This writeup was lead-authored by our senior technical adviser, Sunbin Song, PhD. Sunbin graduated from MIT with a degree in Biology before receiving a doctorate in neuroscience from Georgetown and becoming a research scientist at the NIH. When Sunbin isn't busy researching the brain, she loves to explore how we can best nurture our body, mind and spirit to live more joyful lives. Sunbin on Google Scholar / on ResearchGate
Hi there! Welcome to Maelove’s “More than Skin Deep” series.
In this write-up we'll do a deep dive into how retinoids help your skin and what you should look for when choosing a retinoid skincare product. Let's get started:
Part 1 - What are retinoids? And how did they become so popular in skincare?
Retinoids are a family of Vitamin A related compounds.
While retinoids are famous for their skin benefits, retinoids also play vital roles in many critical bodily functions - from healthy vision to reproduction to embryonic development.
Remember how your mom used to tell you to eat carrots because they’re good for your eyes? That vision benefit comes from beta-carotene, which is a retinoid (beta-carotene’s red-orange pigmentation gives carrots their bright colors).
Retinoids are even used for cancer treatments (orally taken tretinoin has been shown to be effective for treating leukemia) thanks to retinoids’ ability to regulate cell growth cycles (differentiation and apoptosis).
In skincare, as a topically applied product (a fancy way of saying rubbed onto skin), tretinoin (retinoic acid) became the first retinoid to be approved by the FDA for the treatment of acne in 1971. You may have heard of it under its branded name Retin-A.
Interestingly, once topical tretinoin became available to the public, patients using it to treat their acne started noticing improvement in their overall skin condition. Further studies soon followed and in 1995, tretinoin was approved by the FDA for the treatment of sun-damaged, prematurely aged skin.
Other popular topical skincare retinoids you’d have heard of are retinol and retinaldehyde (commonly known as retinal). From here on, when we say “retinoids” we are specifically referring to retinol, retinal and retinoic acid. Note that retinoic acid and tretinoin are interchangeable terms in the context of this article.
See Appendix A for more details on other prescription-based retinoids that are applied topically or taken orally - such as isotretinoin (Accutane), adapalene (Differin) and tazarotene as well as other over-the-counter retinoids such as retinyl palmitate and retinol-mimics like bakuchiol.
Part 2 - What can retinoids do for my skin? And how do they work exactly?
Consistent use of retinoids has been well proven to help keep your skin looking younger and healthier. Let’s dive deeper into how that works! One step at a time.
Part 2A - Retinol and retinal get converted into retinoic acid
Once absorbed into the skin, retinol and retinal must first be converted into retinoic acid. Enzymes in keratinocytes (epidermal skin cells) drive these crucial conversion processes.
Retinal (retinaldehyde) is just one conversion step removed from becoming retinoic acid. Retinol, on the other hand, requires two conversion steps (Retinol -> Retinal -> Retinoic acid).
Technically speaking: It's hard to overstate the importance of enzymes. The dependence on enzymes determines whether a retinoid is actually beneficial to the skin.
For example, beta-carotene, when ingested, is converted into retinal by enzymatic reactions in the gut. However, these enzymes in the cells lining the gut that convert beta-carotene into retinal are not present in skin cells. For this reason, beta-carotene cannot be converted into retinoic acid in the skin and has absolutely no benefit to the skin as a topical retinoid. This is why you can’t just rub carrot juice onto your skin and expect any benefit even though carrot juice is full of retinoids.
Once retinol and/or retinal is converted into retinoic acid, it then activates our skin cells to power the regeneration cycle. To be more specific, the sequence goes like this:
- Retinol or retinal is applied on the skin’s surface.
- Retinol/retinal penetrates into skin cells through the cell membranes (retinoids are lipophilic/fat-loving and are able to diffuse through cell membranes).
- Once inside a skin cell, enzymes help convert retinol into retinal, then retinal into retinoic acid.
- Retinoic acid hitches a ride on a “transporter protein” called CRABP (which stands for cellular retinoic acid binding protein) to get into the cell nucleus.
