Brian Johnson Psilocybin Results

Tom_Clark · December 18, 2025, 9:54pm

Bryan Johnson’s post on psilocybin and longevity
Synopsis
Bryan Johnson reports results from a highly instrumented self-experiment exploring whether psilocybin could function as a longevity-relevant intervention. After two high-dose psilocybin sessions spaced three weeks apart, he observed multi-system biomarker changes that he argues are unusual given his already optimized baseline across sleep, nutrition, exercise, sauna, and hyperbaric oxygen therapy.

Johnson emphasizes that the signal was broad rather than isolated, spanning mental state, metabolic control, inflammation, hormonal stress markers, and brain network dynamics. Notably, continuous glucose monitoring showed a marked improvement in glycemic control following dosing, with reductions in mean glucose and variability that temporarily placed him in the extreme low-risk tail of population distributions. He interprets this as a possible “metabolic reset” mediated by brain plasticity, suggesting downstream effects on liver and pancreatic regulation that could, in theory, rival chronic metabolic medications. He notes durability for at least three days post-dose, though longer persistence remains untested.

Inflammatory markers also shifted favorably, with hsCRP falling to near or below detection thresholds after dosing, while stress hormones showed a pattern of acute activation during the psychedelic peak followed by suppressed cortisol and DHEA in the subsequent recovery window, consistent with a prolonged parasympathetic or “after-glow” phase. Estradiol rose substantially, which Johnson links to serotonergic effects on aromatase activity.

Neurophysiologically, brain connectivity data suggested inhibition of default mode networks and increased sensory-motor integration, aligning with subjective reports of increased openness, creativity, emotional range, and reduced cognitive rigidity. A second dose appeared additive, especially in auditory and language network integration, potentially influenced by the more social setting.

Johnson frames these findings cautiously, emphasizing that this is a single-subject experiment requiring replication, with pending analyses on epigenetics, telomere biology, and the microbiome. While he speculates that psilocybin-induced neuroplastic events could have downstream longevity relevance, he stops short of claiming clinical efficacy, positioning the work as hypothesis-generating rather than definitive.

mtc So great results. I remain skeptical, but hope it pans out. We’re evaluating our perceptions of a chemical whose primary effect is altering perception. There’s a bit of circularity there, me thinks…

Tom_Clark · December 18, 2025, 10:13pm

And from a guy who calls himself “Male:E3,Nof1”; I found this interesting:
“Estradiol levels increased by 200%, consistent with preliminary published evidence that peripheral 5HT2A activation increases cortisol by driving aromatase expression.”
I can’t recall why Johnson dumped our dear cousin 17aE2, who I still flirt with, but he seems to have embraced or accepted the Queen Mother, E2, at least peripherally.

DeStrider · December 18, 2025, 11:08pm

Now the question is how long will these improvements last?

LukeMV · December 18, 2025, 11:11pm

I don’t care what anyone says. I love these n=1 experiments he is doing.

A_User · December 19, 2025, 2:52am

Did Bryan? I still saw it on his Blueprint protocol website recently (though I have to admit, it’s hard to browse and see what he’s doing or what he stopped, even acarbose wasn’t listed, and some other therapies he presumably tried).

Tom_Clark · December 19, 2025, 9:39am

I’m fairly certain I heard him say maybe a year ago that he’d stopped using 17aE2. It caught my attention because of my use of E3. As I recall the general reason was that it didn’t improve his markers and slightly decreased some.

Then I also saw he still had it listed and was puzzled. It crossed my mind that he could have made a specific disclaimer to avoid some type of legal liablility. Another possible reason for his verbal (but not actual) disavowal of 17aE2, is that Its hard to get and he might want to appear more elagiltarian.

I just use some of the European 17aE2 hair tonic occasionally. I don’t think it really provides sufficient dosing, but it just kind of my side squeeze…

AI added a third reason for public denial, but private use: “17aE2 is dangerous for normies not because it’s dramatic, but because it’s quiet, psychological, endocrine, sex-specific, and hard to self-police.”

