Patent Application
20230310305
N/A
The present application is in the area of topical compositions for stimulating hair growth and more specifically relates to the use of a class of cannabinoids known as varins for this purpose.
Human beings are one of the few primates that have head hair that shows essentially indeterminate growth (growth of individual hair strands lasting for several years). (This is also true of the facial hair (beard) exhibited by human males.) Most mammals have body hair (“fur”) that exhibits determinate growth (growth of individual strands lasting only days or weeks) so that hairs are all of a uniform length. This is true also of the sparse body hair that most humans exhibit. It is not clear why human head hair shows an indeterminate growth pattern. In any case human head hair seems to cause a lot of problems. Both males and females may spend a lot of time styling and arranging their hair. Hair is often considered to affect an individual's attractiveness. Therefore, loss of hair is often distressing to an individual.
Androgenetic alopecia (AGA) is a common condition that occurs in both males and females and increases in prevalence with age. It is by far the most common cause of baldness. It generally starts in the third and fourth decades of life and significantly increases in prevalence in women after menopause.2, 3 Is it estimated that 50% of Caucasian males and 19% of Caucasian females are affected by age 50, and there is a lower prevalence and severity of the condition in Asian and black males.4 AGA may adversely impact a person both psychologically and socially, especially in females5 The condition is characterized by follicular miniaturization in a specific pattern due to the effects of systemic androgens and genetic factors.6
In the male pattern phenotype, the hairline regresses at the bitemporal regions and at the vertex, and in the female pattern, there is diffuse thinning with preservation of the frontal hairline; however, the pathogenesis is the same.5, 7 AGA develops due to a disturbance in the cyclic transformation of hair follicles from active hair shaft growth and pigment production (anagen phase) to apoptosis-driven (cell death) hair follicle involution (catagen phase).2
The pathology of hair loss, especially female AGA, is complex with many gaps in our understanding of pathophysiology. In normal head hair growth, the hair follicles cycle through distinct phases.9 Growth, known as anagen phase, can last up to six years. Ninety percent of the follicles are usually in this phase. In this phase the hair shaft extends and thickens due to matrix cell activity. This is followed for the catagen or resting phase. Only about one percent of follicles are usually in this phase. In this phase, the follicle regresses. This is followed by a period of quiescence known as the telogen phase. About nine percent of follicles are usually in this phase. The last phase is call the exogen phase with the release of the hair shaft. The proportion of follicles in anagen phase declines with age.10, 11
The signals that cause the transition between the various phases of the hair follicle growth are not well understood. There is complex signaling cycles between the root sheath and the dermal papillae, involving several protein families including fibroblast growth factors and bone morphogenic proteins; sonic hedgehog and Wnt signaling are involved.11
In males, androgens are usually involved. It is known that in many males, dihydrotestosterone (DHT), synthesized from testosterone by 5a reductases, is a major player.12 The intracellular signaling cascade after androgen receptor binding by DHT is poorly understood. In females, there is less evidence regarding the involvement of androgens. The higher prevalence of AGA in post-menopausal females, however, does indicate some sort of association with hormone levels.13
Consequently, there is considerable economic activity dealing with hair loss. The oldest means of dealing with hair loss is cosmetic including a variety of wigs, toupees, colorants, hair building fibers, etc. However, many individuals seek a more permanent solution to hair loss. The most successful medical answer is probably hair transplantation in which hair follicles are transplanted from a region of the head that has not experienced hair loss to a region where hair has been lost. Unfortunately, hair transplantation is expensive, can be painful, and is limited by the availability of hair follicles from reasons that have not experienced hair loss.
The potential drawbacks to hair transplantation has led to a search for topical compositions and drugs that can counteract hair loss. There is a long history of various herbal compositions that supposedly retard or reverse hair loss. Unfortunately, there is little reliable data to support the efficacy of such compositions. Perhaps the first topical treatment for hair loss that was supported by scientific data was minoxidil. This compound was originally developed as a blood pressure lowering agent that worked by promoting vascular dilation. Patients taking the drug showed enhanced hair growth, and this effect was shown to extend to topical applications of minoxidil (allowing targeted hair growth enhancement).
