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Hair Regrowth with Topical Cannabidiol (CBD)

Abstract-image-cbd-thumbnail

A Case Series for Hair Regrowth with Topical Cannabidiol (CBD)

 Abstract

CbdThe endocannabinoid system (ECS), discovered in the 1990s, is a system involved with maintaining cellular homoeostasis by down-regulating the damaging inflammatory response and upregulating regenerative processes. CB1 receptors are well expressed in the hair follicle cells. Blocking the ECS CB1 receptor with cannabidiol CBD has been shown to result in hair shaft elongation; in addition, the hair follicle cycle (anagen, catagen, telogen phases) is controlled by the ECS vanilloid receptor-1 (TRPV1). CBD has also been shown to increase Wnt signaling which causes dermal progenitor cells to differentiate into new hair follicles and maintains anagen phase of the hair cycle. The effects of CBD on hair growth are dose dependent and higher doses may result in premature entry into the catagen phase via a different receptor known as vanilloid receptor-4 (TRPV4). CBD is fat-soluble and poorly absorbed past the epidermis, but topical application of CBD easily reaches hair follicles where it is a CB1 antagonist, and TRPV1, and TRPV4 agonist.

Several FDA approved medications are currently available but offer limited results. A new drug called SM04554 is at the end of Phase III trials and shows promise as a Wnt signaling agent.

A study was done of 35 (28 men and 7 women) subjects with AGA. They used a once daily topical CBD formulation, averaging about 3-4 mg per day for six months. 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 clear acrylic mold was made of each subject’s head with a one centimeter cut out. The results revealed that men did slightly better than women, and the vertex area did better than the temporal areas. On average there was statistically significant 93.5% increase in nonvellus hair after 6 months of once daily use. All subjects had some regrowth. There were no reported adverse effects.

The exact mechanism of therapeutic effects is not known, the CBD is most likely functioning as a CB1 receptor antagonist and potentially also via Wnt messaging.

The topical CBD formulation has superior results to finasteride and comparable results to 5% minoxidil once daily foam. Since the CBD 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.

Introduction

Androgenetic Alopecia (AGA) is a very common condition, that occurs in both men and women, and increases in prevalence with age. It is by Androgenetic Alopecia (AGA) far the most common cause of baldness and hair thinning. It generally starts in the third and fourth decades of life and significantly increases in prevalence in women after menopause. It is estimated that 50% of Caucasian men and 19% of Caucasian women are affected by age 50. [1] There is a lower prevalence and severity of the condition in Asian and black men.[1] AGA may adversely impact a person both psychologically and socially, especially in women.[2]  The condition is characterized by follicular miniaturization in a specific pattern due to the effects of systemic androgens and genetic factors. [3]

In the male pattern phenotype, the hairline regresses at the bitemporal regions and at the vertex. In the female pattern then is a diffuse thinning with preservation of the frontal hairline. However, the pathogenesis is the same.[2]  AGA develops due to a disturbance in the cyclic transformation of hair follicles from active hair shaft growth and pigment production (anagen) to apoptosis-driven (cell death) hair follicle involution (catagen).

Current Treatment

RogaineTwo medications, minoxidil topical and oral finasteride are FDA approved for the treatment of AGA. Unfortunately, these medications offer limited results. The new combination of topical minoxidil and topical finasteride has shown more promising results.[4] Hair transplantation is the only current successful permanent option, and it requires surgical procedures. Several other medical options, such as antiandrogens such as spironolactone, oral contraceptives, cyproterone, flutamide, dutasteride, prostaglandin analogs and ketoconazole are reported to be beneficial. However, they can be associated with significant adverse effects and are expensive.  Laser and light therapies have also become popular despite the lack of documented profound benefit.[2]

Minoxidil was first evaluated for treatment of hair loss in 1984 as a 1% topical solution.[5] It became clear that higher concentrations were needed. A 12-month double-blind trial [6] was done on 60 subjects with AGA. The use of twice-daily topical 2% and 3% Minoxidil [6] revealed that at month 4 the average total nonvellus hair counts had increased from a baseline mean of 158.2 to 270.2 (71% increase) in the 2% minoxidil group, from 156.6 to 287.0 (83% increase) in the 3% minoxidil group.  At month 12 the means were 415.6 (163% increase) and 448.5 (186% increase) for 2% minoxidil, 3% minoxidil, respectively. The increases from month 4 to month 12 were highly significant for each group (p = 0.0001). More recently, a 5% once-a-day foam has been shown to be equally effective to twice-daily application of lower concentration topical minoxidil.[7]

