Miraculous New Treatment for Hair Loss in Men and Women?

Off-label use of a risky blood pressure drug called minoxidil is growing.

Hair loss is a potentially troubling issue I encounter frequently in the office. It can be devastating, especially for young people and women. Some people can shrug it off, but for others it can degrade self-esteem, body image and self-confidence. Anxiety and depression may increase. If you are married to Will Smith, and another comedian takes a cheap shot at your alopecia, you might even find yourself witnessing an enraged slap unleashed supposedly on your behalf - emotions tied to our appearance can run quite deeply. But besides taking a history, checking some labs, and making the usual recommendations, I am often left wishing I could do more. People want reasons, and treatments.

I read an article in The New York Times recently about a small number of dermatologists repurposing an old, problematic blood pressure medication called minoxidil for the treatment of hair loss. One dermatologist boasts of having treated over 10,000 patients with it already, despite the fact that such use is considered “off-label.” There is no FDA-approved version of minoxidil specifically for hair loss, but clinical experience with using small doses has been accumulating. When taken at a low oral dose, apparently minoxidil works quite well, without many of the feared side effects of higher doses. But as with off-label administration of any medicine, both patients and doctors are taking some chances.

Minoxidil is a medication that causes dilation of arterial blood vessels. It is prescribed in very limited circumstances to patients with difficult to control high blood pressure. It has a lot of potential side effects. I have rarely prescribed oral minoxidil, although I have recommended it as a decent topical treatment for hair loss many times. It’s the active ingredient in Rogaine, and other generic topical versions.

And so here are some thoughts I have as a primary care doctor anticipating that someone will ask me to prescribe oral minoxidil soon. After reading this NYT article, I think the author might have added a dash too much hype and anecdotes to her story, when perhaps she could have presented more of the clinical evidence that is out there. She is correct that no really high quality, prospective clinical trials will be done anytime soon - as oral minoxidil is generic already, and the economics would be disastrous for any corporation. No pharma company would complete a clinical trial, assessing safety and efficacy for treating hair loss, submit their findings to the FDA for official approval, and only then realize their product is still available as a generic for 25 cents a pill.

~What is alopecia?

Alopecia is an umbrella term for hair loss, and there are many different types. The most common cause of hair loss is androgenetic alopecia, known as male- or female-pattern baldness. There is also telogen effluvium, which can occur 2-3 months after a mentally or physically stressful time. Traction alopecia is hair loss that occurs when hair is pulled back too hard and for too long in certain hair styles. Alopecia areata stems from a more autoimmune process wherein the body attacks its own hair follicles, leaving smooth and oval bald patches on the head. More rare are the scarring alopecias, like frontal fibrosing alopecia and central centrifugal cicatricial alopecia.

~The usual treatments for hair loss

Male androgenetic alopecia (also known as male pattern hair loss and male balding) is a benign condition. Some men, especially younger men, seek treatment. Options include oral finasteride (Propecia), which is the only brand name prescription medication with a specific FDA approval for this problem. There is also topical minoxidil 5% solution or foam (Rogaine and a bunch of other brands). Men treated with these options must continue treatment to maintain efficacy. Hair transplantation is another option.

For women this problem is called female pattern hair loss. Genetics and aging are the prime causes, but it can be worsened by excessive levels of androgenic hormones. Sometimes it is treated with medications that block androgenic effects. Topical minoxidil, usually with the addition of oral prescription spironolactone, are considered first line treatments. Finasteride and cyproterone acetate are alternative oral antiandrogens. Much less commonly platelet-rich plasma injections, and low-level laser therapy can be attempted. Oral minoxidil, which is what we are going to review here, is customarily listed as an option when most other treatments have failed (see UpToDate clinical guidelines).

~Does oral minoxidil work?

Well, if you look at some of the before and after pictures online, the answer for a lot of people is yes.

Image borrowed from JAAD 2019; 81: 648-9

As I researched this question, I was excited to find an article published this year by a dermatologist to whom I have referred patients for almost 20 years. Dr. Warren Heymann practices less than a mile from my office, and his summary of low dose oral minoxidil treatment can be found on the American Academy of Dermatology Association website. He shares results about efficacy by citing a review of…

…10 articles comprising a total 19,218 patients (215 women and 19,003 men). Low dose minoxidil ranged from 0.25 to 5 mg daily to twice daily. The strongest evidence existed for androgenic alopecia (male pattern) and alopecia areata, respectively, with 61–100% and 18–82.4% of patients demonstrating objective clinical improvement. Successful treatment of female pattern hair loss, chronic telogen effluvium, monilethrix, and permanent chemotherapy-induced alopecia was also reported.

