Cannabinoid Photo-Rejuvenation: A Clinico-Pathologic Study 

Dermatoheliosis, or photodamage, is characterized by complex alterations in skin structures resulting from acute and chronic UV exposure, leading to accelerated skin aging and a heightened risk of skin cancer. Both genetic and environmental factors play a role in skin aging.

In this study, we sought to assess the effectiveness of a novel topical formulation containing CBD isolate, resveratrol, thyme extract, caffeine, and lecithin in reversing photodamage over a 90-day treatment period.

Introduction

Dermatoheliosis represents a multifaceted alteration affecting various skin structures, which originates from both acute and chronic UV exposure.¹ Photodamage can lead to an acceleration of skin aging and an increased incidence of skin cancers with severity depending on individual skin attributes and exposure levels.^1,2

Recent research from George Washington University School of Medicine and Health Sciences, in collaboration with the Center for Clinical and Cosmetic Research, suggests that cannabidiol (CBD) has potential in preventing skin damage from ultraviolet-A (UVA) radiation. Specifically, in a 14-day trial of 19 subjects, there were statistically significant decreased amounts of UVA-induced redness, DNA damage, and epidermal hyperplasia with nano-encapsulated CBD cream, compared to control cream, applied topically to the skin for 14 days.³

In the realm of skin aging, two distinct factors contribute: intrinsic aging, determined by genetic factors, and extrinsic aging, influenced by environmental elements.⁴ Additional factors like pollution and cigarette smoke further accelerate aging, and women will experience the pivotal role that estrogen plays in influencing the integrity of their skin as they age.⁵ Comprising approximately one-sixth of body weight, the skin actively participates in vital functions such as regulating body temperature, maintaining internal hydration, sensory perception, and immunological surveillance.⁵ Environmental aggressors, notably UV light, induce numerous daily cellular DNA alterations, culminating in cumulative damage that exacerbates the natural aging process.^4-6 Additional factors like pollution and cigarette smoke further accelerate aging.⁴ Aging skin exhibits alterations in keratinocytes and corneocytes, marked by changes in shape, size, and decreased epidermal turnover.⁷ Active melanocytes diminish with age, resulting in uneven pigmentation. A prominent structural change in aged skin is the flattening of the dermo-epidermal junction, primarily caused by the loss of dermal papillae and reduced interdigitation between layers.⁷ This flattening renders the skin more susceptible to shearing forces and increases vulnerability to insult. Moreover, the diminished surface area between layers reduces the cellular supply of nutrients and oxygen, elevating the risk of dermo-epidermal separation—an implicated mechanism in wrinkle formation.⁷ The dermis experiences age-related thinning, accompanied by a decline in the number of mast cells and fibroblasts. Glycosaminoglycans and hyaluronic acid produced by fibroblasts, as well as interfibrillary ground substance, diminish with age, contributing to the structural changes associated with aging skin and dermatoheliosis.⁷

Rising awareness of the impacts of photoaging has driven an increased focus on interventions for both prevention and repair of the photodamaged skin. Regular and appropriate application of sunscreen from an early age is a fundamental preventive measure, believed to reduce the risks associated with UV radiation by approximately 80%.¹ Besides sun protection, other treatments such as retinoids and antioxidants are widely available.^1,7 However, the effectiveness of these treatments to reverse and prevent signs of photodamage remains largely undetermined.¹ Moreover, procedures like dermabrasion and laser resurfacing, known for improving both visible and microscopic alterations in photodamaged skin, have inherent risks and do not prevent photoaging.⁸ The potential regenerative effects of cannabinoids, especially when interacting with cannabinoid receptors on dermal fibroblasts and epidermal cells, suggest that incorporating CBD into skincare products could offer novel and superior cosmetic benefits.⁹ However, formulating a product that enables CBD to deeply penetrate the dermis has been a significant challenge in dermopharmaceuticals, owing to its high lipophilicity and poor transdermal absorption properties.¹⁰ Furthermore, thymol, a prominent chemotype of Thymus vulgaris, has garnered considerable scientific interest for its therapeutic properties, which encompass anti-inflammatory, regenerative, and antitumoral effects.¹¹ The innovative concept of synergizing thymol with CBD in a skincare formulation presents a forward-thinking strategy to selectively target photodamaged cells, offering a potential breakthrough in reversing skin aging and heralding a new frontier in advanced skincare solutions.

Materials and Methods

Participants: A total of 21 participants (17 women and 4 men) were enrolled in the study. The age distribution of the participants included individuals in their 30s (2), 40s (0), 50s (8), 60s (7), and 70s (3), with a mean age of approximately 64 years. Among the participants, 19 were Caucasian, and one participant was a Hispanic male.