- Once inside the cell nucleus, retinoic acid binds to its receptors called RARs and RXRs (which stand for retinoic acid receptors and retinoid-X-receptors), and then all sorts of good things are unleashed. This is because RARs and RXRs regulate epithelial cell (epithelial cells form linings in our body - such as skin, blood vessels, organs) growth and differentiation as well as other signaling cascades that eventually lead to more youthful skin (Babamiri and Nassab 2010, Beckenbach et al. 2015, Mukherjee et al. 2006).
Part 2B - Retinoic Acid inside cell nuclei kickstart all sorts of beneficial biological activities
Once the retinoid is converted into retinoic acid inside the skin cell (keratinocyte), a chain of biological events are unleashed that leads to more youthful skin. Let’s get into those details.
Retinoids resist, combat and reverse signs of aging skin. Retinoids can also shrink pores.
With aging, the skin gets less blood flow (less vascularized) and becomes thinner, more lax and finely lined.
Furthermore, sun-damaged skin is typically characterized by hyperpigmentation spots, rough patches (actinic keratosis), enlarged pores and deep wrinkles.
Retinoids directly combat these changes and lead to thicker, smoother, more vascularized, more elastic, and less wrinkled skin. Both fine wrinkles around the eyes and larger wrinkles such as nasiolabial folds (lines on sides of the mouth) have shown to improve with retinoids. Pore size has been demonstrated to shrink as well.
Retinoids thicken the skin by upregulating the c-Jun transcription factor, which is necessary for proper division and proliferation of cells (Shao et al. 2017). This upregulation of c-Jun by retinoids directly stimulates an increase in the number of skin cells (keratinocytes) and leads to increased skin (epidermal) thickness (Saurat et al. 1994, Kafi et al. 2007, Kong et al. 2015, Shao et al. 2017).
[Figure reproduced from Kong et al. 2015] Application of topical retinoid, even a relatively weak version (0.1% retinol) shows increase in epidermal skin thickness (blue staining). You can also see increase in procollagen (red staining).
Retinoids increase endothelial cell (cells that line blood vessels) proliferation (cell proliferation = an increase in the number of cells as a result of cell growth and cell division), which leads to increase in dermal blood vessel formation by several folds (Shao et al. 2017). More blood flow to the skin means improving skin color/tone and more nutrients to fuel continual skin renewal.
[Figures reproduced from Shao et al. 2017] Application of topical retinoid for one week led to proliferation of endothelial cells (as indicated by red staining), which are used for blood vessel formation.
Retinoids boost collagen in the skin, and other components of the extracellular matrix including fibronectin and elastin. The extracellular matrix (ECM), made up mostly of collagen, sits between your skin cells and gives your skin firmness and elasticity (think of ECM like scaffolding for your skin).
Technically speaking: Retinoids increase ECM production by activating dermal fibroblasts which produce ECM molecules, and by activating the signaling pathway (TGF-β/CTGF) behind ECM enrichment (Shao et al. 2017). Retinoids also inhibit the breakdown of collagen by decreasing collagenase production (collagenases are enzymes that break down collagen) (Saurat et al. 1994; Kafi et al. 2007).
These changes take place at the microstructural level, but the improvement will manifest in measurable decreases in fine wrinkling in chronologically-aged skin (Kafi et al. 2007, Kong et al. 2015).
Retinoids can also treat coarse wrinkling in photoaged (sun-damaged) skin with documented reductions in crow’s feet around the eyes, glabellar wrinkles in between your eyebrows, supralabial wrinkles near the lips, and wrinkles in the nasolabial folds that run from nose to edge of the lips (Bouloc et al. 2014; Creidi et al. 1998).
Reductions in pore size have also been found in retinoid treated skin (Bouloc et al. 2014).
[Figures reproduced from Kong et al. 2015] Reduction in fine wrinkling in middle aged subjects (35-55yo) from topical retinoid application.
Retinoids can treat acne. Retinal, specifically, has a unique antibacterial power
Retinoids combat acne in 2 key ways (Beckenbach et al. 2015, Leydon et al. 2017, Zasada and Budzisz 2019):
(1) Retinoids help keep pores clear- retinoids normalize abnormal desquamation within the sebaceous follicles that lead to microcomedone formation.
(2) Retinoids help decrease the activity of enzymes involved in sebum production.
Retinal (retinaldehyde), in particular, has antibacterial properties as a bonus attribute (retinal is highly reactive due to the aldehyde group in the isoprenoic lateral chain). This gives the retinal its unique antibacterial power and makes retinal even more effective for acne treatment.
