Summary and Key Features
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Cannabinoids include endocannabinoids, endogenous ligands for cannabinoid-responsive receptors throughout the body, phytocannabinoids, bioactive phytochemicals identified from Cannabis sativa plants, and lab-derived synthetic cannabinoids.
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The cutaneous endocannabinoid system is involved with maintaining skin homeostasis, barrier maintenance, and regeneration.
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Evidence most strongly supports the anti-inflammatory and antioxidant properties of CBD. Anti-inflammatory and anti-pruritic effects of CBD and other cannabinoids may also help with skin health and discomfort.
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There are many speculative benefits of cannabinoids in skin care. However, there is limited objective evidence supporting the use of these ingredients in humans.
Introduction
Coinciding with the rapid growth of the cosmeceutical industry is the growth in popularity and accessibility of cannabinoid-containing products. Public interest in topical cannabinoid products, per Google Analytics data, has significantly increased in recent years, and the market for cannabinoid-containing skin care has surged exponentially; the global cannabidiol (CBD) skin care market was valued at over $900 million in 2022 and continues to grow.
Cannabinoids have a long and complex legal history. In the United States, from 1970 until 2018, the Controlled Substances Act classified all parts of the Cannabis sativa plant as a Schedule I drug, prohibiting use for any purpose. In 2018, the Farm Bill legalized hemp and hemp-derived cannabinoid products containing less than 0.3% tetrahydrocannabinol (THC) at the federal level. Internationally, the legal limit of THC varies; some regions prohibit cosmetics from containing more than 0.2% of THC.
Products containing hemp and hemp-derived cannabinoids are increasingly being included as ingredients in cosmeceuticals. Inclusion of cannabinoids in topical cosmeceuticals has the advantage of lowering risk of systemic off-target effects and of avoiding first-pass metabolism. These cannabinoid-containing cosmeceuticals are marketed to consumers as possessing antiinflammatory, hydrating, antioxidant, and antiaging properties. However, there currently is limited high-quality evidence supporting the utility of these ingredients. Here we provide an overview of cannabinoids, the endocannabinoid system (ECS), and the ECS’s role in the skin, and we review available evidence for the usage of cannabinoids in cosmeceuticals.
Introduction to Cannabinoids and the Endocannabinoid System
Cannabinoids are a class of compounds that are derived from the Cannabis plant or that share structural or biologic similarities to delta-9-tetrahydrocannabinol (Δ 9 -THC). There are three main classes of cannabinoids: endocannabinoids, phytocannabinoids, and synthetic cannabinoids. Endocannabinoids are produced endogenously and are the naturally existing ligands for cannabinoid-responsive cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors, which exist in various tissues throughout the body. Phytocannabinoids encompass over 100 bioactive phytochemicals that have been identified in Cannabis sativa plants. Relative concentrations of the two major phytocannabinoids—THC and CBD—classify the Cannabis sativa species into two subtypes: drug-type (also known as cannabis or marijuana) and hemp. Drug-type is characterized by high levels of psychoactive compound Δ 9 -THC and is used for medical or recreational purposes. Hemp contains almost no THC and may contain CBD or other minor cannabinoids, or be devoid of cannabinoids. Synthetic cannabinoids are synthesized in a laboratory to mimic the structure of THC.
The physiologic or pharmacologic effects of cannabinoids occur through interactions with the ECS. The ECS is a complex intercellular signaling network that is involved with maintaining homeostasis throughout the body. The primary receptors of the ECS are CB1 and CB2 receptors, which are G protein-coupled receptors (GPRs). CB1R are present throughout the body but are most highly concentrated in the central nervous system. CB1R are associated with the psychoactive effects of cannabinoids; receptor binding within the central nervous system impacts neurotransmitter release and can alter memory, mood, appetite, sensation of nausea, and modulation of pain sensation. CB2 receptors are most concentrated in the immune system (i.e., hematopoietic cells, spleen, thymus), and CB2 receptor agonism is associated with the immunomodulatory and antiinflammatory effects of cannabinoids.
