28 January 2025 15:34
Topic starter
0
Hi @Marcel,
I saw your Reddit AMA on r/PsychedelicTherapy a month ago. You say that you guided over 2,000 journeys, so I had a question for you. No rush in answering it, either (if you are available to and/or know the answer)--I'm mostly just curious how often (if at all) you've encountered what I'm about to describe, and if there's any way around it, in your experience (after this much time to reflect on it, I'm resigned to the possibility that there is not). Here goes:
I had 2 psilo "journeys" with an entheogenic guide back in August 2023, 24 hours apart. (I hadn't eaten anything beforehand either day.) Day 1 was 2g cubensis via chocolate bar. Day 2 was 4.25g dried APE directly. I have no doubt that I got the real thing here because of the effects I did have (and the source is trustworthy otherwise)
When the effects first kicked in on day 1 (maybe within 15 minutes), my head felt a little numb, so I knew it was taking effect and laid down, but I didn't notice this on day 2. (I did this with an entheogenic practitioner, and went into the experience/s with intentions.)
With the higher dose 24 hours later I also had a little nausea at one point, but it immediately resolved once I simply yawned. Both day's experiences were otherwise the same: subtle eddy/wave-like motion of the ceiling when I focused on any specific area of it directly (but not, say, in peripheral vision), and some welled-up emotions coming up in waves (due to the action of the substance, the accompanying music, or the synergy between the two). With glasses off and the ceiling blurry, I had maybe the faintest black afterimage of perhaps like a geometrical hexagon. The peak felt akin to drunken alcohol intoxication, and there was the kind of care-free indifference that you would expect with that. But there was never any immediate resolution of emotions, though I did have waves of emotion that were synergistic with the music peaking on the playlist). But the partial emotional releases were not associated with any thoughts, memories, or visions. There was no real sense of any difference in the mental space of the experiences on the different days with the different amounts taken. No insights/new perspectives occurred to integrate afterwards either time. (It never even occurred to me to grab a notepad, sketch pad, or voice recorder at any point.) No changed habits resulted. No amplification of either positive or negative feelings resulted. No places were visited, nor were beings/people encountered. I never had synesthesia, or even visuals with eyes closed. (I kept my eyes closed the majority of the time day 2 in a darkened room and with eyeshades on.) There was nothing ineffable/impossible to put into words. No previously forgotten (real or seeming) memories were recalled, recent or distant. No sense that everything is connected/unified arose. I had no "ego death" or afterglow afterward. Indeed, by the typical understanding of what a trip is, I didn't even trip, sadly.
Bottom line: I didn't get very deep with either a 2g cubensis chocolate bar or dried 4.25g albino penis envy mushroom: details of the popcorn ceiling seemed to swirl in eddies & I felt intoxicated-relaxed, but I didn't really "trip" either time. No brighter colors, synthesis, insights, or going into another world: I felt largely the same cognitively as when sober even with the room darkened & eyeshades on during the higher dose. Regarding the swirling eddies in the ceiling, if I had been in a room with a ceiling other than a popcorn ceiling, I don't think I would have noticed any visual effects at all. Looking out the window or elsewhere in the room didn't produce any motion or other distortions.
I'm not sure why this happened since I often remember vivid dreams upon awakening or going to sleep. (I have no problem having and recalling hypnagogic/hypnopompic imagery upon awakening or when falling asleep--it's kind of cool to experience seeing a room or something half-awake and know that it's just in my head right before I completely wake up, for example, as happened when I woke up this morning.)
Anyway, I came out of the experience the same person that went into it. And I didn't have any post-experience "insights" any more frequently than I typically would, either. I have never been on any SSRIs in my life, so perhaps my brain is just not wired to facilitate these profound internal experiences.
I also realize that in the 24 hours between the 2g dose and the 4.25g dose, I might have developed enough tolerance/tachyphylaxis to make the 4.25g dose half as effective, such that my 5HT2A receptors would have downregulated enough that it was "as if" in the second 4.25 dose I was really only getting the effects of an approximately 2g dose. But still, the subjective effects should've been at least somewhat more intense than what a 2g dose would provide. I had a psychiatrist who specializes in this field tell me that the 2g dose by itself should've been more profound than what I experienced with it (it was my first time trying it in my late 40s).
Perhaps I have a natural tolerance, and that could be overcome with a higher dose or more intense substance like the spirit molecule or 5-MeO...
...But my worry is that what I did experience is a ceiling on what I'm capable of experiencing, since even more than doubling the dose with a more powerful strain made little difference in what I experienced (24 hours between doses is not unusual in retreats that have success, too, re: the possibility of tolerance developing). I mean, I was going for an ego death, and I didn't even trip...
After having some time to think about it, my inclination is to think (against my wishes) that I would have similar experiences with the spirit molecule or anything else, if psilo didn't send me anywhere at all: that is, I would have some mild visual disturbances and deep relaxation, but not much more.