In a head to head comparison study conducted by Pechere et al. 1999, it showed a decrease in acne-causing bacteria (called P. acnes) density after 0.05% retinal treatment for 2 weeks (Figure). On the contrary, tretinoin had no effect on P. acnes density.
[Figure reproduced from Pechere et al. 1999] Topical application of 0.05% retinal formula for 2 weeks reduced bacterial density (while 0.05% tretinoin had no effect).
Retinoids can also help with hyperpigmentation
Wait! There’s even more that retinoids can do for your skin. Retinoids can improve hyperpigmentation by inhibiting melanosome transfer to keratinocytes and also reduce epidermal pigmentation by accelerating cell turnover (Leydon et al. 2017, Zasada and Budzisz 2019).
Treating hyperpigmentation is generally more effective when retinoids are used in combination with other ingredients (different ingredients can exert influence in different and complementary ways). Retinoid-hydroquinone combinations can diminish hyperpigmentation more effectively, as can retinoid-glycolic acid, retinoid-arbutin and retinoid-Vitamin C combinations (Mukherjee et al. 2006, Boswell 2006).
Part 3 - Which retinoid is the best?
Retinol, retinal and tretinoin (retinoic acid) all behave slightly differently with different potency and irritation profiles.
So, let's evaluate potency and irritation separately, then consider those two aspects together to decide which retinoid is the most effective overall.
Effectiveness = Potency - Irritation
This will be a nuanced, rather complicated discussion, so the TL;DR version is: In our opinion, retinal is the best because it is as potent as tretinoin and is as well tolerated, if not better, than retinol.
Part 3A - Which retinoid is the most potent?
Why is there such a huge difference in potency between retinol and retinal? The potency difference all comes down to the enzymes.
Remember that retinol is converted to retinal? Then, retinal undergoes conversion to retinoic acid?
The key here is that not all enzymatic conversions are equal. Some are very slow and inefficient, like facetiming over a sketchy cell-phone connection where the video gets cut off every few seconds.
Conversion from retinol to retinal is like that. It’s inefficient and results in a very low yield. It’s what scientists call “rate limiting.” This is the reason that retinol is ten to twenty times less potent than retinal and retinoic acid (Kang et al. 1995, Sorg et al. 2006).
On the other hand, the enzymatic conversion step from retinal to retinoic acid is fast and smooth (Belyaeva et al. 2020). Like facetiming with someone when you are both on super fast wifi networks. What scientists would call “non-rate limiting”.
This is how the retinal appears to be as efficacious as tretinoin at the same concentration level; thanks to the fast and smooth enzymatic conversion process where very little gets lost.
Part 3B - Which retinoid is the most irritating?
So the good news is that retinoids work. Unfortunately, retinoids (and tretinoin in particular) are also notorious for causing skin irritation.
Generally speaking, tretinoin is the most irritating. Then retinol. Retinal is less irritating than both.
- Reddening/erythema - Retinoic Acid/Tretinoin is the worst
- Burning - Retinol is the worst
- Peeling/flaking - These are natural results of the retinoids working. Will fade naturally in 2 to 3 weeks of steady retinoid use.
With tretinoin you’ll get the most skin reddening along with some burning sensations. With retinol you’ll get quite a bit of burning sensations but not skin reddening.
On the contrary, retinal is better tolerated than both tretinoin and retinol resulting in less skin reddening and less of a burning sensation than both (Fluhr et al. 1999).
The caveat to this general claim is in the first few weeks of retinoid use when retinol can be the least irritating of the three simply because retinol is much less potent.
Skin scaling (peeling/flaking) and the resulting loss of skin barrier function (which can lead to transepidermal water loss and dry skin) are associated with a sudden increase in skin cell turnover.
Since tretinoin and retinal are more potent than retinol, it is also true that both tretinoin and retinal can lead to more skin scaling and more dryness than retinol.
However, skin scaling and dryness are transient. As the skin renews and re-normalizes with retinoid use (can range from a few weeks to a few months) these sources of irritation dissipate (Fluhr et al. 1999).
Hence, if initial tolerability to the more potent product (retinal or tretinoin) is difficult, it makes sense to begin with a weaker retinol product for several weeks before switching to the more potent retinal product.