And the elephant in the room: 17aE2 is politically incorrect. A female hormone that helps men but hurts women; won’t go over well with half or more of your audience. Not a way to build a strong coalition.

That said, this isn’t immoral or even especially cynical. I might do the same, a soft verbal de-emphasis paired with a clear, black-and-white listing. It preserves harmony, keeps the movement intact, and still allows Johnson to quietly gather n-of-1 data that may ultimately inform a cleaner, safer 17-alpha analog that actually does help everyone.

He is risking his baseline health and sacrificing time and treasure for the longevity movement, maybe more than anyone else.

Addendum ~ the silence is the signal

There’s a broader question that doesn’t get asked enough: why the near radio silence around E3 and 17α-estradiol, arguably the strongest longevity signals ever produced by the Interventions Testing Program. These aren’t marginal effects ~ they’re fountain-of-youth tier results, especially in males. You’d think the world would be on fire talking about them.

Instead, it’s mostly quiet.

The old joke is “you know you’re over the target when you start taking flak.” In biotech and longevity, the inverse often applies: when something is truly valuable, competitive, and hard to translate safely, you get silence, not noise. Nobody wants to tip their hand. Nobody wants competition. Nobody wants regulatory attention before they’ve locked down IP, analogs, dosing, delivery, and sex-specific risk.

From that perspective, the collective shrug in public may actually be the strongest signal of all.

I’m interested in this for exactly that reason, and I suspect Bryan Johnson is too ~ just with a vastly larger audience and far more constraints. Working quietly, saying little, testing carefully. If dozens of serious longevity companies aren’t already grinding away on improved E3 and 17-alpha analogs, that would be the real surprise. The upside is too large to ignore, and both pathways point in the same direction with unusual strength, particularly for males.

Sometimes the absence of chatter isn’t dismissal. It’s incubation.

One more uncomfortable personal truth

I’ll add a personal confession to make this real. Early on, when I first started exploring E3, I deliberately did not reveal some of my shakier or harder-to-source sellers. Not out of secrecy-for-secrecy’s sake, but simple self-interest. I didn’t want limited sources to run dry before I had fully bought out and stockpiled what I needed for several years (4.5 yrs at current rate). That experience cured me forever of the idea that silence means disinterest.

Strategic radio silence is real, and it operates at every level ~ individual, company, and ecosystem. When something is genuinely scarce, valuable, and not yet safely democratized, the rational response is often to work quietly and say very little.

Tom_Clark · December 19, 2025, 9:57am

He’s got some strong cold hard numbers:
Glucose control: Mean blood glucose ↓ ~8%, variability ↓ ~11%, estimated HbA1c from 4.7% to 4.4% (~6.8% relative reduction), briefly placing him in the top ~0.2% of the population.

• Inflammation: hsCRP dropped below detectable levels after the first dose (~35–100% reduction), with a sustained ~22% reduction after the second dose.

• Stress hormones: Morning cortisol ↓ ~42% and DHEA-S ↓ ~45% several days post-dose, following an acute cortisol spike during the experience.

• Brain networks: Suppression of default mode networks with increased sensory-motor, auditory, and language network integration, consistent with increased plasticity and reduced cognitive rigidity.

• Psychological state: Increased openness, creativity, playfulness, emotional range, and subjective insight, with reduced mental rigidity.

• Thermal physiology: Core temperature ↑ ~1.5–2°F during peak experience, with redistribution of heat toward the core, interpreted as serotonergic autonomic activation.

Bryan explicitly acknowledges key confounding factors, including n=1 self-experimentation, lack of controls, expectation and placebo effects, altered perception and salience under psilocybin, short observation windows, unclear durability, mechanistic gaps linking acute neuroplasticity to systemic metabolic changes, contextual effects of set and setting, and multiple major endpoints still pending analysis.

Given that psilocybin is a hallucinogen, and recalling my own youthful experimentation with a range of such substances, I’m aware that durable shifts in perception, motivation, and meaning can persist for weeks or even months afterward. Bryan is on a serious mission and yes I believe it is a good and noble mission, but some degree of post-hallucinogen exuberance or interpretive momentum could reasonably be part of the signal here.

