Tretinoin, also known as all-trans retinoic acid (sold under a variety of brands including Retin-A), can reverse the signs of aging, but at what cost?
Topical Retinoids to Reverse Skin Aging
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Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.
Sunscreens are intended to prevent further facial photoaging, but can’t dramatically reverse damage presently visible, whereas topical retinoids are the most important drug class to reverse the signs of aging. Also known as all-trans retinoic acid, tretinoin (sold under a variety of brands including Retin-A) is a prescription-only topical form of vitamin A that can visibly improve mild to moderate photodamage, including fine and coarse wrinkles, freckles, other pigmentation, and improve overall skin texture after months of daily use. This is accompanied by a restoration of collagen formation. Skin biopsies taken before and after 10 to 12 months of tretinoin versus placebo found that while skin collagen formation dropped 14 percent in the control group, it rose 80 percent in the retinoic acid group.
The downsides are the side effects, so common they have their own name—“retinoid reaction”—plaguing a high proportion of patients, including redness, stinging, burning, itching, and peeling. Ironically, the constant irritation may be a causal mechanism, constantly forcing the skin to renew. The adverse effects do tend to improve over time after a peak after about two weeks of daily use. And you can minimize the irritation by starting at a lower concentration (for example .025 percent instead of 0.1 percent) and slowly ramping up from applying at first twice a week for a few weeks, then to every other night for a few more weeks, before finally advancing to nightly application as tolerated. Given that a small amount is systemically absorbed, out of an abundance of caution women of child-bearing capacity may want to steer clear, given the severe birth defects caused by a similar drug, isotretinoin (sold formerly as the acne drug Accutane).
There are gentler, less potent, over-the-counter topical retinoids: retinyl, retinol, and retinal. There’s retinyl acetate, retinyl palmitate, retinyl propionate, retinol, and retinaldehyde. Once absorbed into your skin, your body can convert them into small amounts of retinoic acid. However, data is limited on these nonprescription retinoids. The results of clinical trials on the retinyl esters have been routinely disappointing. Even 48 weeks of daily use was found to be ineffective for reducing wrinkles compared to placebo. Retinaldehyde and retinol, however, hold some promise.
There was a 48-week head-to-head trial of retinaldehyde vs. retinoic acid vs. placebo. Now retinoids can be so irritating that it’s hard to blind participants as to whether or not they’re in the control group; so, objective measures that may be less susceptible to placebo effects are especially important. So, what they did is make silicone molds of the crow’s feet wrinkles around the eyes of the participants before and after being randomized to one of those three groups. and then they analyzed scans of the molds using high-resolution digital image processing. The retinaldehyde group showed a similar reduction in fine lines and wrinkles as the retinoic acid group, with less irritation. Only 23 percent of the retinaldehyde group experienced skin irritation, compared to 71 percent in the retinoic acid group, versus 4 percent in the placebo cream group.
Of all the nonprescription retinoid options, retinol may be the preferred choice, though. It causes even less irritation than retinaldehyde (insignificantly different than placebo), and a randomized double-blind, placebo-controlled trial found that 52 weeks of use improved crow’s feet fine lines by 44 percent, and mottled pigmentation by 84 percent. But tretinoin—retinoic acid—has by far the most robust track record of efficacy. So, why not just ask your doctor for a prescription? Because long-term topical tretinoin use may increase your risk of an even more stinging side effect: death.
Topical Tretinoin Therapy and All-Cause Mortality: The Veterans Affairs Topical Tretinoin Chemoprevention trial was to be a six-year randomized controlled trial to see if it could help prevent skin cancer. But the trial had to be stopped early, because significantly more people were dying in the retinoic acid group than in the placebo-cream group. At the time the study was halted, 19 percent of the subjects in the tretinoin group had died, compared to 14 percent in the placebo group. Between 1 to 8 percent of topically applied retinoic acid is absorbed into the bloodstream. Could it be killing people? We don’t know if the increase in deaths was a statistical fluke that happened by chance, or a real biological effect. The probability that we’d see such a discrepancy just by chance is about 1 in 100. Tretinoin continues to be banned in Europe for cosmetic purposes.
Please consider volunteering to help out on the site.
- Draelos ZD. Active agents in common skin care products. Plast Reconstr Surg. 2010;125(2):719-724.
- Levin J, Momin SB. How much do we really know about our favorite cosmeceutical ingredients? J Clin Aesthet Dermatol. 2010;3(2):22-41.
- Huang CK, Miller TA. The truth about over-the-counter topical anti-aging products: a comprehensive review. Aesthet Surg J. 2007;27(4):402-412.
- Griffiths CE, Russman AN, Majmudar G, Singer RS, Hamilton TA, Voorhees JJ. Restoration of collagen formation in photodamaged human skin by tretinoin (Retinoic acid). N Engl J Med. 1993;329(8):530-535.
- Ramos-e-Silva M, Celem LR, Ramos-e-Silva S, Fucci-da-Costa AP. Anti-aging cosmetics: facts and controversies. Clin Dermatol. 2013;31(6):750-758.