What causes skin reddening?
You get more erythema (reddening of your skin) from topical tretinoin compared to retinol and retinal. That’s because tretinoin has something called carboxylic acid attached at its tail end. Carboxylic acid seems to cause skin irritation when applied on the skin’s surface.
Retinol and retinal do not have carboxylic acid in their composition. So when retinol or retinal is applied on the skin, there is no irritation on the skin’s surface caused by carboxylic acid.
We had mentioned in Part 2A that retinol and retinal undergo conversion to retinoic acid. But the conversion to retinoic acid happens inside the skin cells (keratinocytes) where carboxylic acid does not cause problems.
What causes the burning sensation?
That burning sensation often associated with retinoids? That’s when retinoids aggravate the TRP receptors in your skin, which in turn makes your brain register a burning sensation.
TRP receptors are basically nerve endings. You know how you feel the cooling sensation when you apply menthol on your skin? That’s also your TRP receptors getting activated by menthol.
Retinol and tretinoin, when applied at the same dosage, aggravate the TRP receptors about the same. Retinal is gentler than both retinol and tretinoin in terms of TRP receptor aggravation.
[Figure reproduced from Luo et. al 2013] Tretinoin (labeled ATRA in this figure) is equally irritating via TRP receptors as retinol at the same concentration (but keep in mind that in most skincare products retinol concentrations are far higher than tretinoin concentrations). In contrast, retinal is the least irritating via TRP receptors.
What causes peeling/flaking?
Retinoids hit a reset button on your skin’s cell renewal cycle, and this causes an initial disturbance on the skin’s surface.
Technically speaking: The corneocyte arrangement is initially disturbed in the process of normalizing desquamation and there is a loss of cohesion between corneocytes leading to irritation. As the corneocytes rearrange and desquamation normalizes after a few weeks of treatment, cohesion returns and the irritation resolves (Leydon et al. 2017).
The result is that you may see peeling and flaking in the early weeks of retinoid use. Your skin might also seem red and feel more irritated as the old surface cells peel off and raw skin is exposed (which also makes your skin more vulnerable to the sun). You may experience skin dryness as well as the skin barrier function is disturbed and transepidermal water loss accelerates.
The good news is that peeling of the skin tends to be short lived as your skin gets used to the new regeneration cycle.
The first few weeks of retinoid usage will have the most irritation and side effects (such as peeling and dryness) as the skin turns over, renews, and changes its morphology (structural features), but these irritations will disappear over time as the skin resettles into a new, more youthful looking state.
The same is true for increased sun sensitivity in the first few weeks to first few months of usage. In fact, after extended use, retinoids may actually be sun protective (Mukherjee et al. 2006). Hence, usage of retinoids requires patience to obtain optimal results.
Part 3C - Cost-benefit analysis suggests that retinal is the best choice
Tretinoin is by far the most irritating (which is why it’s only available by prescription). Retinal and retinol are much better tolerated and hence available over the counter.
Tretinoin is also the most potent while retinal seems to be about equal in terms of potency. Retinol is much less potent (you’d need about 10 times the amount of retinol to match the potency of retinal or tretinoin).
To be fair to retinol though, you could increase the concentration of retinol to match the potency of retinal or tretinoin. However, retinol at a very high concentration will also be highly irritating (remember the burning sensation caused by TRP receptor aggravation).
Efficacy increases with concentration though irritability also increases with the same. Faster results are seen with higher concentrations
With retinal, you’ll get the high potency without the high irritation. Plus, as an added bonus, retinal is an effective antibacterial that combats acne. So, we think retinal is the best retinoid for skincare use.
The only caveat is in the first few weeks or months of use when the skin is turning over and changing morphology in response to the retinoid. The more effective the retinoid is, the more difficult this initial period of peeling, dryness, and sun sensitivity may be to tolerate. In this initial stage, retinol, because it is less potent, may be advisable.
Part 4 - What are the things to watch out for when using retinoids?
Pause use if pregnant
For orally ingested retinoids (such as Accutane), the biggest concern is that they can disrupt the fetal development.
In contrast to orally ingested retinoids, topically applied retinoids are unlikely to reach the bloodstream (which can affect body functions outside of the skin).