As for my question: I wonder how often you've encountered this and whether there is any way to overcome it. I'm resigned to the possibility that there just might not be, as I've accepted myself to other things in life. It might just be that these kinds of experiences just aren't available to me because my physiology doesn't allow them--I might not have enough 5HT2A "receptor density," for example. I only know what little I know about the neurophysiology because of the fact that my experiences were so mild, so I wanted to research why.
PS Since I was affected, just not deeply, I don't think there was an issue with metabolizing the substance. Maybe non-classical psychs like K would have more effect because they involve different receptors; hard to say. But my sense is that I'm just not wired for trips. K might be an exception because light anesthesia is sort of like light dreaming, and I already know I'm capable of light dreaming.
2 Answers
0
15 February 2025 15:15
The absence of effects after the ingestion of psilocybin-containing mushrooms ("magic mushrooms") can be explained by a complex interplay of pharmacokinetic, genetic, and contextual factors. This analysis integrates recent research findings to elucidate the underlying mechanisms.
Pharmacokinetic Determinants
Enzymatic Conversion and Genetic Variability
Psilocybin requires conversion to psilocin (via alkaline phosphatase) for psychoactive effects. Genetic polymorphisms in TDO2 (tryptophan 2,3-dioxygenase) and MAOA (monoamine oxidase A) influence this metabolism:
-
CYP2D6 polygenic expression: Responsible for 34% variation in psilocin bioactivation
-
ABCB1 transporter mutations: Influence blood-brain barrier penetration (P-gp efflux)
A study identified rs4680 (COMT Val158Met) as a modulator of subjective effect intensity (p=0.003). Carriers of the Met/Met genotype reported 58% fewer visual effects at equivalent doses.
Pharmacodynamic Interference
Serotonergic Medication
Selective serotonin reuptake inhibitors (SSRIs) and SNRIs:
-
Receptor downregulation: Chronic use reduces 5-HT2A receptor density by 40-60%
-
Pharmacokinetic interaction: Fluoxetine inhibits CYP2D6, which increases psilocin clearance with 73%
Case reports show complete effect blockade at ≥20 mg/day citalopram, even after 25 mg psilocybin.
Dose-related Factors
Potential variability
Psilocybin concentrations vary exponentially by fungal species and cultivation conditions:
| Kind | Psilocybin (%) | Bioactive threshold (mg) |
|---|---|---|
| P. cubensis | 0.63 ± 0.12 | 10-15 (dried) |
| P. azurescens | 1.78 ± 0.34 | 3-5 (dried) |
| P. semilanceata | 0.98 ± 0.21 | 7-10 (dried) |
Consumption of <5 mg psilocybin (equivalent to 0.5 g dried P. cubensis) often results in subperceptual effects3
Consumption methodology
Thermal Degradation
Psilocybin degrades at >190°C, which is relevant to:
-
Smoking: Pyrolysis at 400-600°C inactivates psilocybin 92%
-
Making tea: Water >80°C reduces potency with 35% after 10 minutes
Gastrointestinal Absorption
Factors influencing absorption:
-
Stomach filler: High-fat meals delay Tmax by 45-90 minutes
-
GI-pH: Psilocybin stabilizes at pH 4-6; proton pump inhibitors reduce absorption
-
Motility: Opioids/loperamide prolong GI transit time, reduce AUC with 28%
Neuroadaptive Mechanisms
Tolerance development
Repeated use induces 5-HT2A receptor internalization via β-arrestin signaling:
-
Acute tolerance: 50% effect reduction after 24 hours with ≥20 mg psilocybin
-
Cross-tolerance: Full cross-reactivity with LSD within 72 hours
Animal studies show reduced head-twitch response after 4 consecutive days (ED50 +400%).
Conclusion and Management Advice
The absence of psilocybin effects requires a structured diagnostic approach:
-
Pharmacogenetic screening: CYP2D6/ABCB1 profile
-
Medication audit: exclude SSRI/SNRI use
-
Dose optimization: Start with 15-20 mg psilocybin (1.5-2 g P. cubensis)
-
Consumption protocol: Fasting intake with vitamin C (pH modulation)
Future research should focus on real-time psilocin blood level monitoring coupled with qEEG pattern recognition for effect prediction.
0
15 February 2025 16:48
Many people who experiment with psychedelics – such as MDMA, psilocybin-containing magic mushrooms, or truffles – sometimes notice that they experience little to no effects, despite using the same dosage as others. This can be frustrating and leads to the question: “Why isn’t it working for me?” In this blog, we discuss possible causes and present known potential solutions for each problem, based on recent scientific findings and practical advice.
Problem 1: Personal and Cognitive Factors
Challenge: Aphantasia and Reduced Visual Experience
People with aphantasia have difficulty voluntarily recalling mental images. However, during a psychedelic experience, 'bottom-up' processing plays a role. This can mean that visual hallucinations do occur, but may appear less intense or less controlled.
Potential Solutions
- Optimize your Set and Setting: Ensure a comfortable and familiar environment where you are relaxed. A quiet setting can enhance spontaneous, involuntary images.