Only two medications, topical minoxidil and oral finasteride, are FDA approved for the treatment of AGA. Then can be used alone or in combination for synergistic effects.14 The FDA has approved no new medications in over 15 years. Finasteride, a 5a reductase inhibitor, blocks the conversion of testosterone to DHT15 has proven useful in the treatment of AGA3. However, finasteride is associated with several side effects, including sexual dysfunction that in some cases persists after ceasing therapy.16 Despite a small number of studies showing efficacy, the use of finasteride in women remains controversial, and only off-label, uncontrolled studies and anecdotal evidence have reported positive results17. Finasteride treatment in pre-menopausal women is also problematic, requiring concomitant contraceptive treatment due to the teratogenic nature of the compound.17
Topical minoxidil is the only known treatment that is effective in both males and females; however, the mechanism of action is unknown.18 Minoxidil is generally well tolerated but is also associated with several side effects, including an initial increase in hair shedding and exacerbation of hair loss following withdrawal from treatment.19
Unfortunately, these medications offer limited results.20-22 Recently, the combination of topical minoxidil and topical finasteride has shown more promising results.14, 23 Surgical hair transplantation is the only current successful permanent option. Several other medical options, including antiandrogens such as spironolactone, oral contraceptives, cyproterone, flutamide, dutasteride, prostaglandin analogs, and ketoconazole are reported to be beneficial. However, these treatments can be associated with significant adverse effects and are expensive.22 Laser and light therapies have also become popular despite the lack of documented profound benefit.24
A phase III clinical trial of men with AGA was conducted in 2021. The study used an investigational new topical drug called SM04554 which works by modulating the Wnt pathway that is postulated to initiate and maintain the anagen phase of the hair cycle.25 Wnt signaling also causes dermal progenitor cells to differentiate into new hair follicles. It is interesting to note that CBD has also been shown to increase Wnt signaling.26 To date, however, there is little basic science or clinical research on CBD and Wnt signaling.
A 2014 study investigated hair growth in mice using 3% peppermint oil compared to 3% minoxidil and jojoba oil. The results showed that peppermint oil (40% menthol) “showed the most prominent hair growth effects; a significant increase in dermal thickness, follicle number, and follicle depth.” The active ingredient in peppermint oil appears to be menthol, and peppermint oil is normally 40-50% menthol. The researchers suggested that peppermint oil induces a rapid anagen stage.1
Recently, with the increasing acceptance of Cannabis sativa-based therapies, hemp extract has come under consideration as a possible, effective, safe, inexpensive non-prescription, topical AGA therapy. A 2021 case study27 of CBD-rich hemp extract demonstrated 93.5% average increase in hair regrowth. Hemp extract works through the ECS in the body and has novel effects on hair follicle elongation and hair matrix keratinocytes activated through ECS receptors in the hair follicle cells.27 As such, the therapeutic effects of hemp extract should complement the physiologic effects of minoxidil, finasteride, and antiandrogen therapies.
THCV and CBDV are full CB1 antagonists, compared to CBD which is a partial CB1 antagonist.28, 29 Therefore, the therapeutic effects from CB1 blockade should be more marked with the addition of THCV and CBDV.28, 30 31 Until recently hemp extract with significant percentages of THCV and/or CBDV have been unavailable commercially.
