Is Retin-A Safe For Long-Term Use?

Q. A visitor to www.MedShadow.org asked: “I’ve used Retin-A daily as an anti-aging cream for 15 or more years. Is this safe?”

A: Probably yes. Remember, we at MedShadow are not doctors. We are a group of consumers and patients who sift through the internet and talk to doctors and other healthcare providers to dig a little deeper and uncover more information than what is commonly known about a prescription drug.

The FDA has approved Retin-A, generic name tretinoin, for “acne vulgaris” and nothing else. On the Retin-A label it states: “The safety and efficacy of the long-term use of this product in the treatment of other disorders have not been established.” This isn’t necessarily a red flag and doctors are allowed to prescribe “off label.” I called Bausch Health (formerly known as Valeant), the pharmaceutical company that manufactures a variety of strengths of Retin-A and Retin-A Micro. The person answering medical questions was quick to point out that anti-aging is not an indicated use for Retin-A in any of its forms. The longest study on tretinoin lasted four years, which is not much help in indicating very long-term or cumulative effects.

Retin-A is a synthetic form of vitamin A. One can overdose on vitamin A, which can be very serious, but systemic absorption of Retin-A through the skin is considered inconsequential, making that unlikely.  Avoid taking Retin-A while taking tetracycline. As always, discuss with your doctor all drugs and supplements at every visit.

On the issue of long-term use, Ranella Hirsch, MD, a board-certified dermatologist in Boston, directed me to several studies. A report in the American Journal of Clinical Dermatology concluded that retinoids are “suitable as long-term medications, with no risk of inducing bacterial resistance.” Another study tested the safety of tretinoin cream over 52 weeks and found no problems. An earlier study published in the Journal of Dermatological Science reported safety and continued clinical improvement after four years of topical tretinoin on photodamaged skin.

In addition to treating acne, research has shown that Retin-A can help treat precancerous skin conditions such as actinic keratoses. These skin lesions can develop into squamous cell carcinoma over time. In a 2018 study in the Journal of the European Academy of Dermatology and Venereology, applying .05% tretinoin cream to the skin three nights a week for six months reduced the number of actinic keratoses by 60% in women over age 60.

With so much research showing a positive safety profile and benefits of retinoids, experts were surprised when a study appeared to link topical tretinoin use with excess mortality. Researchers recruited over 1,100 veterans, average age 71, to apply tretinoin cream or placebo to their face and ears twice every day. Over the course of the study and follow-up period, unexpectedly, people in the tretinoin group were more likely to die. However, the researchers could not conclude that there was a causal association of tretinoin with death, and stated “we do not conclude that this trial provides appropriate grounds for hesitating to use topical tretinoin in clinical practice in the absence of additional evidence.”

Also, in response to these study results, MedScape carried comments from Guy F. Webster, MD, PhD, clinical professor of dermatology at Jefferson Medical College in Philadelphia. Dr. Webster called the study “unbelievable” because it was the sole study that contradicted 40 years of apparently safe use. He noted that vitamin A is generally considered useful in cancer therapy, and that “plasma vitamin A levels do not change when tretinoin is applied to the skin. So topical tretinoin is as dangerous as eating a carrot.”

Retin-A’s original label warned that the drug is an FDA pregnancy category C, which meant that it’s not known if Retin-A is harmful to a fetus or breastfeeding baby. (The FDA’s A, B, C, D and X pregnancy categories were discontinued in 2015 and replaced with information about the drug that the Agency believes will be more meaningful to patients and healthcare providers than the old letter categories.) As in earlier labels, current Retin-A labels note that in high doses in rats, tretinoin was shown to be teratogenic and fetotoxic (caused birth defects and was toxic to fetuses). No study has shown the same relationship in humans and not all rodent study outcomes can be reproduced in human studies. However, Dr. Hirsch suggests that “people who are trying to conceive, are pregnant or lactating should refrain from using retinoid products. 

If you’ve been taking Retin-A for longer than a few months you’ve worked past the very uncomfortable initial side effects. When first using Retin-A, many people experience redness, burning, stinging, peeling/exfoliation. It’s usually recommended to start using Retin-A slowly, at the lowest dose, perhaps every-other day and work up to a daily regimen and higher doses. Whenever using Retin-A avoid the sun! It makes you more susceptible to sunburn.

With the trend toward reaching puberty earlier, it’s not uncommon for children as young as 7 years old to develop acne. According to guidelines for the diagnosis and treatment of pediatric acne published in the journal Pediatrics, topical retinoids, including Retin-A, Differin (adapalene) and Tazorac (tazarotene), may be used for all types and severities of acne in children of all ages. I wrote a blog on this and found that indeed some children as young as 7-years-old are prescribed Retin-A, Differin, Accutane and antibiotics for acne. 

As for safety and effectiveness in children, a 2019 study in The Journal of Clinical and Aesthetic Dermatology evaluated the use of tretinoin .05% lotion in 729 children aged 9 to 17 who had acne. After 12 weeks of daily use the children using tretinoin had significantly reduced acne compared to those who used a placebo lotion. Improvements were greatest in children age 13 and younger, and side effects like dryness and scaling were mild to moderate overall. 

Many of the standard therapies, including tretinoin, are recommended in treating childhood acne. However testing of these drugs on children is limited, so caution and good sense should be exercised.

The oral drug Accutane (isotretinoin) is also a form of vitamin A but in much more concentrated doses. It can cause severe birth defects, miscarriage and other problems during pregnancy. In order to get a prescription for Accutane you, your doctor and pharmacist must all be registered in the iPledge program and sign documents that assert you understand the risks of the drug and requirements of the program. All women of childbearing age must have two negative pregnancy tests before receiving an initial 30-day prescription and a negative pregnancy test each month before they are allowed to refill their prescription. You can’t even donate blood while on it and for a month after discontinuing the drug.

I also scanned some message boards to see if I could find complaints about Retin-A. Other than the first few weeks of redness and peeling, those who write on message boards seemed to be happy with Retin-A. Good luck! And let me know if you hear anything more than I could uncover.

For more information on how retinoids work, here’s a short primer from Harvard Medical School.