Topical minoxidil is a prodrug that your scalp has to switch on with an enzyme called SULT1A1. How much you have is one of the best predictors of whether topical minoxidil grows your hair, and why oral often works when topical hasn't.
Minoxidil is the most widely used hair-loss treatment in the world. It is also the one people most often quietly give up on. They rub it in twice a day for six months, see nothing, and conclude their hair loss is just untreatable.
In a large share of those cases, the drug was never the problem. The problem was an enzyme. Topical minoxidil only works if your scalp can switch it on, and not every scalp can. The enzyme that does the switching is called SULT1A1.
The short answer: Minoxidil is a prodrug. It is inert until an enzyme in your scalp, SULT1A1, converts it into its active form, minoxidil sulfate. People vary a lot in how much of this enzyme their scalp has, and low activity tracks closely with not responding to topical minoxidil. That is a major reason two people on the identical 5% bottle get completely different results. Oral minoxidil often works when topical hasn't, though the reason is not the tidy "your liver activates it" story people repeat, and it should be used under medical supervision.
The minoxidil you apply is largely inactive at the follicle. The molecule that actually drives hair growth is its sulfated metabolite, minoxidil sulfate. To get from one to the other, your body has to add a sulfate group, a reaction carried out by the sulfotransferase enzyme SULT1A1. No conversion, no active drug, no growth signal.
When you apply minoxidil topically, you are relying on the SULT1A1 sitting in your scalp, specifically in the hair follicle, to do that conversion locally. The drug reaches the follicle at full strength either way. Whether it gets turned on once it arrives depends on how much enzyme your scalp happens to have. That single fact reframes the whole "minoxidil only works for some people" reputation: topical minoxidil is the only major hair-loss drug that is a prodrug requiring local activation at the target tissue.
The enzyme. The clearest demonstration came from Goren and colleagues (2013 and 2014). They plucked individual hairs from patients and ran a roughly $30 chemistry assay on each hair root, measuring how much SULT1A1 activity was present.
In their cohorts, the test tracked with topical minoxidil response at high reported accuracy: low scalp enzyme with non-response, high scalp enzyme with response. Treat that number as suggestive rather than settled. It is a colorimetric enzyme-activity assay from a single group, it measures activity rather than minoxidil sulfate directly, and it has not been independently validated at that accuracy. The insight that survives either way is the important one: scalp activation capacity, not the dose, is a major reason topical works for some people and not others.
That finding does something to the famous "minoxidil works for about 40% of users" line. It suggests the 40% is not a soft average where everyone gets a little benefit. It looks closer to binary: a group of strong responders whose scalps convert the drug, and a larger group of non-converters for whom standard topical doses do very little, no matter how diligently they apply it.
| Strong responder | Non-converter | |
|---|---|---|
| Scalp SULT1A1 activity | High | Low |
| Conversion of minoxidil to minoxidil sulfate at the follicle | Efficient | Limited |
| Likely result from standard topical minoxidil | Visible response | Little to no response |
| Roughly | ~40% of users | ~60% of users |
The practical takeaway is uncomfortable but useful: if topical minoxidil has done nothing for you after a fair trial, the most likely explanation is not that your hair loss is hopeless. It is that your scalp may not be converting the drug.
SULT1A1 expression varies from person to person, and there is evidence it even varies by body region within the same person. Pirmez (2019) offers a telling clue. When a very low 0.25 mg dose of oral minoxidil was given to men, the scalp barely responded, yet 52% of the men reported their beards thickened. Either beard follicles are simply more sensitive to minoxidil, or the enzyme that activates it is expressed at different levels in different regions of the body. Either reading points back to the same theme: local activation capacity, not the drug itself, is the bottleneck.
This is why two people with the same hairline, the same age, and the same 5% bottle can get completely different results. They are not running the same experiment. One scalp is switching the drug on and the other is not.
Here is where the story gets useful, and also where the popular version gets ahead of the evidence. The intuitive explanation is that your liver does the sulfation for you, so oral minoxidil arrives at the follicle already switched on. The newer pharmacology says that is probably not how it works. The liver mainly attaches a glucuronide to minoxidil, not a sulfate (Gottlieb 1972), so it does not produce much minoxidil sulfate. And minoxidil sulfate is a charged, unstable molecule that does not cross from the bloodstream into the follicle easily; it has not been reliably measured circulating in human blood.