FinasterideFinasteride, a type 2-selective 5α-reductase inhibitor, was approved in 1997 as the first oral pharmacologic therapy for the treatment of men with AGA. It was originally developed for the treatment of men with benign prostatic hyperplasia (BPH) at a dose of 5 mg/day. Subsequent studies demonstrated that finasteride was an effective treatment for men with AGA at an optimal dose of 1 mg/day. The net improvement in hair count (finasteride vs. placebo) was 14% at 1 year and 16% at 2 years.[8]

A 48-week-long clinical trial of men with AGA was completed in December 2019. The study used an investigational new topical drug called SM04554. The drug is now entering into Phase III trials, expected to end in January 2021. It has shown some promising results in early Phase I and II trials and works by modulating the Wnt pathway that is postulated to initiate and maintain the anagen phase of the hair cycle. 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.[9] However, to date there is little basic science or clinical research on CBD and Wnt signaling.

Recently, with the increasing acceptance of Cannabis sativa-based therapies, cannabidiol (CBD) has come under consideration as a possible, effective, safe, inexpensive non-prescription, topical AGA therapy. CBD works through the endocannabinoid system (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. As such, the therapeutic effects of CBD would complement the physiologic effects of minoxidil, finasteride and antiandrogen therapies.

ECS and Hair Follicles

The ECS was only discovered in the 1990s. In essence, it is a system involved with maintaining cellular homoeostasis in response to excess oxidative stress. It down-regulates the damaging inflammatory response, and up-regulates regenerative processes. It is comprised of two receptors, cannabinoid receptor 1 and 2 (CB1 and CB2) and has two messenger molecules known as the endocannabinoids, anandamide (AEA) and 2-arachidonylglycerol (2-AG).  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 lines within the skin.[10] CB1 receptors are well expressed in the hair follicle cells. Stimulation of the CB1 receptor  with the endocannabinoids leads to decreased hair shaft elongation. [11];

The hair follicle cycle (anagen, catagen, telogen phases) is controlled by the vanilloid receptor-1 (TRPV1). [12] TRPV1 receptors are found on the hair matrix keratinocytes. Mouse studies have shown that activation promotes hair follicle regression (catagen) and hair matrix keratinocyte apoptosis (cell death) thru retarding hair shaft elongation. [12] Endocannabinoids, and cannabis-derived phytocannabinoids, such as THC and CBD message TRPV1 receptors. It is postulated that CBD has therapeutic effects via TRPV1 receptors by excessive activation of the receptor that they become desensitized. [13]

Tetrahydrocannabinol (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.[11, 12]

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 and tetrahydrocannabivarin (THCV) and cannabidivarin (CBDV) can be used to promote hair growth. [11] CBD is a CB1 antagonist that probably has its effects via negative allosteric modulation of the CB1 receptor. [14, 15]

A very recent study of human hair follicle cultured cells [16] revealed that use of lower doses of CBD resulted in  hair shaft elongation, probably via CB1 antagonism.  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 evaluated in order to obtain positive hair regrowth.

CBD

CBDOver the past decade CBD has been extensively researched for a myriad of therapeutic benefits.[17] CBD does not cause euphoria or addiction. It is very safe, with a very wide therapeutic window and few adverse effects. Topical application of CBD has not been associated with any significant adverse effects.[10, 18] 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 [19] that as many as 14% of the US population has tried CBD products.

CBD is fat-soluble and poorly absorbed past the epidermis, but topical application of CBD easily reaches hair follicles where it is a CB1 antagonist, and TRPV1, and TRPV4 agonist. [16]

Materials and Methods

The study is a case series of adults presenting to a ‘Hair and Scalp’ center in Clearwater Florida. Adult subjects, not currently using minoxidil or finasteride were offered the opportunity to receive the CBD paste free of charge. Thirty-five subjects (28 males, 7 females) had AGA based on the presence of gradually progressing bitemporal and/or vertex alopecia. Clinical diagnosis of AGA with Norwood-Hamilton Classification score of 3V or 4. The predefined endpoints were hair counts obtained in a defined, representative area of scalp hair loss, and investigator clinical assessment of hair growth.