Endocannabinoids are also described to interact with secondary CB-responsive receptors and pathways, including transient receptor protein of vanilloid receptors (TRPV), G protein-coupled receptor 55 (GPR55), resolvins, peroxisome proliferator-activated receptors (PPARs), and ligand-activated ion channels for serotonin. The full breadth of interactions between the ECS and other pathways is not yet understood, as cannabinoids differ structurally and exert numerous effects in the body due to binding affinity for different receptors. A summary of cannabinoid ligands and receptor interactions can be found in Table 20.1 .
| Receptor Type | Name | Ligands | Interaction | |
| Main Receptors | G-protein–coupled cannabinoid (CB) receptor | CB1R | AEA, CBG | Weak partial agonist |
| CBD | Negative allosteric modulator | |||
| THC | Partial agonist | |||
| THCV | Antagonist | |||
| CB2R | AEA | Weak partial agonist | ||
| CBD | Inverse agonist | |||
| CBG, THC, THCV | Partial agonist | |||
| Secondary Receptors | Transient potential ion channels (TRPV) | TRPV1 | AEA, THC | Weak agonist |
| CBD, CBGA, CBGV, THCV | Strong agonists | |||
| CBG | Agonist | |||
| TRPV2 | CBD, CBG, CBGV, THC, THCA, THCV | Strong agonists | ||
| TRPV3 | CBD | Agonist | ||
| THCV | Strong agonist | |||
| THC | Weak agonist | |||
| TRPV4 | AEA, 2-AG | Indirect agonist | ||
| CBDV, THCV | Strong agonist | |||
| THC | Weak agonist | |||
| Peroxisome proliferator-activated receptors (PPAR) | PPAR-α | THC, CBGA | Agonist | |
| CBDA, CBG | Partial agonist | |||
| PPAR-γ | THC, CBD | Agonist | ||
| Serotonin Receptors (5-HT) | 5-HT1A | CBG | Strong antagonist | |
| CBD, THCV, CBDA | Agonist | |||
| 5-HT2A | CBD | Partial agonist | ||
| 5-HT3 | CBD, THC | Antagonist | ||
| Endocannabinoids include: 2-AG , 2-arachidoynyl-glycerol; AEA , anandamide. Phytocannabinoids include: CBC , Cannabichromene, CBD , cannabidiol; CBDA , cannabidiolic acid; CBG , cannabigerol; CBGA , cannabigerolic acid; CBGV , cannabigerovarin; CBN , cannabinol; THC , Trans-∆-9-tetrahydrocannabinol; THCA , ∆9-tetrahydrocannabinolic acid; THCV , tetrahydrocannabivarin. | ||||
Cutaneous Endocannabinoid System
The skin contains its own ECS, which plays a role in maintaining cutaneous homeostasis, skin barrier maintenance, and regeneration. Endocannabinoids are synthesized in the epidermis, hair follicles, and sebaceous glands, and local concentrations are tightly regulated. CB1 and CB2 receptors are found in abundance in the normal skin, including in epidermal keratinocytes, melanocytes, dermal cells, mast cells, sweat glands, hair follicles, and cutaneous nerves. The ECS has been shown to modulate keratinocyte proliferation and cytokine production, sebum production, and hair production and play a significant role in immunoregulation, including a supportive role in decreasing inflammation. Additionally, interactions with TRPV1 ion channels on cutaneous nerves modulate sensory input processing of pain and pruritis. A summary of the receptors and activities of the ECS on various cell types in the skin can be found in Fig. 20.1 .
Dysregulation of the ECS may contribute to skin disease such as dermatitis, acne, and pruritis. Therefore modulation of the ECS is being explored for a therapeutic role in many inflammatory skin diseases including acne, allergic contact dermatitis, dermatomyositis, psoriasis, and scleroderma.
Introduction to Cannabis -Derived Cosmeceuticals
Cosmeceuticals containing Cannabis- derived ingredients can theoretically be categorized as either hemp-only products (devoid of CBD, THC, or other cannabinoids) or products containing cannabinoids. Cannabinoid-containing cosmeceuticals may include CBD, but also other minor cannabinoids present in the hemp plant such as cannabigerolic acid (CBGA), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabinol (CBN), cannabigerovarin (CBGV), and cannabichromene (CBC). Importantly, all of these compounds are nonpsychoactive. A summary of the biosynthetic relationship of cannabinoids and their purported cutaneous effects can be found in Fig. 20.2 .
