Can Sandalore®, a Cheap Synthetic Replacement of Sandal-wood Extracts in Perfumes, Regrow Your Lost Scalp Hair?

It's not clear if natural sandalwood extract will do the same as the synthetic sandalore that's used as a cheap sandal-wood replacement in perfumes (for more info on the difference read the green infobox in the bottom-line).

A recent press release has been the #3 most viewed and debated posts on my social media accounts, recently; second only to my MTHFR and sucralose articles, the press release from my "colleagues" at the University of Münster (obviously I am working on my Ph.D. at the Physics Department, not at the Dermatology Department ;-) created quite a stir not just among SuppVersity readers, but also among the general public from A as Australia to Z as Zambia (well, almost *lol*).

But let's be honest: Is that really surprising? If you take into consideration that >50% of the male population and an ever-increasing number of females is affected by excess hair loss - reasons include regular aging (Van Neste 2004, Trüeb 2005 & 2006), hormonal imbalances (Bergfeld 2009; Blume-Peytavi 2012) - esp. in women w/ PCOS (Goodman 2015), smoking Mosley 1996), medications (Mercke 2000) etc.

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Many of you will remember my hair-loss remedy articles from July 2017 and May 2018. Both of them have already made the TOP-List of most popular articles on the SuppVersity: Hair loss is simply a 'popular' topic I guess ;-) The latter can also be seen if you google "sandalwood hair loss" and count the number of articles that have been published echoing the previously referenced press release that accompanied the publication of the recent study by Chéret et al. in Nature Communications an offshoot of the prestigious scientific journal Nature roughly a week ago.

Obviously, the (science-)news-outlets are well aware that millions of people worldwide are - despite existing hair-loss remedies - still looking for techniques to help them maintain or regrow thick hair. Needless to say that these people will read articles like the one on the website of "The Independent", which features no one else but President Trump as an (obviously) unofficial brand ambassador for the freshly baked (2017) patent holders from Giuliani S.P.A. and reports:

If you haven't done so already, read my previous article about tried and proven methods of battling hair loss and regrowing thick hair: "Hair Loss: Nutrient Deficiencies, Supps, Herbal Shampoo Ingredients, and Egg Yolk Hair Masks for Alopecia | Plus: Carcinogens & Endocrine Disruptors in Your Shampoos" | read more

"With millions of men and women in the UK affected by hair loss, demand for a 'baldness cure' is high. Despite some promising studies over the years, many do not make it beyond the confines of the research lab. 

According to Professor Paus, however, his latest discovery is 'not far at all' from being applied in a clinical context for hair loss. 'Sandalore is already offer-ed as a cosmetic product in Italy by the company that has co-sponsored the current study,' he said. 'A very small, short and preliminary clinical pilot study perform-ed by an independent CRO [contract research organi-sation] in 20 female volunteers w/ topical Sandalore has already suggested a reduction of daily hair loss.' 

[...] Dr Nicola Clayton of the British Association of Dermatologists, who was not involved in the study, said: 'It is a fascinating concept that the human hair follicle, as the authors put it, can ‘smell’ by utilising an olfactory receptor.' She said the group’s data was 'very exciting', although noted that from clinical perspective she could only speculate about the extent to which such a treatment would improve outcomes for patients." (The Indpendent 2018 | my emphasis).

Sounds awesome, doesn't it? Not exactly? Well, I guess, as a Suppversity reader you are smart enough not to believe the often interpretations of contemporary research in mainstream-media articles that are based on already hyperbolically written press releases by now ;-)

So, what's the verdict on the actual data? Can rubbing the synthetic sandalwood scent onto your scalp stop hair loss in the tracks and (re-)grow full hair?

To answer this question it is imperative to read and analyze the previously referenced article in Nature Communications (Chéret 2018), as well as related research (assuming it exists) that supports the notion that there's a hitherto overlooked alternative way to interpret the phrase 'your skin smells...' - namely, in the sense of 'smelling' = 'your skin's olfactory [=relating to the sense of smell] receptors detect a smell and trigger changes in protein/peptide and gene expression that exert far-reaching, important physiological effects'.