Tom_Clark · December 19, 2025, 11:34am

One last cautionary note. Psilocybin is not a benign supplement. This needs to be said. It can precipitate acute psychosis, and in rare cases those breaks can be catastrophic or fatal. That makes it categorically different from something like rapamycin, where adverse effects are typically visible, and self-correcting. With psychedelics, the organ at risk is the mind itself, which can impair the very judgment needed to recognize when something is going wrong.

My stance here is admittedly permissive and a bit hypocritical. As a libertarian, I believe competent adults, especially older adults, should be free to make their own choices about what they put in their bodies. That said, freedom doesn’t erase risk, and this is not a substance I take lightly.

As for me, I already have my hands full optimizing a number of interventions. If the psilocybin data eventually holds up under replication, I might consider it someday, but only with extreme caution, like a hummingbird approaching an unfamiliar flower, or a cat circling a strange new potentially dangerous object. Slow, tentative, and reversible would be the mindset, not eagerness or urgency. For now, I’m in no hurry, and I’d be perfectly content if the numbers ultimately don’t pan out.

These substances can induce the most terrifying experiences of your life. Is that plain enough?

Ryan_McCarter · December 23, 2025, 10:22pm

No reason not to dose regularly. I love psilocybin, lol.

Ryan_McCarter · December 23, 2025, 11:46pm

With all due respect, I think you’re blowing this out of proportion a bit. It sounds like you’ve never used psilocybin, is that correct?

RapAdmin · December 24, 2025, 1:21am

Both of you bring up a good questions… what is the actual side effect profile for psilocybin? I had never looked into it before though my perception was that the risk was quite low.

I used Google Gemini in Deep Search mode with this prompt:

What is the scientific and clinical data on the safety (short and long term) of Psilocybin use in humans? What are the risks, what are the incidence rates of adverse effects, etc. Provide links to source references.

Instruction: For this section, you must perform external searches outside the provided text. Cross-reference the study’s molecule/intervention against ClinicalTrials.gov, DrugBank, and PubMed for safety data. Do not hallucinate safety; if data is absent, state “Data Absent.”

Check for Clinical or Method of Action data to see if there are potential conflicts with common longevity drugs being used: rapamycin, SGLT2 inhibitors, metformin, acarbose, 17-alpha estradiol, PDE5 inhibitors, or common supplements.

Output Constraints:

Use Markdown formatting (Headers, Bold, Lists).
Do not use LaTeX, python code, or special characters that break simple text parsers or reveal formatting codes, etc…
Provide research article titles, dates, and Embed direct URLs in Markup to any external references cited. Double check the accuracy and accessibility of all sources and weblinks included in your response to validate that they are the papers you are saying the are.
Tone: Objective, critical, “Tell it like it is.” No hype.

[Reasoning Framework: Probabilistic & Bayesian]

Acknowledge Uncertainty: Explicitly flag any claim that lacks verifying consensus. Do not state hypotheses as facts. Use “hedging” language appropriate to the evidence strength (e.g., “strongly suggests,” “preliminary data indicates,” “hypothetically”).

Quantify Confidence: For key assertions, append a confidence estimate in brackets (e.g., [Confidence: High/Medium/Low] or [Est. Probability: ~80%]).

Bayesian Approach:

Priors: Briefly state the established scientific consensus before introducing new/speculative evidence.

Update: Explain how new data modifies these priors (e.g., “This study increases the likelihood of X, but does not prove it”).

Alternative Hypotheses: Always list at least one plausible alternative explanation or confounding factor (e.g., “Reverse causality,” “Selection bias”).

Evidence Hierarchy: Distinguish between mechanism (in vitro/murine) and outcome (human clinical data). Discount mechanistic speculation if human outcome data is absent.