Hemp Seed Oil
Hemp seed oil is high in polyunsaturated fatty acids (PUFAs) and essential fatty acids (omega-3 and omega-6) and contains other antioxidants such as tocopherol (vitamin E). There are limited studies assessing the effect of hemp seed oil on human skin; however, many of the purported effects of this compound come from knowledge of the benefits of individual ingredients. Given the rich fatty acid content, hemp seed oil use may be considered for its hydrating and moisturizing properties, similar to other oils such as avocado, argan, or grapeseed oils. Additionally, the fatty acid content of hemp seed oil may confer an antiinflammatory or antinociceptive effect. For example, α-linolenic acid (omega-3) has antiinflammatory and immunoregulatory properties, and phytol obtained from hemp seed oil exerted antiinflammatory activity in human monocyte-macrophages. Lastly, antioxidant molecules present in hemp seed oil, such as vitamin E, have an important role in protection of cells from oxidative stress. Hemp seed oil is generally safe for topical use; however, a potential increase in phototoxicity was observed in one study 48 hours after application.
Cannabinoid-Containing Cosmeceuticals
Antiinflammatory Properties
Skin inflammation can contribute to skin aging, dyschromia, poor wound healing, and exacerbation of a primary inflammatory skin disease. Therefore there are many benefits to a cosmeceutical that can mitigate these effects by reducing inflammation.
In general, the ECS is known to play a role in immunoregulation and decreasing inflammation. Both CB1 and CB2 receptors have been implicated in modulating cutaneous inflammation; mouse keratinocytes with absent CB1 receptors and absent CB2 receptors have an exacerbated inflammatory phenotype. CB1 receptors are highly expressed in activated T cells and are proposed to modulate peripheral inflammation through various mechanisms. CB2 receptors are highly expressed by macrophages and lymphocytes in skin, and their agonism helps regulate B- and T-cell differentiation and TH1/TH2 cytokine balance. Effects of CB signaling also include decreasing proinflammatory cytokine release and production in epidermal keratinocytes.
Research is still preliminary, but many phytocannabinoids including CBD, CBDA, CBGA, CBG, and CBC have demonstrated antiinflammatory properties in laboratory or mouse models. CBD does not significantly interact with CB1R and CB2R, and instead may exert an antiinflammatory effect through antioxidant activity, interactions with adenosine receptors, or indirect upregulation of endocannabinoid anandamide (AEA) through inhibition of its metabolic enzyme fatty acid amide hydroxylase. In an in vitro model of allergic contact dermatitis, CBD elevated AEA levels and inhibited release of inflammatory cytokines without exhibiting a cytotoxic effect. In vitro , CBDA, CBG, CBC, and CBGA also demonstrated an antiinflammatory effect in human keratinocytes. Despite abundant preclinical and anecdotal evidence suggesting an antiinflammatory benefit of cannabinoid-containing cosmeceuticals, there are limited clinical studies available substantiating these claims.
Antiaging/Antioxidant Effect
ECS signaling decreases the skin’s oxidative damage; CB1R knockout mice demonstrate accelerated skin aging due to decreased antioxidant capacity, increased reactive oxygen species (ROS), and a proinflammatory environment. There are numerous studies exploring the antioxidant capacity of cannabinoids, particularly for CBD. Direct antioxidant effects of CBD include interrupting free radical chain reactions, reducing prooxidants, and increasing transcription of antioxidant enzymes including superoxide dismutase and glutathione peroxidase. In vitro studies support CBD’s induction of antioxidant pathways, reduction of ROS, and protective effects against oxidative damage in human keratinocytes. In vivo assessment of topically applied CBD in a mouse model confirmed skin and systemic effects minimizing redox changes including upregulation of glutathione reductase and thioredoxin reductase activity, decreased ultraviolet (UV)-induced lipid peroxidation, and upregulation of peroxisome proliferator–activated receptor gamma (PPARγ) receptor. CBG and an unspecified hemp extract also reduced ROS in vitro . Despite strong evidence for the antioxidant properties of CBD (and potentially CBG), human clinical studies will be valuable to confirm these findings.
