What are the side effects of low-dose rapamycin? No more than a placebo

Side effects of low-dose rapamycin have been tracked over a full year once. That trial gave healthy, normally ageing adults either a placebo - a dummy capsule containing no drug - or 5 mg or 10 mg of rapamycin once a week for 48 weeks, and unwanted effects, including serious ones, came up about as often in the rapamycin groups as in the placebo group [6]. Blood test results stayed inside normal ranges in all three groups [6].

Two further trials, neither with a placebo group, point the same way. Eighty-six people with chronic fatigue syndrome took 6 mg a week for up to 90 days with no serious side effects recorded [2]. Sixteen people with sarcoidosis, an inflammatory condition that leaves lumps in the skin, took a daily dose for four months - a much heavier exposure than weekly - and the researchers reported no serious side effects and no deaths [7].

The familiar catalogue of rapamycin side effects comes from different patients taking much more of it. Among 106 kidney transplant recipients taking it daily to stop the body rejecting the new organ, 44% came off the drug, usually because of its side effects [14]. Reviews of transplant care name protein leaking into the urine, a sign of kidney strain, and high drop-out rates as recurring problems with this family of drugs [12].

Cancer doses are heavier again, and that is where the specific problems are counted. In a trial of 410 patients taking either 10 mg daily of everolimus, a close chemical relative of rapamycin, or a placebo, mouth ulcers affected 64% on the drug against 17% on placebo, rash 49% against 10%, diarrhoea 34% against 10%, tiredness 31% against 14%, and infections 23% against 6% [3]. Most were mild or moderate; blood sugar high enough to count as severe hit 5% on the drug and 2% on placebo [3].

The immune suppression that makes rapamycin useful after a transplant [12] is what people taking it weekly tend to ask about. None of the low-dose trials reported more infections, and none of them were big enough to settle it [6][2][7].

Rapamycin blocks mTOR, a protein switch inside cells that reads how much food and growth signal is around; switched on, it tells the cell to build and divide and holds back autophagy, the cell's own recycling system for clearing out damaged parts [2][8].

Blocking that switch is useful in several directions at once, which is why the same molecule is both a transplant drug and a cancer drug, and is now being tried for ageing. Immune cells need mTOR to multiply and attack a transplanted organ, so damping it protects the new kidney [12]. Tumours and the benign growths of a genetic condition called tuberous sclerosis lean on the same switch, and drugs in this family are licensed to treat several of them [8].

Dose and timing separate those uses from the longevity one. Transplant and cancer patients take rapamycin or its relatives every day, aiming at a steady level in the blood [3][7][12]. The longevity trials gave it once a week, leaving long gaps in which the drug clears, and that is the schedule under which side effects stayed level with placebo [6][2].

Sugar handling is the mechanism-level worry. Blocking mTOR interferes with the way the body manages blood glucose, and a year of daily rapamycin gave male mice outright diabetes [15].

The year-long trial was not built as a safety trial. Its main measurement was visceral fat, the fat packed around the organs, read off a body scan, with side effects and blood tests followed alongside [6]. A study that size can show that common problems are not appearing; it cannot rule out a rare serious one, and 48 weeks is the whole of the controlled human record for weekly dosing.

The two supporting trials are weaker. The chronic fatigue study had no comparison group at all, so its side effects had nothing to be measured against, and of the 86 people who started, 70 reached the first monthly check [2]. The sarcoidosis trial followed sixteen people, all but one of them White, at a single hospital [7].

This evidence does not carry over to:

• anyone taking rapamycin daily rather than weekly, where the burden is plainly higher [12][14]
• transplant recipients and cancer patients, whose doses, illnesses and other medicines all differ [3][12][14]
• pregnant women, children and teenagers, who appear in none of these trials
• people already taking drugs that suppress the immune system

The diabetes finding is in mice, not people, and it took a year of daily treatment in males. Female mice developed milder glucose problems rather than diabetes, and oestrogen appeared to protect them [15].

Rapamycin is prescription-only and approved for transplant and certain tumours, not for ageing [8]. Starting it, stopping it or changing the dose is a decision for a doctor who knows the person's history.

Rapamycin therapy appears on the service menus of longevity clinics in the directory, and unlike a scan or a sauna it needs a prescriber rather than a technician. A first visit is a medical consultation - history, current medicines, baseline blood tests - because blood markers are what the trials watched for change [6]. Anyone weighing it up is weighing a 48-week safety record in healthy adults [6] against a longer, heavier one in patients taking far more of the drug every day [3][12][14]. Dose and schedule are what separate the two: once a week in the healthy-adult trial [6], every day in the transplant and cancer studies [3][12].