What else can the research tell us about sandalore? Most of the practically relevant research on the influence of sandalore on the non-olfactory tissue has unquestionably been done in the skin. The most exciting result, so far, has probably been the observation that the sandalore-induced activation of the OR2AT4 receptor stimulates the keratinocytes and ramps up cell proliferation and migration, thus promoting the regeneration of keratinocyte monolayers in an in vitro wound scratch assay (Busse 2014). In view of this promising research, it's no wonder that two of the authors of the study at hand have already filed a patent on sandalore's use as "wound healing agent" in whatever form may prove suitable (ointment, cream, gel, etc.) before they knew it could be an effective anti-hair-loss treatment (A patent has already been filed for this purpose, too. It describes a number of potential consumer products, including shampoos, conditioners, hair rinse, hair coloring agents, permanent-wave agents, wax, hair spray, and mousse).

Table 1: The list of known ligands of the various olfactory-receptors in our bodies is longer than you may have thought and it includes old friends and foes including short-chain fatty acids, lactate, or even ketones (Chen 2018). Whether and to which extent their well-known health-effects are actually mediated by interactions with olfactory receptors does yet have to be finally determined for each outcome and target tissue in particular.

As you may have guessed, though, our skin is not the only tissue that expresses 'smell-receptors'. In fact, if you dig somewhat deeper into the literature, you will find that OR2AT4 and other olfactory receptors are present in the heart, the lungs, sperm, the brain (neurons), and even cancerous tissues. The omnipresence of these receptors in the human body inspired researchers all over the world to speculate that ligands that either block or activate certain olfactory receptors may help prevent or counter or at least ameliorate glucose control in diabetes, blood pressure in hypertension, tumor cell proliferation, apoptosis, metastasis in cancer, and the invasiveness, as well as the occurrence of obesity, and atherosclerosis (for a list of potential receptor ligands and their effects, check out Table 1 from the most recent review by Chen et al. (2018).

Out of the many olfactory receptors in our body, the subcutaneous olfactory receptor OR2AT4 is the receptor of interest here - it is one of the previously hinted at plethora of olfactory receptors that are not located where you'd probably look for them, i.e. in your nasal epithelium. These 'extra-nasal' receptors are considered to be part of an evolutionarily ancient chemosensory signaling system that had (initially) nothing to do with 'smelling' and everything with other important physiological functions related to human cell physiology in the skin (Gelis 2016) and elsewhere (earlier findings point to sperm and the enterochromaffin cells of the gut | Flegel 2015, Braun 2007 | learn more in the blue infobox).

Chéret et al. got news for you: When your skin 'smells' synthetic sandalwood scents, ...

The novel finding of the international research team from the University of Münster, the Ruhr-University Bochum, the University of Manchester, and the Monasterium Laboratory, Skin and Hair Research Solutions GmbH is that the activation of a specific type of these receptors, the OR2AT4 receptors, in the human skin will stimulate not just wound healing (which has previously been demonstrated by the same research team, by the way | Busse 2014), but, as the press release claims, also hair growth.

Figure 1: Illustration of the different stages of the hair cycle from Alonso 2006.

In that, the effect is thought to be a direct response to the activation of the receptor by a molecule that has hitherto been considered to be nothing but a cheap replacement of natural sandalwood extracts for the perfume industry (Mimoun 1996). If Chéret et al. are right, though, this substance that goes by the name sandalore docks to a receptor on human hair follicle cells and prolongs the anagen phase (=growth | see Figure 1), i.e. the active phase, of the hair cycle, while decreasing keratinocytes apoptosis (=cell death | see Figure 1) and increasing increasing the production of hair-growth promoting IGF-1 in the outer root sheath (ORS | the epidermal basal layer which envelopes the entire hair follicle) of the hair follicles. And, in fact, in the present study, the scientists from University of Münster were able to demonstrate that...

• humans express the OR2AT4 receptor in their skin, ...
• any effects on the hair follicles are mediated by the OR2AT4 receptor, ...
• said effect is multi-factorial, i.e. it is the result of a downregulation of pro-apoptotic and the upregulation of anti-apoptotic genes, as well as the activation of the IGF pathway, and... 
• the activation of the OR2AT4 receptor is required to sustain hair follicle growth...

by co-administering a substance called Phenirat®, which blocks the OR2AT4 receptor, as well as the use of a specific knock-down of OR2AT4 in human hair follicles. What they did not do, however, is to provide evidence that an actual hair-growth effect will occur in response to the use of shampoos, conditioners, hair rinse, hair coloring agents, permanent-wave agents, wax, hair spray, or mousse, which contain sandalore or, as the researchers prefer to write to highlight that they patented its use for this purpose, "Sandalore®".

