Melasma, solar lentigines, or post-inflammatory hyperpigmentation--these are just some of the common causes of uneven skin tone that people have to live with. The lesions may be skin-deep, but the effects are far-reaching. Both anecdotal and scientific evidence show that the conditions contribute to negative self-perception, impair social interactions, and ultimately lead to poorer quality-of-life (Darji et al., 2017; Jiang et al., 2018).
If you suffer from hyperpigmentary disorders, you are probably already familiar with available treatments. The likes of hydroquinone, retinoids, alpha hydroxy acids, and Vitamin C have been mainstays in the industry. Therapies like microneedling, laser resurfacing, and chemical peels may also be used in tandem with topical agents.
But while these treatments have been improving the human complexion for years, the search continues for ever better options--and one that is generating a lot of buzz is cysteamine.
What is cysteamine?
Cysteamine is a compound that is produced in the process of breaking down dietary fat and converting it into energy. Mammalian cells produce this substance naturally, so you find it in your body, in the animal products you eat--and even in human breast milk (Desai et al., 2021)!
The fact that it is already present within our bodies provides good evidence for its safety profile. The fact that it fulfills a critical physiological function tells us that there could be several applications for this compound in disease conditions.
What are the indications for cysteamine?
Cysteamine was first introduced as a drug in the 1950s. It has been tested as a treatment for a wide variety of conditions, from sickle cell anemia to radiation poisoning, paracetamol toxicity to HIV-1 infection. However, results have been variable so development always fell through. Among these, it has only been successfully used as an oral treatment for cystinosis, a rare genetic disorder that leads to kidney disease.
With further research and technological advancements, researchers now have a renewed interest in cysteamine. There are trials exploring its use in neurodegenerative disorders like Parkinson’s disease, Huntington’s disease, non-alcoholic fatty liver disease, and malaria (Besouw et al., 2013).
But among the medical fields, perhaps there is none more excited for the potential of cysteamine than dermatology. With powerful depigmenting effects, this up-and-comer could just earn a spot in the hearts (and medicine cabinets) of those who suffer from hyperpigmentary disorders.
How does cysteamine improve hyperpigmentation?
Cysteamine’s skin lightening effect was first noted in black goldfishes. A study by Chavin and Schlessinger (1966) found that application of cysteamine on these fishes turned them white. This was soon followed by another study by Frenk et al. (1968) which compared the effect of cysteamine to hydroquinone on black guinea pigs. In a case of David versus Goliath, it was found that cysteamine was more effective at depigmentation.
If evidence from 60 years ago shows that it works better than the gold standard, why is it only now that cysteamine is being used as a depigmenting agent?
Funnily enough, it’s because it stinks---literally. Cysteamine has a foul, pungent odor that was not acceptable to many patients and consumers. In fact, cystinosis patients who take oral cysteamine tend to develop halitosis or bad breath (Besouw et al., 2007), which is one reason why people discontinue its use. In addition, it can be quite unstable, readily converting to cystamine when oxidized. These issues have limited its therapeutic use.
But there is no doubt that cysteamine is a potent depigmenting agent. It has multiple mechanisms of action that promote an even-toned and healthy complexion:
Enzyme inhibition
Cysteamine is able to stop the process of skin darkening in its tracks by inhibiting not just one, but two key enzymes (Atallah et al., 2020). Tyrosinase is required for the first few steps of melanin production, since it is responsible for producing its precursors. Peroxidase is involved in the final steps of producing eumelanin, which is the dark brown or black-colored type of skin pigment. With both these enzymes out of commission, the process of pigment production is effectively stopped.
In addition, cysteamine binds copper (Besouw et al., 2013; Desai et al., 2021). There is clear evidence that tyrosinase’s molecular structure includes a pair of copper ions at its active site (Solano, 2018). When cysteamine hoards the free copper, tyrosinase cannot perform effectively.
Sequestration of melanin precursors
As if inhibiting enzymes isn’t enough, cysteamine also interacts with the products of these enzymatic reactions and diverts them from being used in the next steps of pigment production (Qui et al., 2000). It withdraws melanin precursors from the process. So if there are a couple of enzymes that do manage to escape from the clutches of cysteamine, the precursors they make will still not get to the finish line to become melanin.
Antioxidant activity
Our bodies sustain damage at the cellular level by the production of free radicals. These unstable chemicals wreak havoc, and one of our body’s natural defenses are antioxidants. Cysteamine has been found to stimulate the entry of an amino acid cysteine into cells, where it undergoes chemical reactions to produce the powerful antioxidant glutathione.
Endogenous glutathione is critical to making sure the cells in our body are in top form--including the cells in our skin. By scavenging for those harmful free radicals, glutathione keeps our skin protected.
Is cysteamine effective?
Based on published research, the answer is a resounding yes.
Numerous case reports have shown that cysteamine works well on a wide variety of patients, skin types, and hyperpigmentary disorders. Cysteamine has been used to successfully treat an Indian man with extensive post-inflammatory hyperpigmentation from back acne (Vyas, 2021).
