Rapamycin Dosage Guide: Protocols, Calculator & Safety

Rapamycin stacks with multiple other longevity interventions, with specific combinations ranging from well-motivated to counterproductive.

Well-motivated combinations:

• Metformin: complementary mechanisms (metformin activates AMPK, rapamycin inhibits mTOR; both converge on caloric restriction mimicry). Many longevity-practitioners (Attia, Barzilai) use metformin for diabetic/prediabetic patients and rapamycin for broader longevity; combination in non-diabetic patients is more debated but mechanistically coherent. The Konopka et al. 2019 finding that metformin blunts exercise adaptationmay apply more weakly to rapamycin, though direct comparison data are limited.
• NMN or NAD precursors: rapamycin suppresses protein synthesis and could theoretically reduce NAD+ biosynthesis; NAD+ precursors address this pathway directly. The combination is common in integrated longevity protocols.
• Exercise (especially resistance training): rapamycin's anti-anabolic effect on muscle is a theoretical concern for resistance-trained individuals. The practical workaround: time the weekly rapamycin dose away from resistance-training days (typical strategy: dose on a rest day or lowest-intensity day, train hardest 3-5 days after dose). Aerobic exercise does not appear meaningfully affected by weekly pulsed rapamycin.
• Adequate protein intake: counterintuitive but important — rapamycin suppresses mTORC1 and protein synthesis, but adequate dietary protein remains essential for maintaining muscle mass. Protein intake of 1.2-1.6 g/kg/day (higher for older adults) is appropriate during rapamycin use.
• Omega-3 fatty acids: counteract rapamycin's modest hyperlipidemic effect; 2-4 g/day EPA+DHA is a reasonable adjunct.
• Vitamin D repletion: vitamin D deficiency is common and has independent effects on immune function; supplementing to 25(OH)D 40-60 ng/mL is appropriate.
• Berberine: AMPK activator with metformin-like effects; reasonable alternative to metformin for longevity combination stacks.
• Magnesium: general repletion supports multiple longevity pathways and is often deficient.
• Caloric restriction or time-restricted eating: rapamycin pharmacologically mimics caloric restriction; additive effects with dietary restriction are mechanism-supported but not rigorously tested in humans. The combination may produce stronger effects than either alone but also stronger muscle-preservation concerns.
• Senolytic interventions (dasatinib + quercetin, fisetin): rapamycin is senomorphic (modulates senescent cell behavior) while senolytics eliminate senescent cells; the combination addresses both aspects of cellular senescence biology.

Potentially problematic combinations:

• Resistance training for muscle hypertrophy: rapamycin blunts mTORC1-mediated muscle protein synthesis. For individuals with active muscle-gain goals, dose scheduling matters substantially. Some longevity practitioners recommend holding rapamycin during focused hypertrophy phases and resuming during general maintenance.
• Surgical procedures: impaired wound healing. Hold rapamycin for 2-4 weeks before elective surgery and until adequate wound healing after.
• Acute infections: some practitioners hold rapamycin during acute illness to support immune response; others continue given Mannick data. Emerging consensus is to hold during significant acute infections.
• Pregnancy planning or pregnancy: rapamycin is contraindicated; effective contraception is required.
• Live vaccines: discuss with prescribing physician; typically held around live vaccine administration.
• High-dose antioxidants during training: same "blunting hormetic adaptation" concern as with NAC and vitamin C; less relevant for general health than for athletic performance optimization.

Counterproductive combinations:

• Grapefruit / grapefruit juice: absolutely avoid. Elevates rapamycin levels dramatically.
• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin): avoid unless specifically managed with dose adjustment.
• Strong CYP3A4 inducers (rifampin, St. John's Wort, carbamazepine): reduce rapamycin efficacy; avoid during rapamycin use.
• Live vaccines without clinical oversight: defer and coordinate with prescribing physician.