- Sunder S. Relevant topical skin care products for prevention and treatment of aging skin. Facial Plast Surg Clin North Am. 2019;27(3):413-418.
- Choi EJ, Kim N, Kwak HS, et al. The rates of major malformations after gestational exposure to isotretinoin: a systematic review and meta-analysis. Obstet Gynecol Sci. 2021;64(4):364-373.
- Zussman J, Ahdout J, Kim J. Vitamins and photoaging: do scientific data support their use? J Am Acad Dermatol. 2010;63(3):507-525.
- Green C, Orchard G, Cerio R, Hawk JL. A clinicopathological study of the effects of topical retinyl propionate cream in skin photoageing. Clin Exp Dermatol. 1998;23(4):162-167.
- Creidi P, Vienne MP, Ochonisky S, et al. Profilometric evaluation of photodamage after topical retinaldehyde and retinoic acid treatment. J Am Acad Dermatol. 1998;39(6):960-965.
- Kang S, Duell EA, Fisher GJ, et al. Application of retinol to human skin in vivo induces epidermal hyperplasia and cellular retinoid binding proteins characteristic of retinoic acid but without measurable retinoic acid levels or irritation. J Invest Dermatol. 1995;105(4):549-556.
- Randhawa M, Rossetti D, Leyden JJ, et al. One-year topical stabilized retinol treatment improves photodamaged skin in a double-blind, vehicle-controlled trial. J Drugs Dermatol. 2015;14(3):271-280.
- Darlenski R, Surber C, Fluhr JW. Topical retinoids in the management of photodamaged skin: from theory to evidence-based practical approach. Br J Dermatol. 2010;163(6):1157-1165.
- Weinstock MA, Bingham SF, Lew RA, et al. Topical tretinoin therapy and all-cause mortality. Arch Dermatol. 2009;145(1):18-24.
- Schilling LM, Dellavalle RP. Dealing with unanticipated mortality in a large randomized clinical trial of topical tretinoin. Arch Dermatol. 2009;145(1):76.
- Scientific Committee on Consumer Safety. Opinion on Vitamin A (Retinol, Retinyl Acetate, Retinyl Palmitate) Scientific Committee on Consumer Safety; Brussels, Belgium: 2016.
Motion graphics by Avo Media
Below is an approximation of this video’s audio content. To see any graphs, charts, graphics, images, and quotes to which Dr. Greger may be referring, watch the above video.
Sunscreens are intended to prevent further facial photoaging, but can’t dramatically reverse damage presently visible, whereas topical retinoids are the most important drug class to reverse the signs of aging. Also known as all-trans retinoic acid, tretinoin (sold under a variety of brands including Retin-A) is a prescription-only topical form of vitamin A that can visibly improve mild to moderate photodamage, including fine and coarse wrinkles, freckles, other pigmentation, and improve overall skin texture after months of daily use. This is accompanied by a restoration of collagen formation. Skin biopsies taken before and after 10 to 12 months of tretinoin versus placebo found that while skin collagen formation dropped 14 percent in the control group, it rose 80 percent in the retinoic acid group.
The downsides are the side effects, so common they have their own name—“retinoid reaction”—plaguing a high proportion of patients, including redness, stinging, burning, itching, and peeling. Ironically, the constant irritation may be a causal mechanism, constantly forcing the skin to renew. The adverse effects do tend to improve over time after a peak after about two weeks of daily use. And you can minimize the irritation by starting at a lower concentration (for example .025 percent instead of 0.1 percent) and slowly ramping up from applying at first twice a week for a few weeks, then to every other night for a few more weeks, before finally advancing to nightly application as tolerated. Given that a small amount is systemically absorbed, out of an abundance of caution women of child-bearing capacity may want to steer clear, given the severe birth defects caused by a similar drug, isotretinoin (sold formerly as the acne drug Accutane).
There are gentler, less potent, over-the-counter topical retinoids: retinyl, retinol, and retinal. There’s retinyl acetate, retinyl palmitate, retinyl propionate, retinol, and retinaldehyde. Once absorbed into your skin, your body can convert them into small amounts of retinoic acid. However, data is limited on these nonprescription retinoids. The results of clinical trials on the retinyl esters have been routinely disappointing. Even 48 weeks of daily use was found to be ineffective for reducing wrinkles compared to placebo. Retinaldehyde and retinol, however, hold some promise.
There was a 48-week head-to-head trial of retinaldehyde vs. retinoic acid vs. placebo. Now retinoids can be so irritating that it’s hard to blind participants as to whether or not they’re in the control group; so, objective measures that may be less susceptible to placebo effects are especially important. So, what they did is make silicone molds of the crow’s feet wrinkles around the eyes of the participants before and after being randomized to one of those three groups. and then they analyzed scans of the molds using high-resolution digital image processing. The retinaldehyde group showed a similar reduction in fine lines and wrinkles as the retinoic acid group, with less irritation. Only 23 percent of the retinaldehyde group experienced skin irritation, compared to 71 percent in the retinoic acid group, versus 4 percent in the placebo cream group.