Figure 2: Hair cycle score and staging were evaluated in treated and vehicle HFs from 3 donors (independent experiments) after 6 days of culture using Ki-67/TUNEL immunofluorescence and Masson–Fontana histochemistry (Chéret 2018).

In Figure 2 you can see how the exposition to sandalore affected the hair follicle growth cycle in human skin samples from the temple-region, which is one of the most 'hair-loss-susceptible' regions on our scalp, and the occipital (back of the head) region, where hair loss usually occurs last. Overall, the analysis of the response of the skin patches that were exposed to 500µM of sandalore and their comparison to control (vehicle) and (co-)treatment with the OR2AT4 receptor inhibitor Phenirat confirm the aforementioned benefits: (a) sandalore can profoundly prolong the anagen (=the active phase of the hair growth cycle) and (b) shorten the catagen (=transitional phase in the hair growth cycle, during which growth stops) stage in the life-cycle of your hair.

So it works, Great!? Well, I should remind you that what the scientists haven't demonstrated (yet) is that the growth-prolonging/-promoting effects of sandalore are still relevant if the hair follicles are exposed to an environment that promotes hair loss, instead of the neutral or even hair-growth friendly environment in the Petri dishes of a sterile lab.

I have to admit, it is likely that this is the case, but it is absolutely unpredictable which of the stimuli will gain the upper-hand: The hair-loss-stimulus of e.g. excess DHT, a lack of estrogen, the mere process of aging, etc. or the hair-growth-stimulus sandalore exerts by activating the OR2AT4 receptor.  Practically speaking this means:

1. A significant, let alone visible (re-)growth of hair would only occur if the hair-growth-promoting effect of sandalore is significantly more pronounced than the effects of inhibitory factors that shorten the anagen growth phase, and hence impair hair-growth and prepone the transition into the regressive catagen phase of the hair cycle. 
2. The maintenance of thick hair can only be expected to be achieved if sandalore's growth-promoting effects are about as potent as the effects of the factors that promote the transition into the catagen and telogen phase (cf. Figure 1).
3. At best a small reduction of the transition-speed from full to thin and, eventually, no hair can be expected if the effects of the purported anti-hair-loss remedy are less potent than those individual factors which cause hair loss, in the first place.

For whom sandalore will ultimately be useful, ultimately depends on which of these three possibilities will be observed in the real-world (and/or clinical human trials). Possible answers to that question are: those who suffer from thinning hair and want to regrow thick hair (i), individuals who want to stop their excessive hair loss in the tracks (ii), or people for whom hair loss is not an issue and the small effect (iii) of sandalore is not countered by the growth inhibiting apoptotic environment that is characteristic of those of us who're 'going bald one hair at a time'.

Hair loss is more prevalent in men, but it is by no means a male exclusive. Some treatment modalities, however, are sex-specific, with finasteride being effective only in men (and women w/ PCOS) and laser light or topical minoxidil having research support in form of studies in men and women.

So what's the verdict, then? It is just what the scientists write in the conclusion to their paper: "Taken together, [their] ex vivo data suggest that olfactotherapy by topically applied cosmetic OR2AT4 ligands like Sandalore® may promote human hair growth by prolonging anagen and inhibiting premature catagen development (e.g., in androgenetic alopecia and telogen effluvium)" (my emphasis in Chéret 2018).

For Donald Trump (see article on independent.co.uk) and everyone else who is proud of his/her superb head of hair, this means that we don't know if smelling like sandalwood for hours - which is an almost certain side effect of using pertinent products - will do anything for them but scare everyone away who hates the woody smell of sandalwood.

The chemical structure of the naturally occurring alhpa- and beta-santanol molecules and the artificially synthesized sandalore are significantly different (from the patent)

Don't ask bro! No, as hinted at previously, you can not simply use sandalwood extracts or native sandalwood oil. Sandalore's chemical structure is "quite distinct from the [corresponding] ingredients of natural sandalwood oil, that is, α-santalol e β-santalol" (Patent). Hence, you mustn't expect to see the same results with natural sandalwood extracts/oils as with sandalore.