A randomized, double-blind clinical trial conducted by Mansouri et al. (2015) recruited 50 melasma patients to test the efficacy of cysteamine. Half the patients were put on a cysteamine regimen, and the other half were given a placebo. At the start of the study, the baseline measurements were taken using a skin colorimeter device to gauge the contrast between the patient’s normally pigmented skin and their melasma patches. By the end of the 4-month study period, the average color difference of the cysteamine group went from 75.2 all the way down to 26.2, while the placebo group went from 68.9 to a mere 60.7. The cysteamine group also had lower scores on the Melasma Area Severity Index (MASI) compared to those who used the placebo. Based on scores given by experts using the Investigator’s Global Assessment scale and the questionnaire filled out by the patients, the improvement was palpable.
These results were similar to the study conducted by Farshi et al. (2017) which used a newer and more technologically advanced skin colorimeter. The cysteamine group went from a color difference of 72.3 to 23.8 at the end of the study period.
A double-blind, randomized clinical trial conducted by Saki (2021) found that cysteamine 5% cream was able to reduce the colorimeter reading between normally pigmented skin and senile lentigines on the hands of 30 patients. It is important to note that conventional depigmenting treatments, including Kligman’s formula, are largely ineffective against lentigines, also known as sun spots or liver spots. So this is big news for those who suffer from this hyperpigmentary condition!
A systematic review conducted by Ahramiyanpour (2021) included five randomized clinical trials, two case reports, and one case series on the use of 5% cysteamine cream on melasma patients. They concluded that it is an effective depigmenting agent that had minor and temporary side effects, but more studies with larger number of participants and over a longer period of time are needed to cement its status as a player in the melasma treatment industry.
With the buzz cysteamine has generated, there is a growing body of research to find out how to harness its effects in an even more effective way. Atallah et al. (2021) found that liposomal encapsulation of cysteamine improved the molecule’s chemical stability and its ability to penetrate into the deeper layers of the skin.
How does cysteamine compare to other depigmenting agents?
Based on a number of studies, cysteamine appears to hold its own among the giants in the industry. Most studies show that it works just as well as Kligman’s solution, if not better than. It is consistently associated with less adverse effects than other depigmenting agents, likely because it only inhibits enzymes rather than damage the cells involved in melanin production (Downie et al., 2020).
A case report of a woman with chronic and severe post-inflammatory hyperpigmentation from recurring facial rashes found that four months of cysteamine treatment did more to improve the dark marks compared to a previous bout of treatment with topical adapalene 0.1% gel and Kligman’s formula (Mathe et al., 2020). Another case report showed that cysteamine is effective and safe in a 44-year old woman with melasma resistant to Kligman’s formula (Kasraee et al., 2018). The patient was followed for the next three years and no adverse effects were reported.
Studies conducted by Lima et al. (2020) and Nguyen et al. (2021) found that cysteamine 5% lightened the skin in treating women with facial melasma, but it was not as effective as hydroquinone 4%. However, it was well-tolerated and had less adverse side effects.
A double-blind, randomized clinical trial conducted by Karrabi et al. (2021) recruited 50 patients suffering from epidermal melasma. Half of the participants were asked to apply modified Kligman’s formula (4% hydroquinone, 0.05% retinoic acid and 0.1% betamethasone), while the other half were asked to apply cysteamine 5% cream. At the end of the 4-month study period, the cysteamine group has a significantly better modified MASI score. In this study, cysteamine was not only more effective than the top-choice melasma treatment, it also had less adverse effects.
A single-blind, randomized clinical trial conducted by Karrabi et al. (2021) found that applying cysteamine 5% cream for 30 minutes before bed for four months was just as effective as transdermal injections of tranexamic acid every 4 weeks for two months. However, the tranexamic acid therapy was more likely to result in redness, itching, stinging, and irritation as compared to cysteamine.
What are the benefits of cysteamine?
Safe for all skin types
Depigmenting agents and therapies may cause a wide variety of side effects, including itching, redness, peeling, and a stinging or burning sensation (Solano et al., 2006). On the other hand, studies consistently show that cysteamine is very well-tolerated by a wide variety of patients.
Another potential side effect is hypo- or hyperpigmentation, especially in Fitzpatrick skin types that tan rather than burn under sun. For example, long-term and unsupervised use of topical hydroquinone has been associated with the development of exogenous ochronosis (Bhattar, 2015), while microneedling has been known to cause post-inflammatory hyperpigmentation due to damage to the skin (Gowda et al., 2021), especially in darker-skinned patients. Meanwhile, cysteamine has been successfully used in Fitzpatrick skin types III and above with no reported dyspigmentation side effects (Downie et al., 2020; Mathe et al., 2020).
Does not cause sun sensitivity
Cysteamine is compatible with sun exposure (Atallah et al., 2020), unlike other depigmenting agents that tend to make the skin more reactive to UV rays. It can be applied throughout the year, regardless of how intense the sunlight is. That being said, sunscreen and sun protection measures are still crucial to skin health, regardless of skin type and condition.
Convenient application
Cysteamine 5% creams are applied one to two times a day to the hyperpigmented areas of the skin. It is left on for 15 minutes, then washed off using soap and water. This is followed by applying moisturizer and sunscreen.
Relatively fast results
Most clinical trials and case reports on cysteamine show a significant and visually apparent improvement in 8-12 weeks of use. To maintain its effect, it should be used as maintenance therapy twice weekly. There are no reported issues with long-term use, so cysteamine can be used indefinitely.
This content is for general information only and is not a substitute for medical advice.
References:
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