Why tretinoin helps minoxidil work: the enzyme behind the combination

When Dr. Adam Lewenberg started adding tretinoin to minoxidil in his Manhattan practice in 1986, the reasoning was practical. Plain minoxidil helped some patients at the crown and did little for others. Tretinoin, the active ingredient in Retin-A, seemed to make the scalp more receptive. He couldn't fully explain why. Researchers have since filled in a large part of the answer.

Minoxidil has to be switched on

Minoxidil as it comes out of the bottle is not the form that grows hair. Inside the hair follicle, an enzyme called sulfotransferase converts it into minoxidil sulfate, the active form. The amount of that enzyme varies a great deal from person to person.

That variation explains a pattern anyone who has used minoxidil has seen. Two people use the same product the same way for a year. One regrows hair and the other sees nothing. In many cases the difference is not effort or product quality. The second person's follicles simply make too little of the enzyme to activate the drug.

Where tretinoin comes in

In 2019, a group of researchers including Andy Goren, Rodney Sinclair and Ralph Trüeb tested whether tretinoin could change that. They measured sulfotransferase activity in plucked hairs from people predicted to be minoxidil non-responders, applied topical tretinoin for five days, and measured again. In their group, 43% of the predicted non-responders became predicted responders. Their conclusion was that tretinoin raises the follicle's own production of the enzyme.

That finding fits with older work. A small 1990 crossover study found that applying tretinoin before minoxidil roughly tripled how much minoxidil the skin absorbed. So tretinoin appears to help in two ways: more minoxidil gets in, and more of what gets in is activated.

What the clinical evidence shows

The first controlled data came in 1986, the same year Dr. Lewenberg developed his formula. Bazzano and colleagues reported in the Journal of the American Academy of Dermatology that a combination of tretinoin and low-strength 0.5% minoxidil produced terminal hair regrowth in 66% of 56 patients after a year.

The picture since then is encouraging but not settled. One randomized trial found the combination performed about the same as minoxidil alone. A 2025 review in Skin Appendage Disorders concluded that the evidence does not yet support tretinoin as a first-line treatment for everyone, but that it is a reasonable add-on, especially for people who have not responded to minoxidil by itself.

What this means if you use minoxidil

• Give minoxidil a fair trial first. Most people need four to six months of consistent use before judging results.
• If it isn't working, ask about tretinoin. It is prescription-only in the US. A dermatologist or licensed telehealth service can decide whether it suits you and at what strength.
• Order matters. Apply tretinoin to a dry scalp, let it dry fully, then apply minoxidil. That was the core of Dr. Lewenberg's method.
• Expect some irritation at first. Redness and flaking are common. Many people start every other night.
• Know the cautions. Because tretinoin raises absorption, it can raise minoxidil side effects too. Don't use tretinoin if you are pregnant, trying to conceive or breastfeeding.

Dr. Lewenberg worked from what he saw in thousands of patients, not from enzyme assays. It is satisfying to see the lab work arrive decades later and point in the same direction.