Studies show no detectable effect of topical tretinoin on blood plasma levels. And in 25 years of topical tretinoin use, there have been no cases of related fetal disruption (Beckenback 2015, Mukherjee et al. 2006).
Nonetheless, topical retinoids are still not advised for pregnant women because the stakes are so high. Why take the risk when there are other great ingredients (such as Vitamin C, Niacinamide and AHA) that are fine to use during pregnancy?
Be diligent with sun protection
Retinoids are associated with increased sun sensitivity during the first few months of use as the surface skin cells rearrange and slough off as retinoids reboot the skin renewal cycle. Basically, you are peeling old skin and exposing new skin, so it makes sense to apply UV protection diligently.
Thankfully, heightened sun sensitivity disappears after the skin finds a new normal after several months of usage (Leydon et al. 2017, Mukherjee et al. 2006).
Part 5 - OK, I’m convinced. What should I look for in a retinoid skincare product?
Retinal (retinaldehyde), in our opinion, provides the best balance of high potency with relatively little irritation (with an added bonus of acne-fighting power). Retinal is what we recommend you to look out for when shopping for retinoid products.
For someone with sensitive skin who is new to retinoids, retinol in low to medium concentration (0.1% to 0.3%) could be a good way to start acclimating their skin to retinoids.
Tretinoin is available by prescription, and if tretinoin is what your doctor recommends to treat a specific condition, then go with your doctor’s recommendation. However, we believe tretinoin is the worst of the 3 retinoids for routine skincare purposes because tretinoin causes so much irritation.
The rule of thumb is simply to use the most potent formula your skin can tolerate. And just stick to using it consistently for the long run to reap lasting results.
Part 6 - How should I use retinoids and what other products go well with them?
Generally speaking, retinoids become less effective when exposed to sunlight, so we recommend applying retinoids once daily in the evening so you can get the maximum benefit from each application.
However, there is no reason that you can’t use retinoids in the morning. Just keep in mind that it might not be as effective as applying at night. And certainly don't go wild sun tanning and use a good sunscreen daily.
If your skin can tolerate it, you can layer retinoids with any other product, including AHA/BHA and Vitamin C.
Give plenty of time between applying different products, to let each product get absorbed on its own. Well formulated products should require no more than 2 minutes to absorb between each step.
Retinoids can reduce sebum production, and in the initial stages of skin skaling can lead to increased moisture loss, which can lead to skin dryness. So, incorporate products with other soothing ingredients in your routine. Niacinamide (Vitamin B3) and Panthenol (Vitamin B5) are both good skin conditioning ingredients that can help.
Based on skin concerns, here are other key ingredients we recommend to use along with retinoids:
Acne treatment and prevention: Retinal specifically (due to its unique antibacterial power), BHA/AHA and niacinamide
Wrinkle treatment and prevention: Retinal or retinol, Vitamin C, AHA and sunscreen (zinc oxide for UVA and UVB rays protection)
Pigmentation treatment: Retinal or retinol, arbutin, Vitamin C, kojic acid and AHA
Part 7 - Final thoughts
To recap, retinoids are extensively studied and proven skincare ingredients that combat signs of sun-damage and aging.
On the other hand, retinoids can be irritating, and these irritations cause many people to give up on retinoid treatment prematurely.
The first few weeks will have the most irritation such as peeling and sun sensitivity as the skin changes its morphology, but these morphologically related sources of irritation will disappear over time. Hence, usage of retinoids requires patience.
Other sources of irritation such as burning sensations from TRP channel activation, or irritation from the carboxylic acid end of tretinoin can be lessened by using a retinal (retinaldehyde) product instead of retinol or tretinoin.
Have patience and you will start to see results after a few weeks to months (depending on the strength of the product - the stronger it is, the quicker it will yield results).
Retinal is the stronger and superior ingredient, but if you’re new to retinoids then your skin might prefer a lower concentration (0.1% to 0.3%) retinol in order to ramp up to the stronger retinal.
The best product is the one you’d actually use, so find a product that you enjoy using and stick to it regularly. As your doctor would tell you, adherence and consistency are the keys to achieving success and retaining good results for the long run.
Why we wrote this
There is so much information about skin care on the internet, and it can be bewildering to figure out what to believe.