Photoprotective Effect
While sunscreen remains the backbone of skin protection from UV radiation, antioxidants may confer additional benefit by decreasing free radical damage. Therefore the ECS’s antioxidant role has been expected to aid in protecting from UV-induced DNA damage, and photoprotective effects of a variety of topical cannabinoids are actively being explored (e.g., ClinicalTrials.gov Identifier: NCT05279495). CBD is regarded to be the phytocannabinoid with the greatest photoprotective effect due to its antioxidant properties and ability to reduce ROS in vitro and in vivo . Interestingly, during in vitro testing of a CBD-containing sunscreen, CBD exhibited a dose-dependent protective effect on both keratinocyte and melanocyte viability after UVB radiation.
Treatment of Photomelanosis or Pigmentation-Related Disorders (Melasma, Freckles)
The normal effects of the ECS on melanocytes are concentration dependent; at low concentrations endocannabinoids stimulate melanin synthesis and enhance tyrosine kinase gene expression and activity through CB1R signaling, while at higher concentrations endocannabinoids induce melanocyte apoptosis through a TRPV1 mediated pathway. Administration of CBD stimulated melanin synthesis and tyrosinase activity in vitro in human melanocytes. Given the effects on melanogenesis, the ECS may be a useful target for pigmentary disorders, however current evidence is limited.
Skin Barrier Function: Modulation of Intercellular Lipids and Skin Hydration
Much of the data available about cutaneous lipid modification and cannabinoids are from studies of these compounds as antiacne agents. CB1R and CB2R are present on human sebocytes, and CB2 signaling enhances lipid synthesis by sebocytes. Sebocyte response to cannabinoids is likely dependent on the type of cannabinoid used, and utility of various cannabinoids may depend on skin type. Notably, in cultured human sebocytes, CBD acted as a sebostatic agent, inhibiting lipogenesis and suppressing sebocyte proliferation via activation of TRPV4. In additional in vitro studies of minor cannabinoids and sebocytes, basal sebaceous lipid synthesis was suppressed by CBC and THCV but was increased by CBC and CBGV.
The relationship between the ECS and ceramides has also been explored. A 2018 review by Di Scala et al. highlighted that AEA selectively binds cholesterol and ceramides; this binding complex blocks the degradation pathway of both lipids. This mechanism may result in increased availability of these lipids. Additionally, N-palmitoylethanolamine (PEA), an endocannabinoid-like lipid mediator that potentiates the physiologic effects of AEA, was found to stimulate generation of ceramides via a CB1-dependent mechanism in vitro . CBD was also shown to increase ceramides in a mouse model.
There are limited studies in humans assessing skin hydration from cannabinoid-containing products. In one in vivo study, application of 1% CBD solution increased expression of aquaporin-3 and dermal water content compared to control mice; however, this effect was not observed at 3% CBD concentration. A clinical study of 66 individuals with asteatotic eczema found that a PEA/AEA emollient caused significant improvement in scaling, dryness, and itching of skin after 28 days. However, the emollient vehicle group was also effective in improving these parameters, and both groups were equally effective in reducing transepidermal water loss (TEWL) and skin surface hydration. Lastly, a 0.1% CBG serum tested in a 20-subject vehicle-controlled clinical study demonstrated reduced TEWL compared to placebo and reduction in the appearance of redness.
Further research is required to substantiate claims that CBD and other cannabinoids improve skin barrier function or hydration, and some have suggested that hydrating properties of cannabinoid-containing skin care may be due to other compounds present in the formulation.
Wound Healing
The ECS may regulate physiologic wound healing through regulation of proliferation and differentiation of epidermal keratinocytes, fibroblast function, and cutaneous inflammation. CB2R signaling is thought to promote wound healing through accelerating reepithelialization, reducing inflammation, and an antifibrotic effect that reduces scar formation. The relationship between promising preclinical findings for CB2R agonism and wound healing requires further exploration. There is some evidence that topical cannabinoid application may reduce pain associated with wounds. One observational study of three patients who self-initiated topical CBD use for epidermolysis bullosa cited faster wound healing, decreased blistering, and decreased pain. Additionally, CBN, CBD, CBC, and CBG have demonstrated antimicrobial activity. There are limited controlled clinical trials on the role of cannabinoids in wound management, and existing clinical studies have major limitations. Generally, topical cannabinoid-containing products should not be applied to severe or open wounds, as other ingredients in the formulations may be harmful to damaged skin and the complete effects of application are still not known.