Dosing-timing integration with other interventions:

The weekly pulsed rapamycin dose creates a roughly 72-hour window of peak mTORC1 inhibition (typically hours 24-96 after dosing), with progressive decline thereafter. Practical integration strategies:

• Dose weekly on the same day (most users choose Monday or a rest day)
• Lightest workouts in the 24-72 hours post-dose; harder training in days 4-7
• Fasting or time-restricted eating during days 1-3 post-dose to amplify autophagy effects (common strategy, not rigorously trial-tested)
• Most protein-demanding nutrition on days 5-7 (when mTORC1 inhibition is lower)
• Major social/travel events scheduled in the later half of the weekly cycle if stomatitis is a concern

Synergistic longevity protocols:

The Attia-style longevity protocol combines rapamycin (weekly) with metformin (daily for appropriate patients), statins (where indicated), low-dose aspirin (where risk-benefit supports), high-dose EPA/DHA (2-4 g/day), vitamin D repletion, Mg repletion, B-complex adequacy, NAD+ precursors (NMN or NR), regular resistance training, Zone 2 cardio, adequate sleep, and time-restricted eating. The specific combinations vary by patient but rapamycin is typically positioned as the most mechanistically-supported pharmacological component alongside comprehensive lifestyle optimization.

The Blagosklonny framework emphasizes rapamycin as the centerpiece based on his hyperfunction theory of aging (age-related disease reflects persistent growth-signaling, and mTOR inhibition addresses the root cause). This theoretical framework provides a strong rationale for rapamycin as the primary intervention even without detailed combination protocols.

Dosing ranges by protocol type:

• Beginner longevity: 3-5 mg weekly
• Intermediate longevity: 5-8 mg weekly
• Advanced longevity: 6-10 mg weekly, some protocols up to biweekly 10-15 mg
• Transplant-dose (for reference, not longevity): continuous daily dosing 2-5 mg/day with trough levels 5-15 ng/mL
• TSC/LAM (for reference, approved indications): variable, target trough 5-15 ng/mL
• PEARL trial dose range: 5-10 mg weekly

Formulations:

• Rapamune tablets: branded sirolimus, 0.5 mg, 1 mg, 2 mg tablets; pharmaceutical-grade
• Generic sirolimus tablets: same as Rapamune, typically 0.5-2 mg tablets; widely available at standard pharmacies
• Rapamune oral solution: 1 mg/mL liquid formulation; faster absorption, used in transplant settings; allows fine dose titration
• Compounded formulations: available from specialty pharmacies; variable quality
• Not recommended: research-chemical-market rapamycin; no guarantee of pharmaceutical grade or accurate labeling

Timing:

• Consistent weekly day: most protocols emphasize same day each week
• Food: may be taken with or without food; fatty meals slow absorption slightly but don't substantially change total exposure
• Time of day: typically evening dosing to minimize daytime side effects; some protocols use morning dosing
• Relative to training: typically dose on rest days or lowest-intensity training days; avoid resistance training for 24-48 hours post-dose if hypertrophy goals

Storage:

• Tablets: room temperature in original packaging; stable for years per labeling
• Oral solution: refrigerate; stable 30 days after opening per labeling
• Keep away from children: standard medication safety
• Travel: tablets stable without refrigeration; oral solution requires cool-chain

Bioavailability:

• Tablets ~15% bioavailable; oral solution ~25% bioavailable
• High inter-individual variability
• Grapefruit dramatically increases bioavailability (DO NOT USE)
• Co-administration with ketoconazole, clarithromycin increases bioavailability (avoid)

Cost:

• Generic sirolimus 1 mg tablets: typically $1-3 per tablet at retail pharmacy; $50-150/month for 5-8 mg weekly depending on pharmacy and insurance status
• Compounding pharmacy: variable, sometimes more expensive
• Out-of-pocket for off-label use is the norm

Dosing adjustment principles:

• If CBC shows significant thrombocytopenia (<150K platelets) or neutropenia: reduce dose or hold
• If LDL or triglycerides markedly elevated: add lipid-lowering therapy or reduce dose
• If HbA1c drifts up >0.3%: assess glycemic control, consider dose reduction
• If stomatitis severe: temporarily reduce dose or hold briefly
• If any pulmonary symptoms: evaluate immediately, consider discontinuation

Whole-blood trough level monitoring (optional for longevity dosing):

• Draw 24 hours after weekly dose (just before next dose)
• Target range varies by protocol; typically 1-3 ng/mL for longevity dosing
• Above 5 ng/mL at trough suggests over-dosing for longevity purposes
• Levels used for fine-tuning rather than primary dosing decisions