Google Gemini response

Full response here: https://gemini.google.com/share/46ef5a4986db

Some key parts of the response:

Adverse Event	Incidence (Est.)	Severity	Onset	Mechanism
Elevated BP/HR	> 50%	Mild-Moderate	Acute (Peak)	Sympathomimetic / NE Release
Headache	20 - 40%	Mild-Moderate	Delayed (Offset)	Rebound Vasodilation / NO
Nausea	15 - 30%	Mild	Acute (Onset)	5-HT3 Agonism (Gut/CTZ)
Anxiety/Fear	10 - 30%	Variable	Acute	Amygdala Reactivity / Dissolution
Fatigue	Common	Mild	Post-Acute	Metabolic Exhaustion
Suicidal Ideation	~3-5% (TRD only)	Severe	Sub-acute (1-3 wks)	Behavioral Activation
Psychosis (Persistent)	< 0.1%	Severe	Chronic	Latent Schizophrenia Activation
Death	0%	N/A	N/A	N/A

“You state ‘No Deaths,’ but what is the incidence of ‘Psychiatric Scarring’—persistent destabilization or existential distress that doesn’t meet the threshold of an SAE but degrades Quality of Life?”

Answer: This is likely underreported. Clinical trials use binary endpoints (SAE vs. non-SAE). They rarely capture “ontological shock” or the destabilization of one’s worldview that can persist for months. While not “toxic” in a cell-death sense, this existential distress can lead to functional impairment, strained relationships, and anxiety—a “Quality of Life” decrement that observational data suggests is more common than the clinical trial literature admits.

Table 2: Longevity Drug Interaction Summary

Drug Class	Specific Agent	Interaction Mechanism	Risk Level	Clinical Consequence
mTOR Inhibitor	Rapamycin	Direct mTOR inhibition	CRITICAL	Blocks neuroplasticity/therapeutic effect.
SGLT2 Inhibitor	Canagliflozin	UGT1A9 / UGT1A10 Inhibition	HIGH	Potentiates toxicity (High Cmax/AUC).
Biguanide	Metformin	AMPK activation inhibits mTOR	MODERATE	May blunt neuroplastic response.
Estrogen	17-beta Estradiol	UGT1A9 Inhibition	MODERATE	Increased psilocin exposure.
Estrogen	17-alpha Estradiol	Weak UGT1A9 interactions	LOW	Likely minimal PK alteration.
PDE5 Inhibitor	Tadalafil	Hemodynamic opposition	LOW-MED	Risk of orthostasis/tachycardia.
Alpha-Glucosidase	Acarbose	Gut-restricted	NEGLIGIBLE	Safe.

Conclusions and Recommendations

The synthesis of the available scientific and clinical data leads to a clear conclusion: Psilocybin is not a “free lunch” in longevity medicine.

While the physiological toxicity (organ damage) is low in healthy, unmedicated adults, the interaction toxicity and functional antagonism with common longevity protocols are significant. The “Longevity Paradox” is that the very drugs used to extend life (Rapamycin, Metformin, SGLT2 inhibitors) fundamentally conflict with the mechanisms required for psilocybin’s neural benefits.

Recommendations for the Longevity Specialist:

The Rapamycin Washout: Patients must discontinue Rapamycin for at least 5 half-lives (approx. 2 weeks) prior to psilocybin therapy to unblock the mTOR pathway and permit neuroplasticity.
The SGLT2 Stop: Canagliflozin/Dapagliflozin must be held for 3-4 days pre-session to prevent UGT1A9 inhibition and potential psilocin toxicity.
Vascular Screening: Patients over 50 should undergo carotid ultrasound and echocardiography (to rule out valve pathology) prior to engaging in either macrodosing or chronic microdosing.
Microdosing Caution: Chronic microdosing should be viewed with extreme skepticism due to the 5-HT2B valvulopathy risk; intermittent “pulsed” macrodosing appears safer for the heart.
Genotype Awareness: Consider UGT1A9 status when determining starting doses.

Confidence Statement: The acute safety profile is established with High Confidence. The drug interaction risks are established with High Mechanistic Confidence but require clinical validation. The long-term valvulopathy risk is Medium Confidence based on receptor affinity priors.