Is that better than what we have now? It’s hard to definitively say. I did find another meta-analysis of 23 trials comparing various treatments head-to-head (for men). Based on these conclusions, however, oral minoxidil might not be more effective than existing treatments. Dutasteride, which is very similar to finasteride (Propecia), seems to work the best. But as an antiandrogen, it can have more side effects like decreased sexual interest, ability, and even testicular pain. Technically speaking, prescribing dutasteride for hair loss would also be “off-label.” Here is how the meta-analysis ranked potential treatments in terms of how well they are expected to work for male-pattern hair loss:

The results of this meta-analysis indicate that 0.5 mg/d of oral dutasteride has the highest probability of being the most efficacious treatment, followed by these agents in decreasing order of efficacy: 5 mg/d of oral finasteride, 5 mg/d of oral minoxidil, 1 mg/d of oral finasteride, 5% topical minoxidil, 2% topical minoxidil, and 0.25 mg/d of oral minoxidil.

Note that 5 mg of minoxidil per day is basically a whole pill. In terms of expected efficacy, a low dose 1/4 pill should intuitively fall between 5 mg of minoxidil and 1 mg of finasteride/Propecia in the comparative analysis above, winning a bronze medal.

And then looking specifically at women, I found this following clinical trial:

A 24-week, open-label trial that randomly assigned 52 patients (with female pattern hair loss) to either oral minoxidil (1 mg per day) or once-daily application of minoxidil 5% solution did not find a statistically significant difference in effect on total hair density (12 versus 7 percent increase, respectively) [50]. However, the adverse event of mild hypertrichosis occurred more frequently in the oral minoxidil group than in the topical minoxidil group (27 versus 4 percent). Other adverse events in the oral minoxidil group included a slight increase in mean heart rate at rest and one occurrence of pretibial edema.

Yet most people find that using Rogaine and other topical formulations of minoxidil is a messy job. And waiting 2-4 hours to allow complete drying before lying down in bed sounds inconvenient, to say the least.

~How does minoxidil work?

The exact mechanism of action is still unclear, but suffice it to say that minoxidil works through a combination of vasodilation, upregulation of vascular endothelial growth factor (VEGF), and better cutaneous blood flow with resultant increase in oxygen and growth factor delivery to the hair follicle. There is also more stuff going on with potassium channel activation and T-cell immunomodulatory effects. Minoxidil is converted to an active sulfonated form in the scalp, and when given orally, more activation occurs in the liver and platelets than when administered topically.

~What are the potential adverse and side effects?

At higher doses, minoxidil is a crummy medication for treating high blood pressure. Medical guidelines recommend using it as an add-on for patients already being treated with multiple other medications, but in whom good blood pressure control has been elusive, and other options are not suitable.

Here is the boxed warning you might find in the U.S. if your doctor prescribes minoxidil for hypertension:

ALERT: US Boxed Warning: Cardiac effects:

Minoxidil may produce serious adverse effects. It can cause pericardial effusion, occasionally progressing to tamponade, and it can exacerbate angina pectoris. Reserve for hypertensive patients who do not respond adequately to maximum therapeutic doses of a diuretic and 2 other antihypertensive agents.

In experimental animals, minoxidil caused several kinds of myocardial lesions and other adverse cardiac effects.

Appropriate use:

Administer under close supervision, usually concomitantly with therapeutic doses of a beta-adrenergic blocking agent, to prevent tachycardia and increased myocardial workload. Usually, it must be given with a diuretic, frequently one acting in the ascending limb of the loop of Henle to prevent serious fluid accumulation.

This is doctor-speak for “be careful.” Full disclosure, like the rapid mumbling of risks during a pharmaceutical commercial, would also include: cardiac effects like ECG changes (T-wave changes 60%), edema (reversible, 7% to 10%), pericardial effusion (occasionally with tamponade, 3%), angina pectoris, cardiac failure, pericarditis, and tachycardia. There are possible dermatologic effects like hypertrichosis (which means excssive hair growth anywhere on the body, and can occur in up to 80%), bullous rash (rare), skin rash, Stevens-Johnson syndrome (rare), toxic and epidermal necrolysis. Endocrine & metabolic effects could include sodium retention, water retention, and weight gain. Followed by other, more rare possibilities.

~But how often do these side effects occur with just a low dose?

As they say, the dose makes the poison. Most medications have a higher risk of side effects at higher dosages. I was able to find one study published in the Journal of the American Academy of Dermatology that looked at what happens with low dose minoxidil:

A total of 1404 patients (943 women [67.2%] and 461 men [32.8%]) with a mean age of 43 years (range 8-86) were included…. The most frequent adverse effect was hypertrichosis (15.1%), which led to treatment withdrawal in 14 patients (0.5%).

Systemic adverse effects included lightheadedness (1.7%), fluid retention (1.3%), tachycardia (0.9%), headache (0.4%), periorbital edema (0.3%), and insomnia (0.2%), leading to drug discontinuation in 29 patients (1.2%). No life-threatening adverse effects were observed.

Hypertrichosis is excessive hair growth anywhere on the body, not just androgen-dependent sites. 15% is a pretty high rate, but contrasts favorably with the up to 80% reported rate of hypertrichosis in patients taking minoxidil at higher dosages for the treatment of hypertension. Less than 1% of patients discontinued treatment because of it, and it was reported mostly in the temples and sideburn areas. This study found a median dosage of 1.63 mg was used, and the median treatment duration observed was about 8 months.