The females were ages 46-76 and the males 28-72.  The subjects gave their written informed consent for this 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 topical paste in a small 2 oz jar and advised to apply a thin layer once each morning to the areas of baldness. The subjects were advised that she could use blow dryers, conditioners and other hair preparations. The paste was replaced as needed throughout the six-month trial.

The paste was made of high CBD cannabis sativa (hemp) flower that had been ultrapulverized into a fine powder. This chalk-like green powder was independently analyzed by Cannalysis Labs in Santa Ana, CA. It was found to contain 10.78% CBD, and 0.21% THC, and there was no detectable THCV or CBDV. This powder was infused into a lanolin base paste and natural Emu oil carrier. Each 2 oz jar contained 1000 mg of the power, or 108 mg of CBD. The subjects were advised to apply thin layer of the paste over all bald or balding areas once each morning. The 2 oz jar lasted approximately one month, which is an average daily dose of 3-4mg of topically applied CBD.

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 clear acrylic mold was made of each subject’s head. The front of the mold was positioned at the hair line, with additional measurements from the tip of the nose to the front of the mold. A one-centimeter square was removed from the mold in the area of greatest alopecia, which was either in the temporal or vertex region.  The hair count was done within the 1 cm area.  The nonvellus hairs within the one square centimeter were pulled through the opening with a surgical skin hook. A Bodelin ProScope with fifty times magnification was used to perform hair counts.

Results

ResultsThe specific data and hair count for each subject is demonstrated in Table 1.

Temporal Area – This Table reveals that hair counts in the temporal area increased an average of 74.1% in men, and 55.2% in women. In men the number of hairs increased from baseline of 20.6 to 33.7 (paired t-test p< 0.01)  in the temporal area, and in women from 20.3 to 30.5 (paired t-test p< 0.01)

Vertex Area –  In the vertex area the hair counts increased an average of 120.1% for men, and 64.9% for women.  In men, the number of hairs increased from baseline of 16.8 to 32.9 (paired t-test p< 0.01) in the temporal area, and in women from 18.7 to 30.7 (paired t-test p< 0.01).

For all males, the baseline hair count was 18.28 (95% Confidence Interval +/- 3.02) and at six months it was 33.21 (95% Confidence Interval +/- 4.86).

For all females, the baseline hair count was 19.57 (95% Confidence Interval +/- 4.83) and at six months it was 30.57 (95% Confidence Interval +/- 7.51). The pair t-value for men before and after difference was 7.38, p <0.00001. The pair t-value for women before and after difference was 5.56, p =0.0014.

The hair count increased 93.5%, from 18.5  to 32.7 (p< 0.001)  when temporal and vertex areas were combined. In general males and the vertex area did the best. All subjects had some increase in hair count. In general, the increased hair counts were associated with a cosmetically pleasing result.

One-third of the patients reported some slightly increased hair shedding during the first month of treatment, this was no longer was noted at the two-month visit. Otherwise there was no reported adverse effects from use of the paste.

Discussion

This case study supports significant hair regrowth benefits in both men and women with AGA. In general men did slightly better than women, and the vertex area did better than the temporal areas. On average there was 93.5% increase in nonvellus hair after six months of once-daily use. All subjects had some regrowth.

Discussion CBDAlthough the exact mechanism of therapeutic effects is not entirely clear, the CBD is most likely functioning as a CB1 receptor antagonist, via negative allosteric effects, and potentially also via Wnt messaging. The dosing of the CBD needs to be further evaluated as preclinical research suggests that higher doses of CBD may cause agonistic effects at TRPV4 receptors which can cause premature entry of the hair follicle into the catagen phase.

The safety of topically applied CBD has been previously well documented. Once again there is no reported significant adverse effects for six-month application of this CBD topical.

The topical CBD formulation has superior results to finasteride and comparable results to 5% minoxidil once daily foam. Since the CBD 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.

Further research with topical liposomal nano-particle CBD is planned. In addition, comparative, cross-over studies with minoxidil should be considered.

Conflict of interest and financial and other disclosures:

The authors adhered to the US “Federal Policy for the Protection of Human Subjects” (“Common Rule”)

The authors/investigators have no economic interest in, does not act as officer or a director of, any outside entity whose financial interests would reasonably appear to be affected by this research study or its findings. The authors/investigators have no personal, business, or volunteer affiliations that may give rise to a real or apparent conflict of interest. Relevant Federally and organizationally established regulations and guidelines in financial conflicts are abided by.

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