If you still want to give this new hair-loss remedy a try, I guess, buying an oil that either has "sandalore" or "givaudan", "synthetic sandalwood" or the phrase "sandalwood fragrance oil" on the label (ordered according to likelihood that what you buy is actually the cheap synthetic stuff you want to rub onto your skin) is probably the best you can do to increase your chance of success. On the other hand, you should stay away from products that are labeled as "natural", "native", or "pure". While those may be the go-to products for people who want to design an rarefied perfume, the different chemical structure of their constituents (compared to the synthetic sandalore) will reduce the IMHO already rather slim chance that you'll see significant hair-growth on a bald(-ing patch of your) scalp even further... if you need formulation suggestions for N=1 experiments, the "examples" section in the patent may inspire you.

And the fact that Prof. Paus from the University of Münster claims that "[a] very small, short and preliminary clinical pilot study performed by an independent CRO [contract research organization] in 20 female volunteers with topical Sandalore has already suggested a reduction of daily hair loss," doesn't mean that large(r) scale peer-reviewed human trials will (a) confirm this result and, more importantly, (b) prove that the effect is significant enough to turn a balding scalp into a hotbed for human hair follicles.

If you asked me for my best guess of how effective it's going to be, I'd say that sandalore is probably going to fall into the previously mentioned category of products that will help you preserve the status quo - hopefully with more pronounced effects than the average caffeine shampoo or liquid, the effects of which I've discussed in my previous hair-loss-remedy review | Comment!

References:

• Alonso, Laura, and Elaine Fuchs. "The hair cycle." Journal of cell science 119.3 (2006): 391-393.
• Bergfeld, Wilma. "Diffuse hair loss: its triggers and management." Cleveland Clinic journal of medicine 76.6 (2009): 361.
• Blume-Peytavi, Ulrike, et al. "Skin academy: hair, skin, hormones and menopause–current status/knowledge on the management of hair disorders in menopausal women." European Journal of Dermatology 22.3 (2012): 310-318.
• Braun, Thomas, et al. "Enterochromaffin cells of the human gut: sensors for spices and odorants." Gastroenterology 132.5 (2007): 1890-1901.
• Busse, Daniela, et al. "A synthetic sandalwood odorant induces wound-healing processes in human keratinocytes via the olfactory receptor OR2AT4." Journal of investigative dermatology 134.11 (2014): 2823-2832.
• Chen, Zhe, et al. "The diversified function and potential therapy of ectopic olfactory receptors in non‐olfactory tissues." Journal of cellular physiology 233.3 (2018): 2104-2115.
• Chéret, Jérémy, et al. "Olfactory receptor OR2AT4 regulates human hair growth." Nature communications 9.1 (2018): 3624.
• Flegel, Caroline, et al. "Characterization of the olfactory receptors expressed in human spermatozoa." Frontiers in molecular biosciences 2 (2016): 73.
• Gelis, Lian, et al. "Functional characterization of the odorant receptor 51E2 in human melanocytes." Journal of Biological Chemistry (2016): jbc-M116.
• Goodman, Neil F., et al. "American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society disease state clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome-part 1." Endocrine Practice 21.11 (2015): 1291-1300.
• Mercke, Yekaterina, et al. "Hair loss in psychopharmacology." Annals of clinical psychiatry 12.1 (2000): 35-42.
• Mimoun, Hubert. "Catalytic opportunities in the flavor and fragrance industry." CHIMIA International Journal for Chemistry 50.12 (1996): 620-625.
• Mosley, J. G., and A. C. C. Gibbs. "Premature grey hair and hair loss among smokers: a new opportunity for health education?." Bmj 313.7072 (1996): 1616.
• Trüeb, Ralph M. "Aging of hair." Journal of cosmetic dermatology 4.2 (2005): 60-72.
• Trüeb, Ralph M. "Pharmacologic interventions in aging hair." Clinical interventions in aging 1.2 (2006): 121.
• Van Neste, Dominique, and Desmond J. Tobin. "Hair cycle and hair pigmentation: dynamic interactions and changes associated with aging." Micron 35.3 (2004): 193-200.