Hair
The data regarding hair and cannabinoids suggest cannabinoids, particularly CBD, may have varied effects on hair growth based on concentration. Within the hair follicle, topical CBD is a negative allosteric modulator of CB1 receptor, expressed within the hair follicle cells, and an agonist of TRPV1 and TRPV4, both located on hair follicle keratinocytes. CB1, TRPV1, and TRPV4 receptor activation all decrease hair shaft elongation, promote premature hair follicle regression, and have an overall negative effect on hair growth.
Given CBD’s negative modulation of CB1 receptors, CBD has been theorized to promote hair growth. CBD also stimulates the Wnt/β-catenin pathway, which is involved with hair regeneration and growth. Additionally, it has been proposed that CBD desensitizes the TRPV1 receptor, leading to an indirect improvement in growth. In one study, low-concentration CBD decreased catagen-promoting inflammatory cytokine production by hair root sheath keratinocytes through adenosine receptor-mediated signaling. A case series of 35 individuals with androgenetic alopecia found that daily application of a topical hemp-derived CBD oil for 6 months resulted in significant improvement in hair growth, although notably, there was no control group included in this study. One-third of participants in this study experienced a self-resolving increase in shedding that occurred during the first month of CBD application.
Conversely, data from a study by Szabó et al. (2020) supported an association between CBD and decreased hair growth, especially at higher concentrations. In this study, conducted in human organ–cultured scalp hair follicles and outer root sheath keratinocytes, high-concentration CBD activated TRPV4, leading to decreased hair growth, reduced hair shaft development, and cell apoptosis.
There are no available data regarding other cannabinoids, and given the lack of human clinical trials assessing topical cannabinoids’ effects on hair growth, no definitive conclusions can be made.
Safety and Tolerability
Human clinical studies of topical cannabinoids report minor side effects such as pruritus, burning, erythema, and stinging, and topical cannabinoid-containing products are generally regarded to be safe for use. However, cannabinoid-containing products purchased from unregulated or illegal sources may result in exposure to contaminants or THC levels above legal limits. Additionally, there are limited data regarding long-term use of topical cannabinoids. In general, toxic overdose is unlikely using a topical product (e.g., cream, lotion, oil), as there is negligible systemic absorption; however, sensitivity or allergy is possible. There has been one reported case of CBD oil–induced SJS-TEN. Importantly, oral CBD may result in drug–drug interactions, as it is an inhibitor of CYP2C19.
One of the most important safety considerations for cannabinoid-containing cosmeceuticals is that per current regulations, hemp and hemp-derived products are not subject to vigorous review by regulatory bodies such as the US Food and Drug Administration (FDA); therefore there is no legal standard regarding standardization of these products, proper dosages, labeling, assessing safety and side effects, or assessing interactions with other drugs. Consumers may not be aware of the regulatory status of these products when purchasing them; in one study only 47% of CBD-containing products included that they were not FDA approved on the label, and in a 2020 survey of young adults living in the United States, over one-fourth mistakenly believed that CBD was approved by the FDA, was tested for safety, and had proven efficacy for effects the products were marketed for.
These considerations are especially relevant as over-the-counter (OTC) CBD products are often found to have discrepancies in labeled and measured active ingredient concentrations. An analysis of 89 CBD-containing products purchased from US-based and online stores found that only 24% of products were within 10% of advertised CBD content: 18% were overlabeled and 58% were underlabeled (i.e., contained >10% less or more CBD than advertised). Other studies have found similar labeling discrepancies. Further, little is known about appropriate therapeutic dosing for cannabinoids, and therefore there is significant variability in concentrations of ingredients in OTC products; one analysis of CBD oils sold online noted concentrations ranging from 0.10 mg/mL to 655.27 mg/mL.
Conclusion
Cannabinoids may be a valuable ingredient in cosmeceuticals given the multifactorial role of the ECS in the skin; however, future research will be required to discern which cannabinoid type and dosages are most appropriate for different cosmetic concerns. The evidence most strongly supports the antiinflammatory and antioxidant properties of CBD, and the known antiinflammatory and antipruritic effects of CBD and other cannabinoids may also help with skin health and discomfort. In general, despite an abundance of speculative benefits of cannabinoids in skin care, there is limited objective evidence supporting the use of these ingredients in humans. Additional research on cannabinoid cosmeceuticals can help clarify or confirm some of the patterns documented here. Given the increased attention to cannabinoid-containing products, regulations and research are expected to improve in coming years.
Further Reading
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