So oral minoxidil most likely still has to be activated at the follicle, the same step as topical. Why it so often works when topical has not is genuinely unresolved: it may deliver more parent drug, more steadily, or reach the follicle by a route topical cannot. What is not established is the tidy "the liver switches it on and ships the active drug" story. What is solid is the clinical record.
Sinclair (2018) built the modern low-dose oral protocol, and later work compared the routes directly. Ramos (2020) ran a head-to-head in 52 women over 24 weeks: 1 mg oral minoxidil versus 5% topical solution. Hair density slightly favored oral (about +12% versus +7.2%, statistically a tie), but the difference that mattered was shedding. Oral significantly reduced shedding on the Sinclair shedding score while topical did not, and shedding is the endpoint that most determines whether people stick with treatment past the three-month mark.
Standard oral minoxidil is absorbed quickly and cleared quickly, which produces a spike-and-trough curve: a sharp peak, then a fall-off. The idea behind smoother-release oral minoxidil is to smooth that curve. Instead of a single spike, the goal is a steadier, lower level of minoxidil through the day at the same total dose, rather than a large bolus all at once. That is a formulation design goal about the shape of exposure, not a claim that it activates the drug any differently, and not a promise of superior regrowth versus immediate-release dosing.
On safety, low-dose oral minoxidil is well documented. In the largest safety study to date (Vano-Galvan 2021, 1,404 patients), there were zero cases of pericardial effusion and zero life-threatening events at the 0.25 to 5 mg doses used for hair, a sharp contrast to the 10 to 40 mg antihypertensive doses that gave oral minoxidil its old reputation. Oral minoxidil should be used under medical supervision.
The plucked-hair SULT1A1 test from the Goren work exists, costs about $30, and tracks with topical response. Almost no clinic actually runs it, and given the assay caveats above, it is best treated as one input rather than a verdict.
You do not necessarily need the lab result to act on the insight, though. The logic is straightforward: if topical-only minoxidil has produced no meaningful change after a genuine multi-month trial, a non-converting scalp is a leading explanation; oral minoxidil, under medical supervision, is the most common way people get around it; and a clinician can discuss the SULT1A1 test if you want more information before committing to a topical-only plan.
If you are wondering which everyday drugs and supplements compete for that same enzyme, we cover it in what blocks SULT1A1. And to understand what minoxidil does once it is switched on, see how minoxidil actually works at the follicle. Not sure where you fall? Take the hair quiz or see treatment options.
Minoxidil is a prodrug that your scalp has to activate with an enzyme called SULT1A1. People vary a lot in how much of this enzyme their scalp has, and low activity tracks closely with not responding to topical minoxidil (Goren 2014). So the main variable is your scalp's activation capacity, not the dose or your diligence.
SULT1A1 is a sulfotransferase enzyme in the hair follicle that converts inactive minoxidil into its active form, minoxidil sulfate, by attaching a sulfate group. Without that conversion, applied minoxidil reaches the follicle but is never switched on, which is why scalp SULT1A1 activity predicts topical minoxidil response.
It often does, and it is a common next step under medical supervision. The old explanation, that the liver activates minoxidil so oral bypasses a low-enzyme scalp, is not well supported, because the liver mostly glucuronidates minoxidil and minoxidil sulfate does not travel well to the follicle. Why oral rescues is still an open question, but the clinical benefit is real.
It is one input, not a verdict. The plucked-hair test costs about $30 and tracks with topical response, but it is a single-group colorimetric activity assay not independently validated at its reported accuracy, and few clinics run it. You can act on the same insight without it: if topical has done nothing after a fair trial, low scalp activation is a leading explanation.
Only modestly, if at all. SULT1A1 is largely non-inducible and mostly set by genetics. The only lever with any human-scalp data is topical tretinoin, and even that is a weak, single-group signal measured as enzyme activity rather than hair. No supplement or food has been shown to meaningfully raise it.
This article is for educational purposes only and is not medical advice. Oral minoxidil is used off-label for hair loss and should be undertaken only under the supervision of a licensed clinician; topical minoxidil is FDA-approved for that use. Always consult a qualified healthcare provider before starting any new treatment.