Fitzgerald Wrinkle Scale Assessment: The participants’ wrinkles were assessed using the Fitzgerald Wrinkle Scale prior to the beginning of the study, categorized as follows:

Level 1 (just perceptible): 2 females

Level 2 (shallow): 5 females, 2 males (total 7)

Level 3 (moderate depth): 6 females, 1 male (total 7)

Level 4 (deep with defined edges): 2 females, 1 male (total 3)

Level 5 (very deep, redundant folds): 1 female

After the subjects provided signed informed consent, a 3-mm full-thickness skin biopsy was extracted from behind the left ear. Following the removal of sutures approximately 5 to 7 days later, each participant received instructions for the once-daily bedtime application of the formulated cream to an area approximately the size of a silver dollar behind the left ear, adjacent to the biopsied region. Throughout the 90-day trial period, subjects were regularly contacted via text messaging to confirm compliance with the once-daily application of the formulation. After the completion of the 90-day trial, participants returned to the clinic for a repeat 3-mm skin biopsy near the prior biopsy site, well within the application area of the formulation.

Formulation: The formulation comprises 99.5% CBD isolate, combined with resveratrol, thyme extract, caffeine, and lecithin.

Ethical Issues: Each participant signed a nationally recognized informed consent form, approved by the Institutional Review Board (IRB). There was a complete separation between the Principal Investigator (PI) and the financial supporters of this study to ensure ethical conduct. 

Human Use Approval: Informed consent for the study adhered to compliance with 42 CFR Part 11 and the Common Rule 45 CFR 46.

Dropout and Compliance: One participant, a 60-year-old female, dropped out of the study halfway due to severe illness, requiring hospitalization for herpes zoster and a respiratory infection. She discontinued the cream when her illness manifested. The study initially started with 21 subjects but concluded with 20 due to the dropout.

Non-Responsive Participants: It is important to note that three female participants did not exhibit a dramatic decrease in solar elastosis. Compliance with the cream application is questioned in these cases. The participants in question include a 51-year-old female with level 3 wrinkles, a 60-year-old female with level 3 wrinkles, and a 74-year-old female with level 5 wrinkles. Further investigations into compliance issues were considered in evaluating the outcomes for these individuals.

Data Analysis

Histopathological assessment of molecular markers of photodamage, including solar elastosis, capillary density, inflammation, and dermal edema, was performed by an independent dermatopathologist. Each category underwent meticulous evaluation, graded on a four-tier scale (nil, mild, moderate, severe). Solar elastosis was scrutinized for alterations in elastic fibers, while capillary density reflected vascular changes. Additionally, the extent of inflammation and the presence of dermal edema were thoroughly examined. Quantitative analysis of the data was conducted using the Wilcoxon signed-rank test, allowing for a robust statistical evaluation of the efficacy of our topical formulation. 

Results and Discussion

After the 90-day period of daily application of our formulated compound, the analysis of skin biopsies from all 20 subjects demonstrated remarkable improvements. Solar elastosis and capillary density, key markers of photodamage, exhibited a statistically significant decrease (P for trend < 0.001) across all evaluated categories (Figure 1 and Figure 2). These results provided compelling evidence of the formulation’s efficacy in reversing photodamage at both the dermal and cellular levels. Upon histologic examination of skin biopsy slides, a conspicuous reduction in dermal solar elastosis was evident, characterized by a notable decrease in density and intensity of elastotic fibers (Figure 3 and Figure 4). The dermal fibers exhibited a pater appearance, indicative of the diminished accumulation of elastin material, thus reflecting the pronounced decrease in solar elastosis following the application period (Figure 5 and Figure 6). Similar results are seen after CO2 facial skin resurfacing procedures. This study illustrates that with this compounded formula, which penetrates deep into the dermis, solar elastosis can be reduced significantly without undergoing an invasive, ablative procedure such as CO₂ laser procedure. The possibility of developing skin cancers associated with UV damage is greatly reduced by reducing or eliminating solar elastosis.

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

This histopathological observation underscores the efficacy of the formulated compound in mitigating the adverse effects of photodamage on dermal tissue architecture. It is noteworthy that an increase in inflammation was uniformly observed across all subjects in the post-application biopsies. This finding suggests a complex interplay between the formulation’s regenerative effects and the skin’s inflammatory response. Dermal edema, while showing a slight increase in all subjects after the application period, demonstrated a nuanced response. The modest elevation suggests a potential transient effect on skin hydration, warranting further investigation into the formulation’s impact on dermal water content and its role in skin health.

This illustrates the potential therapeutic efficacy of our compound blend in mitigating photoaging’s impacts on the skin by using a topical product as efficacious as ablative procedures in reducing solar elastosis. We believe the synergistic effect of thymol and CBD with a vehicle that strongly promotes dermal penetration renders our formulation unique. This combination allowed for profound dermal penetration that addresses signs of dermatoheliosis at the cellular level, while highlighting the innovative and unparalleled efficacy of our product. Our blend amplifies the regenerative capabilities of both extracts, harmoniously optimizing skin rejuvenation and shielding against the multifaceted aspects of skin aging.  

We have presented here a novel compound, with deep penetrating properties, using herbs with known value that can be as efficacious as CO2 laser resurfacing in eliminating solar elastosis. Further studies will be ongoing. 

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