The ECS was discovered in the 1990s. In essence, it is a system involved with maintaining cellular homeostasis in response to excess oxidative stress. It downregulates the damaging inflammatory response, and it upregulates regenerative processes. It is comprised of at several receptors, including cannabinoid receptor 1 and 2 (CB1 and CB2), vanilloid receptor-1 (TRPV1) and vanilloid receptor-4 (TRPV4). It has at least two messenger molecules known as the endocannabinoids, anandamide (AEA) and 2-arachidonylglycerol (2-AG).32 One of the many systems that the ECS is involved with is thermoregulation within the skin. There are a substantial number of CB1 and CB2 receptors on various cell types within the skin.33 CB1 receptors are well expressed in hair follicle cells.34
The hair follicle cycle (anagen, catagen, and telogen phases) is controlled by the TRPV1.35 TRPV1 receptors are found on hair matrix keratinocytes. Mouse studies have shown that activation TRPV1 receptors promotes hair follicle regression (catagen) and hair matrix keratinocyte apoptosis (cell death) and retardation of hair shaft elongation.35 Endocannabinoids, and cannabis-derived phytocannabinoids, such as tetrahydrocannabinol (THC) and CBD, message TRPV1 receptors. It is postulated that CBD has therapeutic effects via TRPV1 receptors by such excessive activation of the receptor that then become desensitized. 36
THC is a CB1 receptor agonist, and it has been shown to dose-dependently inhibit hair shaft elongation, decrease proliferation of hair matrix keratinocytes, and induce intraepithelial apoptosis and premature hair follicle regression (catagen). These effects from THC were inhibited by a selective CB1 antagonist.34, 35
The available research suggests that THC and other CB1 agonists can be used to manage unwanted hair growth, and likewise, CB1 antagonists, such as CBD, THCV and CBDV, can be used to promote hair growth.34 CBD is a CB1 partial antagonist that probably produces its effects via negative allosteric modulation of the CB1 receptor.37, 38 Whereas, THCV and CBDV are full neutral CB1 receptor antagonists.29
A recent study of human hair follicle cultured cells revealed that use of lower doses of CBD resulted in hair shaft elongation, probably via CB1 antagonism.39 However, much higher doses resulted in premature entry into the catagen phase, probably via a different receptor, the vanilloid receptor-4 (TRPV4). Therefore, the dosing of the topical CBD needs to be controlled to obtain positive hair growth.
Over the past decade, CBD has been extensively researched for a myriad of therapeutic benefits.40 CBD does not cause euphoria or addiction. It is safe, with a wide therapeutic window and few adverse effects. Topical application of CBD has not been associated with any significant adverse effects.33, 35 CBD in an oral form has been FDA approved for treatment of recalcitrant epilepsy. CBD in sublingual, oral, inhaled, and topical versions are relatively inexpensive and widely available as nutraceuticals. It is estimated that 14% of the U.S. population has tried CBD products.41
The cannabinoids such as CBD are fat-soluble and poorly absorbed through the epidermis, but properly formulated topical applications reach hair follicles where it is a CB1 antagonist and TRPV1 and TRPV4 agonist.39
THCV and CBDV, known together as the ‘varins,’ have not been as extensively researched because of the dearth of available hemp (low-THC Cannabis sativa) extract containing any significant amounts of these two cannabinoids. There has been considerable research of ingested varins derived from marijuana (high-THC Cannabis sativa) for the treatment of epilepsy42, obesity43 and diabetes mellitus.43
A study was conducted on subjects with androgenetic alopecia (AGA), to determine if daily topical application of a formulation with high CBD, THCV and CBDV concentrations would result in improved hair regrowth in the area of the scalp most affected by AGA. The study included 31 (15 men and 16 women, 27 Caucasian, 2 Asian and 1 mixed race) subjects. Participant ages ranged from 31 to 65 for the females and 39 to 64 for the males. The subjects gave their written informed consent for the six-month trial. The study adhered to the Helsinki guidelines and was institutionally approved. None of the subjects were currently using minoxidil or finasteride. No other hair loss treatments were used during the six months of the research study.
They used a once daily topical application of a high in CBD, THCV and CBDV cannabis extract formulation, averaging about 33 mg per day for six months. A hair count of the area showing the most significant alopecia was carried out before treatment was started and again after six months of treatment. To facilitate consistent hair count analysis, a permanent tattoo mark was placed at the point showing maximum hair loss on the scalp.