Of all the nonprescription retinoid options, retinol may be the preferred choice, though. It causes even less irritation than retinaldehyde (insignificantly different than placebo), and a randomized double-blind, placebo-controlled trial found that 52 weeks of use improved crow’s feet fine lines by 44 percent, and mottled pigmentation by 84 percent. But tretinoin—retinoic acid—has by far the most robust track record of efficacy. So, why not just ask your doctor for a prescription? Because long-term topical tretinoin use may increase your risk of an even more stinging side effect: death.
Topical Tretinoin Therapy and All-Cause Mortality: The Veterans Affairs Topical Tretinoin Chemoprevention trial was to be a six-year randomized controlled trial to see if it could help prevent skin cancer. But the trial had to be stopped early, because significantly more people were dying in the retinoic acid group than in the placebo-cream group. At the time the study was halted, 19 percent of the subjects in the tretinoin group had died, compared to 14 percent in the placebo group. Between 1 to 8 percent of topically applied retinoic acid is absorbed into the bloodstream. Could it be killing people? We don’t know if the increase in deaths was a statistical fluke that happened by chance, or a real biological effect. The probability that we’d see such a discrepancy just by chance is about 1 in 100. Tretinoin continues to be banned in Europe for cosmetic purposes.
Please consider volunteering to help out on the site.
- Draelos ZD. Active agents in common skin care products. Plast Reconstr Surg. 2010;125(2):719-724.
- Levin J, Momin SB. How much do we really know about our favorite cosmeceutical ingredients? J Clin Aesthet Dermatol. 2010;3(2):22-41.
- Huang CK, Miller TA. The truth about over-the-counter topical anti-aging products: a comprehensive review. Aesthet Surg J. 2007;27(4):402-412.
- Griffiths CE, Russman AN, Majmudar G, Singer RS, Hamilton TA, Voorhees JJ. Restoration of collagen formation in photodamaged human skin by tretinoin (Retinoic acid). N Engl J Med. 1993;329(8):530-535.
- Ramos-e-Silva M, Celem LR, Ramos-e-Silva S, Fucci-da-Costa AP. Anti-aging cosmetics: facts and controversies. Clin Dermatol. 2013;31(6):750-758.
- Sunder S. Relevant topical skin care products for prevention and treatment of aging skin. Facial Plast Surg Clin North Am. 2019;27(3):413-418.
- Choi EJ, Kim N, Kwak HS, et al. The rates of major malformations after gestational exposure to isotretinoin: a systematic review and meta-analysis. Obstet Gynecol Sci. 2021;64(4):364-373.
- Zussman J, Ahdout J, Kim J. Vitamins and photoaging: do scientific data support their use? J Am Acad Dermatol. 2010;63(3):507-525.
- Green C, Orchard G, Cerio R, Hawk JL. A clinicopathological study of the effects of topical retinyl propionate cream in skin photoageing. Clin Exp Dermatol. 1998;23(4):162-167.
- Creidi P, Vienne MP, Ochonisky S, et al. Profilometric evaluation of photodamage after topical retinaldehyde and retinoic acid treatment. J Am Acad Dermatol. 1998;39(6):960-965.
- Kang S, Duell EA, Fisher GJ, et al. Application of retinol to human skin in vivo induces epidermal hyperplasia and cellular retinoid binding proteins characteristic of retinoic acid but without measurable retinoic acid levels or irritation. J Invest Dermatol. 1995;105(4):549-556.
- Randhawa M, Rossetti D, Leyden JJ, et al. One-year topical stabilized retinol treatment improves photodamaged skin in a double-blind, vehicle-controlled trial. J Drugs Dermatol. 2015;14(3):271-280.
- Darlenski R, Surber C, Fluhr JW. Topical retinoids in the management of photodamaged skin: from theory to evidence-based practical approach. Br J Dermatol. 2010;163(6):1157-1165.
- Weinstock MA, Bingham SF, Lew RA, et al. Topical tretinoin therapy and all-cause mortality. Arch Dermatol. 2009;145(1):18-24.
- Schilling LM, Dellavalle RP. Dealing with unanticipated mortality in a large randomized clinical trial of topical tretinoin. Arch Dermatol. 2009;145(1):76.
- Scientific Committee on Consumer Safety. Opinion on Vitamin A (Retinol, Retinyl Acetate, Retinyl Palmitate) Scientific Committee on Consumer Safety; Brussels, Belgium: 2016.
Motion graphics by Avo Media
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Topical Retinoids to Reverse Skin Aging
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Content URLDoctor's Note
What Is the Most Important Anti-Aging Cream Ingredient? That was the question posed and answered in my previous video. In the next two videos, I look at the benefits of topical niacinamide and topical vitamin C.
For more on how to live your longest, healthiest life, preorder my new book How Not to Age. (As always, all proceeds I receive from all of my books are donated to charity.)
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