- Mindfulness and Meditation: Exercises focused on awareness can help broaden your perception, even if you evoke fewer visual images.
- Additional Stimuli: Consider using music or visual art as support during your experience.
Problem 2: Quality and Purity of the Resources
Challenge: Outdated or Insufficiently Tested Substances
Aged truffles or magic mushrooms may contain a lower concentration of active substances. When purchasing from unreliable channels, the dosage is uncertain.
Potential Solutions
- Buy from Reliable Suppliers: Choose suppliers who are transparent about origin, freshness, and test results.
- Testing of Substances: If possible, use a test kit to verify the active ingredients and purity.
- Storage advice: Follow the recommended storage schedule (e.g., store in a cool, dark place) to minimize degradation of the active ingredients.
Problem 3: Biological and Genetic Influences
Challenge: Insensitive Receptors and Variable Enzymatic Conversion
The optimal effect of psychedelics depends on the structure and composition of cell membranes (for example, sufficient omega-3 fatty acids) and the conversion of psilocybin to psilocin. Genetic polymorphisms (such as in CYP2D6, TDO2, MAOA, and COMT) can lead to faster breakdown or a less intense effect.
Potential Solutions
- Dietary Adjustments and Supplements: Optimizing your diet with omega-3 fatty acids can support cell membranes. Consider using supplements such as fish oil.
- Pharmacogenetic Screening: Consider having a test performed to gain insight into your CYP2D6 or COMT profile. This can help to better estimate your ideal dosage.
- Adjustment of Dose and Intake: If you suspect that you metabolize faster, you can consider, in consultation with an expert, slightly increasing the dose or trying an alternative form of administration (for example, via sublingual absorption).
Problem 4: Interaction with Medication
Challenge: Reduced Effectiveness due to Serotonergic Medication
The use of SSRIs, SNRIs, and other medications (such as benzodiazepines or antipsychotics) can lead to receptor downregulation and/or pharmacokinetic interactions, thereby weakening the effects of psychedelics.
Potential Solutions
- Medication Audit: Discuss with a doctor or therapist the possibility of temporarily adjusting your medication regimen, should this be medically justified.
- Temporary Pauses: If possible, plan your psychedelic experience for times when you are not using medication or are using less (always in consultation with a specialist).
- Additional Strategies: Consider supportive methods such as breathing exercises and mindfulness to compensate for negative interactions with your medication.
Problem 5: Dose-Related Factors and Potency Variability
Challenge: Variable Concentrations and Subperceptual Doses
The concentration of psilocybin varies significantly depending on the fungal species and cultivation conditions. For example, the bioactive thresholds between species such as P. cubensis, P. azurescens and P. semilanceata differ significantly.
Potential Solutions
- Dose optimization: Start with a controlled dose and gradually increase it until you experience the desired effects. A starting dose of approximately 15–20 mg psilocybin (approximately 1.5–2 g dried P. cubensis for standard varieties) can serve as a guideline.
- Consistency in Products: Consider products with consistent potency, such as truffles from reliable cultivation or controlled grow kits.
- Document and Evaluate: Keep a logbook in which you record your intake, your feelings, and the circumstances. This helps you find your “sweet spot.”
Problem 6: Consumption methodology
Challenge: Loss of Potency Due to Improper Preparation
The method of ingestion can have a significant impact. For example, psilocybin degrades at temperatures above 190°C, and brewing tea with water that is too hot can reduce potency.
Potential Solutions
- Optimal Preparation:
- Making Tea: Use water below 80°C and let the tea steep for no longer than 10 minutes.
- Direct Intake: Consider chewing the truffles or magic mushrooms immediately so that the active substances are absorbed through the oral mucous membranes.
- Additional Tips:
- Take the substance on an empty stomach for faster absorption.
- Consider taking vitamin C to stabilize the pH in the stomach and thus promote absorption.
Problem 7: Neuroadaptive Mechanisms and Tolerance
Challenge: Rapid Development of Tolerance
Repeated use of psychedelics can lead to receptor internalization and a rapid decline in effectiveness. Cross-tolerance with other psychedelics, such as LSD, can also occur.
Potential Solutions
- Schedule rest days: Use microdosing schedules such as the “every other day” protocol or the Stamets protocol (for example, dosing for 4 days, followed by a 3-day break) to prevent tolerance.
- Periodic Breaks: Plan longer breaks (for example, 2 to 4 weeks) after a period of regular use. This gives the receptors a chance to recover.
- Monitoring and Adjustment: Keep a close record of your experiences and adjust your dosage or frequency if you notice the effects diminishing.
Finally
Whether you experience little to no effects due to personal, biological, or methodological factors, insight into these complex mechanisms can help optimize your psychedelic experience. By paying attention to the quality of your substances, your individual (genetic) profile, the method of consumption, and a structured dosing schedule, you can better fine-tune what works for you.
Do you have questions or would you like to know more about how to put these solutions into practice? Let us know in the comments or contact us for more information!