The subjects were photographed in a standard manner before and after the study. The photographs were compared for improvements in ‘scalp coverage’ by an independent physician. The qualitative scale included “none”, “mild”, “moderate”, “extensive” improvement of scalp coverage.
A hair count of the greatest area of alopecia was carried out before treatment was started and again after six months of treatment. To facilitate consistent hair count analysis a permanent black tattoo dot was placed at the point of maximum hair loss on the scalp. The non-vellus hairs within the 1 cm2 around the tattoo were pulled through the opening of a one-centimeter mold with a surgical skin hook and a hair count taken using a Bodelin ProScope with 50× magnification.
For all males, the baseline hair count was 6.13/cm2 and at six months, it was 21.20/cm2 (one-tailed paired t-test p<0.00001). This represented an average increase of 246% or 15.50 additional hairs in the one square centimeter mold. For all females, the baseline hair count was 12.69/cm2 and at six months, it was 28.75/cm2 (one-tailed paired t-test p<0.00001). This represented an average increase of 127% or 15.50 additional hairs in the one square centimeter mold. For all adults the baseline hair count was 9.50/cm2 and it increased after six months to 25.00 (one-tailed paired t-test p<0.00001). This represented an average increase of 164% or 15.50 additional hairs in the one square centimeter mold. All subjects showed some increase in hair count. The increase ranged from 31.25% in a female (16 to 21 hairs/cm2) to 2000% in a male (1 to 21 hairs/cm2). In general, the increased hair counts were associated with a cosmetically pleasing result.
This case study showed that topical hemp extract high in THCV, CBDV, CBD, menthol and peppermint oil is associated with significant hair regrowth in both men and women with AGA. This topical was superior to high-CBD hemp extract alone.27 In general, men did better than women. On average, there was a 164% (p<0.00001) increase in non-vellus hair after six months of once-daily use. All subjects had some regrowth and cosmetic benefits.
Although the exact mechanism of therapeutic effects is not currently known, CBD is most likely functioning as a CB1 receptor antagonist, via negative allosteric effects, and potentially also via Wnt messaging. THCV and CBDV are acting as full CB1 neutral antagonists and via TRPV1 agonism. The menthol and peppermint (40% menthol) are most likely acting by promoting the rapid onset of anagen phase1. Although the test was carried out on head hair, the formulation is effective on any region supporting non-vellus hair such as the beard.
The safety of topically applied cannabis extract has been previously well documented. Once again, there are no reported significant adverse effects for six-month topical application of cannabis extract.25, 26
Topical cannabis formulation results in superior results to finasteride and 5% minoxidil once daily foam. Since this extract works through novel mechanisms entirely different from finasteride and minoxidil, it can be used in conjunction with these current drugs and would be expected to have synergistic effects.
The following description is provided to enable any person skilled in the art to make and use the invention and sets forth the best modes contemplated by the inventor of carrying out his invention. Various modifications, however, will remain readily apparent to those skilled in the art, since the general principles of the present invention have been defined herein specifically to provide an improved hair growth promoting treatment based on a topical treatment high in cannabis-derived CBD, THCV and CBDV
Study Design. The study was a case series of adults presenting to a “Hair and Scalp” center in Clearwater, Florida. Adult subjects, who were not currently using minoxidil or finasteride, were offered the opportunity to receive the hemp-based formulation free of charge. Thirty-one subjects (15 males, 16 females, 27 Caucasian, 2 Asian and 1 Mixed race) had AGA with Norwood-Hamilton Classification score of 3V or higher. The predefined endpoints were hair counts obtained in a defined, representative area of scalp hair loss, and investigator clinical assessment of hair growth.
Participant ages ranged from 31 to 65 for the females and 39 to 64 for the males. The subjects gave their written informed consent for the six-month trial. The study adhered to the Helsinki guidelines and was institutionally approved. None of the subjects were currently using minoxidil or finasteride. No other hair loss treatments were used during the six months of the research.
