Rapamycin (Sirolimus) Mental Health and Mood Impact: What the Evidence Shows

What the human data on rapamycin and mood actually show

The clearest human signal comes from the PEARL trial, published in Aging in 2025: a 48-week, decentralized, double-blind, placebo-controlled trial in healthy, normative-aging adults [1]. Participants took placebo, 5 mg or 10 mg of compounded rapamycin once weekly. Self-reported emotional well-being improved in the 5 mg group (partial eta-squared 0.108, p=0.023), as did self-reported general health (0.166, p=0.004) [1]. Lean tissue mass and self-reported pain improved in women taking 10 mg. No other significant effects were found [1].

Adverse and serious adverse events were similar across all three groups, and blood biomarkers stayed within normal ranges [1]. The authors concluded that low-dose intermittent rapamycin was relatively safe over 48 weeks and that efficacy was not established; the trial had no lifespan outcome [1].

Two limits matter when reading the mood result. The trial tested compounded rapamycin, and compounded drugs are not FDA-approved — the FDA does not verify their safety, effectiveness or quality before they are marketed [3]. And a secondary survey score in a healthy volunteer cohort is not a test of rapamycin as a depression treatment.

The primary endpoint was body fat, not mood

PEARL's primary outcome was visceral adiposity measured by DXA scan, which did not change significantly (p=0.942) [1]. Well-being and general health came from established surveys used as secondary measures. A separate 2014 immune-function study in older adults measured antibody response to influenza vaccine, and it used everolimus (RAD001), a different drug from sirolimus [5].

Cognition: what has been measured in people

One small randomized pilot is the main human cognitive dataset. Kraig and colleagues randomized 25 generally healthy adults aged 70 to 95 to rapamycin 1 mg daily or placebo; 11 in the rapamycin group and 14 in the placebo group completed at least 8 weeks [4]. The study monitored standard clinical laboratory tests, oral glucose tolerance tests, physical performance, and cognitive function with three tools — the Executive Interview-25, the Saint Louis University Mental Status Exam and the Texas Assessment of Processing Speed [4]. Reported side effects in the rapamycin group were facial rash (1), stomatitis (1) and gastrointestinal issues (2), and the rapamycin group had statistically significant decreases in hemoglobin, hematocrit, red cell count and red cell indices (RDW, MCV, MCH) [4].

In rats, rapamycin reduced late-phase long-term potentiation in hippocampal slices — the protein-synthesis-dependent form of synaptic strengthening — while the early phase was unaffected, and it blocked BDNF-induced synaptic potentiation [6]. That is laboratory work on brain tissue, not evidence of a cognitive effect in people taking weekly low doses.

What the label says, and does not say, about psychiatric effects

The Rapamune label's most common adverse reactions (30% or more) in renal transplant prophylaxis are peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, increased creatinine, constipation, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain and thrombocytopenia [2]. In the LAM study, the 20%-or-more list is stomatitis, diarrhea, abdominal pain, nausea, nasopharyngitis, acne, chest pain, peripheral edema, upper respiratory tract infection, headache, dizziness, myalgia and hypercholesterolemia [2]. Depression and anxiety appear on neither list. Those rates come from transplant and LAM dosing, not the once-weekly doses used in longevity trials [2].

The label's warnings and precautions cover immunosuppression and malignancy, hypersensitivity and angioedema, fluid accumulation and wound healing, hyperlipidemia, decline in renal function, proteinuria, interstitial lung disease, calcineurin-inhibitor-associated HUS/TTP/TMA, embryo-fetal toxicity, male infertility and live vaccines [2]. None of those items is a psychiatric warning.

Drugs that change sirolimus blood levels

Sirolimus is a substrate of both CYP3A4 and P-glycoprotein [2]. The Rapamune label identifies ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin and clarithromycin as strong inhibitors, and rifampin and rifabutin as strong inducers, and says to avoid concomitant use with them [2]. St. John's wort is on the label's list of agents that could decrease sirolimus concentrations [2]. Cannabidiol can raise sirolimus blood levels, and the label advises monitoring and a possible Rapamune dose reduction [2]. The label states that grapefruit juice must not be taken with Rapamune or used to dilute it [2].