Dr. Heymann cites 14 studies including 442 patients on low dose minoxidil at doses between 0.25 and 5 mg for 8 different types of alopecia, and found pretty similar rates. “Hypertrichosis was observed in 24% of patients. Pedal edema occurred in 2% and was also associated with higher doses. Postural hypotension and heart rate alterations occurred only in 1.1% and 1.3% of patients, respectively. The authors concluded that low dose oral minoxidil is a safe and well-tolerated treatment for hair loss, presenting a lower adverse effect rate than standard doses.”

And finally, yet another study confirms that dosage considerations really matter in terms of side effects. In this study 5mg of minoxidil was used, which is the upper limit of what is considered “low dose,” and found the following:

Photographic assessment of the vertex area by an expert panel revealed 100% improvement (score > + 1), with 43% of patients showing excellent improvement (score + 3, 71–100% increase). The frontal area also showed a significant response but less than that of the vertex area. Common side effects were hypertrichosis (93% of patients) and pedal edema (10%). No serious cardiovascular adverse events and abnormal laboratory findings were observed.

~Comments on the NYT readers’ comments.

These are some of my comments on the comments by readers of the original article, and your comments on my comments on their comments would be totally meta, so go for it at the end of this deep dive!

One commenter writes about how he has used a combination of oral minoxidil + finasteride to great effect. This should definitely be monitored by a physician, but combinations of Propecia + Rogaine have also been shown to be superior either agent alone.

Another commenter jabbed at physicians who would use a medication off-label for a cosmetic condition, but refuse to use Ivermectin off-label to treat a life-threatening condition like Covid-19. This is really a flawed analogy for many reasons, but I will just note that Ivermectin only showed possible clinical utility in a test tube, at really high doses, and was never found in respectable studies to help… yet some physicians keep prescribing Ivermectin “off-label” based upon the strength of their convictions over conclusive evidence to the contrary. I recently counseled a patient NOT to take the Ivermectin his other physician had prescribed him instead of FDA-authorized, clinically-proven, and safety-assured Paxlovid. But that is a tale for another day…

Others comment about a phenomenon that I have seen not infrequently in my own practice - hair loss after Covid, especially in women. Fever, illness, and stress can all cause premature shedding of the hair (called telogen effluvium). This is usually temporary, starts weeks to several months after infection, and often recovers within 6-9 months. It is totally unclear whether minoxidil would help speed this recovery along, or make it more complete.

There is a lot of dialogue about whether treating a condition like hair loss is vanity. Some men and women accept their balding and move on, and take pride in not caring what others might think. But for others, especially with premature balding, hair loss can be a devastating process, with psychological, developmental, and social costs. This burden should never be judged, especially if we have not been through it ourselves.

And then there are the comments that sound like advertising testimonials - thick lustrous black hair, oral minoxidil working when nothing else did - but also stories of too much hair, and in the wrong places like nose, ears, and sideburns.

~In conclusion.

It would seem that oral minoxidil for hair loss has been used under the radar by some dermatologists for some time now. There are low to decent quality scientific and clinical studies out there, but no high quality, randomized, prospective clinical trials. And because of simple economics there won’t be any. Low dose oral minoxidil seems to work at least as well as some other more commonly used options, and it’s a lot easier than messy topical solutions and foams. Anecdotal reports, and slightly hyped NYT articles are creating more optimistic buzz. Alone or in combination, oral minoxidil presents another way to try to help people distressed with alopecia. Women bear a higher burden when it comes to the stigma of hair loss, as they do with other unfair expectations of physical appearance. Side effects particularly in the cardiovascular system, and excessive hair growth in other places need to be considered and watched. We always need to proceed with caution in the world of off-label prescribing. Patients and physicians should be aware of the precautionary principle, defined as:

a broad epistemological, philosophical and legal approach to innovations with potential for causing harm when extensive scientific knowledge on the matter is lacking. It emphasizes caution, pausing and review before leaping into new innovations that may prove disastrous.

I don’t see much potential for such a small dose to be ultimately proven disastrous. It seems like there is enough clinical experience and even evidence out there. But even if one person out of a hundred develops a serious cardiac problem, most of us would have deep regrets. I think I’ll let a dermatologist named Dr. Antonella Tosti have the second-to-last word, writing in Dermatology World Insights and Inquiries:

Consider prescribing low dose oral minoxidil in all hair diseases. It improves thickness and overall hair volume. Patients prefer an oral treatment to topical therapy and compliance is usually very good. Hypertrichosis is common, but most patients are so happy with results that they would rather epilate/depilate and continue treatment!

Consider is the key word - with your dermatologist, and probably your family doc, if they’ve taken some extra time to brush up on this off-label stuff. We know how to treat hypertension on-label, and are wary of minoxidil in higher dosages.

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