The subjects were given a 60 ml (nominally two ounce) dispenser of product and advised to apply a thin layer once each morning to the areas of baldness. The dispenser contained 30 ml of formulation plus 30 ml of HFA 134a (1,1,1,2-tetrafluoroethane) propellant. It will be appreciated that each gram dispensed would contain about 0.5 g HFA and about 0.5 g formulation. However, the HFA evaporates essentially instantly leaving 0.5 g of formulation. The formulation was composed of a whole plant cannabis extract (CBD 60.00%, CBDV 12.63%, THCV 3.71%, delta 9 THC 0.18%, cannabigerol (CBG) 0.86% and cannabinol (CBN) 0.05% as independently analyzed by ACS Laboratory, Sun City Center, Florida). Each one ounce (approximately 30 g) of the formulation contained active ingredients of 1 g of the cannabis extract, 2 g saw palmetto seed extract, 1 g of menthol, 0.2 g of peppermint oil infused into a vehicle of 2.5 g of ethanol, 0.3 g pulegone, 0.6 g of Emu oil, 1 g of dimethicone and 21.4 g isolanolin. The one-ounce foam spray lasted approximately one month on average. This is an average daily dose of approximately 1 g of the formulation containing approximately 33 mg of the cannabis extract. The subjects were advised that they could use blow dryers, conditioners, and shampoos. The formulation was replaced as needed throughout the six-month trial.
A hair count of the greatest area of alopecia was carried out before treatment was started and again after six months of treatment. To facilitate consistent hair count analysis a permanent black tattoo dot was placed at the point of maximum hair loss on the scalp. The non-vellus hairs within the 1 cm2 around the tattoo were pulled through the opening of a one-centimeter mold with a surgical skin hook and a hair count taken using a Bodelin ProScope with 50× magnification.
Results. For all males, the baseline hair count was 6.13/cm2 and at six months, it was 21.20/cm2 (one-tailed paired t-test p<0.00001). This represented an average increase of 246% or 15.50 additional hairs in the one square centimeter mold. For all females, the baseline hair count was 12.69/cm2 and at six months, it was 28.75/cm2 (one-tailed paired t-test p<0.00001). This represented an average increase of 127% or 15.50 additional hairs in the one square centimeter mold. For all adults the baseline hair count was 9.50/cm2 and it increased after six months to 25.00 (one-tailed paired t-test p<0.00001). This represented an average increase of 164% or 15.50 additional hairs in the one square centimeter mold. All subjects showed some increase in hair count. The increase ranged from 31.25% in a female (16 to 21 hairs/cm2) to 2000% in a male (1 to 21 hairs/cm2). In general, the increased hair counts were associated with a cosmetically pleasing result.
Independent physician review of the photographs revealed evidence of ‘mild’ to ‘extensive’ scalp coverage improvements for all subjects.
This study demonstrates that topical hemp extract high in THCV, CBDV, CBD, menthol and peppermint oil is associated with significant hair regrowth in both men and women with AGA. This topical was superior to high-CBD hemp extract alone.27 In general, men did better than women. On average, there was a 164% (p<0.00001) increase in non-vellus hairs after six months of once-daily use. All subjects had some regrowth and cosmetic benefits.
The inventive topical cannabis formulation results in superior results to finasteride and 5% minoxidil once daily foam. Since this extract works through novel mechanisms entirely different from finasteride and minoxidil, it can be used in conjunction with these current drugs and is expected to have synergistic effects.
The following claims are to be understood to include what is specifically illustrated and described above, what is conceptually equivalent, what can be obviously substituted. Those skilled in the art will appreciate that various adaptations and modifications of the just-described preferred embodiment can be configured without departing from the scope of the invention. The illustrated embodiment has been set forth only for the purposes of example and that should not be taken as limiting the invention. Therefore, it is to be understood that, within the scope of the appended claims, the invention may be practiced other than as specifically described herein.
The present application is based on and claims the priority and benefit of U.S. Provisional Patent Application Ser. No. 63/327,332, filed on 4 Apr. 2022.
| Number | Date | Country | |
|---|---|---|---|
| 63327332 | Apr 2022 | US |