We wanted to summarize the main, validated scientific findings on the what and the how of beneficial skincare ingredients in a deep, but fun and easy to understand (hopefully) manner. That way, you'll be better informed about how skincare ingredients and products work. We hope that you’ll also be empowered to filter information and have more productive conversations with your physician.
This writeup is not a sales pitch but is meant to provide you with helpful information that can be verified with available public information. So, there are no mentions of proprietary research or specific product recommendations.
Appendix A - Other related compounds
There are four generations of retinoids, with the first generation (non-aromatics) being naturally occurring and covered earlier: retinol (also known as all-trans retinol), retinal (or retinaldehyde), tretinoin (also known as all-trans retinoic acid or Retin-A), isotretinoin (also known as 13-cis retinoic acid or Accutane), alitretinoin (also known as 9-cis retinoic acid), retinyl-palmitate, and retinyl-acetate (Babamiri 2010, Beckenbach et al. 2015, Mukherjee et al. 2006, Zasada and Budzisz 2019).
Second, third, and fourth-generation retinoids are synthetic. The second generation includes etretinate and acitretin (mono-aromatics), the third generation includes bexarotene, adapalene and tazarotene (poly-aromatics), and the fourth generation includes Seletinoid G (Beckenbach et al. 2015, Mukherjee et al. 2006).
Table: Systemic prescription therapies reproduced from Beckenbach et al. 2015
Systemic therapies (oral ingestion) include isotretinoin (Accutane) for severe, therapy-refractory forms of acne, alitretinoin for hand-eczema, while etretinate or acitretin are preferred for psoriasis or ichthyosis (Beckenback 2015).
Rare skin diseases such as Pityriasis rubra pilaris and Darier’s disease may also be treated with these prescription retinoids (Beckenback 2015).
Bexarotene is used for cutaneous T-cell lymphoma (Beckenback 2015).
Systemic retinoids may have a very long half-life as they are stored in fat tissue. For example, etretinate and acitretin is highly lipophilic and may be detected in the body two years after therapy. Alitretinoin, isotretinoin, and bexarotene may linger in the body for months.
As these systemic retinoids can lead to birth defects in growing embryos, caution should be used with systemic retinoids. Other adverse effects are notable for systemic therapies though some are more specific for the particular compound. Bexarotene for example may cause hypothyroidism due to its selective RXR agonist activity (Goldfarb et al. 1987; Beckenback 2015).
Table: Topical prescription therapies reproduced from Beckenbach et al. 2015
Tretinoin (retinoic acid and the most investigated retinoid) is used for acne, intrinsic aging and photoaging, post-inflammatory hyperpigmentation, and melasma (Beckenback 2015, Mukherjee et al 2006). Efficacy increases with concentration though irritability also increases with the same. Faster results are seen with higher concentrations (Leydon et al. 2017, Mukherjee et al. 2006).
For Adapalene and Tazorotene, unlike the first generation of retinoids, these polyaromatics have differing affinities for RAR receptor subtypes. Hence, they may have value for targeted purposes. Adapalene is less irritating than tretinoin and can be prescribed for Acne treatment. Tazarotene is similarly irritating as tretinoin, but has efficacy in Psoriasis (Leydon et al. 2017, Mukherjee et al. 2006). These prescription-only creams may be useful in those with severe acne or psoriasis.
For retinyl-acetate and retinyl-palmitate (retinyl esters), enzymes required for a first step of cleavage of the ester bond to turn these esters into retinol are present in the skin, but are too slow and inefficient for there to be much meaningful conversion. For this reason, these retinoids have not been found to be as effective as retinol (Mukherjee et al. 2006, Sorg et al. 2006, Zasada and Budsisz 2019).
Bakuchiol, a relatively little studied retinol-like compound has been shown in a limited clinical trial to have similar efficacy as retinol in terms of wrinkle surface area and hyperpigmentation but with less irritation (Dhaliwal et al. 2019).
However, in this study, subjects applied bakuchiol twice a day compared to retinol application once a day nightly suggesting bakuchiol may require more upkeep.
Further, retinol is a weaker retinoid than retinal and the comparison between bakuchiol and retinal has not been done. Lastly, bakuchiol has not been as extensively studied as retinoids have been. However, as more studies in bakuchiol are conducted, it could prove to be a useful compound for skincare.
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