturally occurs in our body and plays an important role in the breakdown of neurotransmitters such as serotonin, dopamine, and noradrenaline. 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 amount of MAO, psychedelic substances are broken down more quickly. This means that the substance remains active in the body for a shorter period 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 substance may reach the brain. This can reduce the intensity and duration of the psychedelic experience. This may explain why some people experience less intense effects after taking the same dose.

Solution:

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

Cross-tolerance

Cross-tolerance occurs when the use of one substance reduces sensitivity to another, often related substance. This occurs 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 listed below may play a role in the cross-tolerance for psychedelic substances. With higher intake of the substances listed below, you increase the chance that the body will start to anticipate repeated intake and may therefore also break down the psychedelics more quickly.

Melatonin

Melatonin is a hormone that is involved in regulating the sleep-wake cycle. It also affects certain receptor processes in the brain. An increased melatonin level can alter the brain's sensitivity to other substances, which may cause psychedelics to work less well.

Tyramine

Tyramine is a biogenic amine that is found in certain foods and in the body as a breakdown product of neurotransmitters. It can affect the breakdown of neurotransmitters and therefore also the receptor sensitivity. Through its interaction with enzymes such as monoamine oxidase (MAO), tyramine can affect the balance in the brain and thus change the 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, there can be a modulation in the brain that affects the response to psychedelics. This can contribute to reduced efficacy 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 through 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 the synapses by blocking its reabsorption.
Influence on psychedelics: Many psychedelics, such as LSD and psilocybin, exert their effects via serotonin receptors (especially the 5-HT₂A receptor). Prolonged use of SSRIs can make these receptors less sensitive (downregulation), which leads 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: Because of their calming effect, benzodiazepines can dampen 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 action.
Influence on psychedelics: Because these drugs directly counteract the effects of psychedelics on these receptors, they can significantly weaken the effects of psychedelics or even completely block them.

Some other antidepressants, such as tricyclic antidepressants or serotonin-norepinephrine reuptake inhibitors (SNRIs), can also affect the serotonergic system and thereby indirectly reduce the effects of psychedelics. Furthermore, mood stabilizers and anticonvulsants can adjust 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 lead to people having a lower amount or less functionally active SERT. People with the so-called ‘short’ variant generally have less SERT, resulting in an elevated level of extracellular serotonin.

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

Changed serotonin balance: Lower SERT activity leads to less reuptake of serotonin, which can cause the baseline serotonin levels in the brain to be higher. This can affect how the receptors respond to a psychedelic substance.
Adjustment of receptor sensitivity: Due to a chronically elevated extracellular serotonin level, the serotonin receptors (e.g. 5-HT₂A) can be adjusted in sensitivity or number (downregulation). As a result, the stimulation by a psychedelic drug can be less strong.

Downregulation

With repeated stimulation of specific receptors, the number or sensitivity of those receptors can decrease (downregulation). This mechanism occurs frequently with chronic use of amphetamines. Downregulation causes the brain to try to prevent overstimulation with frequent use, which can make the effects of a new dose of psychedelics less intense.

MTHFR and COMT

COMT

The COMT gene codes for the enzyme catechol-O-methyltransferase, which plays an important 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 that relatively more dopamine remains in the synaptic cleft.

Because dopamine is involved in emotional processing, motivation, and cognitive functions, these differences can influence how a psychedelic trip is experienced. A higher dopamine level (such as in the Met/Met variant) can, for example, lead to stronger emotional and cognitive effects, while a faster breakdown (such as in Val/Val) can potentially provide a more “calmed” experience. This modulation of dopaminergic signaling can affect the intensity or “color” of the trip, especially in combination with the primary serotonergic effects of many psychedelics.

MTHFR

The MTHFR gene (methylenetetrahydrofolate reductase) plays a crucial role in folate and methyltransferase 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 the activity of MTHFR, leading to a reduced availability of folate and an impaired methylation status.
This can result in less efficient serotonin synthesis and metabolism.

Since many psychedelics (e.g., psilocybin and LSD) exert their effects via serotonin receptors (such as the 5‑HT₂A receptor), reduced MTHFR activity could affect the 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 affect each other. A combination of a “slow” COMT variant (Met/Met) with an MTHFR variant that reduces methylation capacity could together lead to a changed 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 than 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 (degradation and conversion) of psychedelic substances via enzymes in the cytochrome P450 system.

Metabolism

Psilocybin → PsilocineThe liver converts psilocybin (the non-active form) into psilocin, the substance that actually causes the psychedelic effects. Reduced liver function can slow down this conversion, causing the peak of the trip to come later or last longer.
LSD It is largely metabolized in the liver. Individual variations in liver enzymes can influence the duration and intensity of the trip.
DMT and MAO inhibitorsDMT is normally rapidly broken down by MAO enzymes in the liver. MAO inhibitors (such as in ayahuasca) block this process, allowing DMT to remain active and enabling a prolonged 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.
Antagonists or inducers of these enzymes (for example 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) the breakdown of psychedelics can be slowed down, leading to an unpredictable or prolonged trip.
Overburdened liverIf the liver has to process many other substances (for example through medication or poor diet), the metabolism of psychedelics can be affected.

Conclusion

There is no single cause for a reduced response to psychedelic drugs; multiple 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. This can make it different for each individual why a standard dose does not produce the desired effects.

Recommendations

Check the purity and freshness of the substance: Make sure your truffles, mushrooms or MDMA come from a reliable source and, if possible, have them tested for composition.
Be aware of any interactions: Avoid simultaneous use of other substances such as THC, melatonin or tyramine, which can weaken the effects of psychedelics.
Consider nutrition and supplements: Optimal intake of omega-3 fatty acids can contribute to better receptor function. Healthy nutrition generally also supports neurotransmission.
Be aware of medication use: If you are taking medications such as SSRIs, benzodiazepines or antipsychotics, discuss with a doctor the potential impact on your psychedelic experience.
Pay attention to your body and genetic factors: Although genetic predisposition (such as variations in SERT, COMT or MTHFR) is not easy to change, awareness of this can help you have realistic expectations. If in doubt, it is advisable to consult a specialist.
Caution with MAO inhibitors: Use passionflower or other MAO inhibitors only with the appropriate knowledge and preferably under expert advice to avoid unexpected effects.

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Little to no effect from truffles and MDMA