A total of 199 articles were found through the aforementioned search strategy. There were 43 duplicated articles and 88 irrelevant articles (often about non-dermatologic use of cannabinoids or studies not relevant to cannabinoids). These were removed for a total of 68 articles. Figure 1 summarises the results of the search. Select additional articles were subsequently added at the editors’ recommendation.

Fig. 1 Studies included in this review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) strategy for study selection Full size image

The results were grouped into five mechanisms of action of cannabinoids—pain, itch, inflammation, proliferation, and fibrosis. A summary of pertinent results separated by mechanism or symptom is provided in Table 1.

Table 1 Summary of findings of relevant studies organised by cannabinoid mechanism of action and type of study (in vitro vs in vivo). Potential applications to dermatologic conditions related to cannabinoid mechanism of action are suggested Full size table

Pain

Pain is a predominant feature of many dermatologic conditions [11]. Cannabinoids have shown promise in modulating pain pathways in vitro and in vivo and in reducing pain in animal and human studies [12,13,14].

Cannabinoids have been shown to impact pain pathways in vitro through their influence on TRPV1, a cation channel involved in nociception that is expressed by the majority of nociceptive primary sensory neurons. TRPV1 may play a key role in the transmission of pain, and also the development of neuropathic pain through sensitisation [12, 15]. In one study, the endocannabinoid AEA (1–30 nM, 10 min) led to reduced TRPV1 activity in rat cultured primary sensory neurons in an inflammatory environment, independent of CB1 or CB2 receptors [12]. In another study, CB1 receptor agonist HU210 (0.01–1 μM, 10 min) inhibited TRPV1 activity and sensitisation in cultured rat dorsal root ganglion cells [16]. Other compounds, including PPAR-γ and fatty acid amide hydrolase (FAAH) may also be implicated in pain modulation by cannabinoids [3].

Cannabinoids have also demonstrated benefit for pain in animal models of neuropathic pain and inflammation [3, 13]. In one study of an induced inflammatory mouse model induced by intraplantar injection of complete Freund’s adjuvant (CFA), intraplantar injection of 5 mg/mL cannabinoid receptor agonists arachidonyl-2′-chloroethylamide (ACEA) or R-(+)-methanandamide (methAEA) attenuated allodynia and hyperalgesia through a CB1 receptor-dependent mechanism [17]. In streptozotocin-induced diabetic mice with neuropathic pain, intranasal (0.1–0.2 mg/kg) or intraperitoneal (0.1–2 mg/kg) administration of CB1 and CB2 agonists demonstrated antinociceptive effects [18]. Additionally, in studies of neuropathic (sciatic nerve constriction) and inflamed (CFA or carrageenan intraplantar injection) rats, oral or injected cannabidiol (CBD) reduced hyperalgesia to thermal and mechanical stimuli in a CB1/2 receptor-independent, TRPV1-dependent manner [19, 20].

In vivo studies demonstrate that cannabinoid receptor agonists ACEA and methAEA (5 mg/mL) have been shown to decrease Aδ nociceptor responses in CFA-induced inflamed skin through a CB1 receptor-dependent mechanism [17]. CB1 receptor agonism with SR141716A (100 nM, 10 min) has also been demonstrated to decrease sensory neuron function in both streptozotocin-induced diabetic and non-diabetic rats [13]. In the same diabetic mouse model, intranasal (0.1–2 mg/kg) or intraperitoneal (1–20 mg/kg) CBD led to decreased microglial density and activation, which are features associated with the pathophysiology of neuropathic pain [18].

Human data are also promising. In a randomised, double-blind study, patients with peripheral neuropathic pain received a sublingual or oropharyngeal spray containing Sativex, a cannabis plant extract containing tetrahydrocannabinol (THC) and CBD, or placebo [21]. Patients receiving the cannabinoid spray demonstrated significant improvements in global pain scores, sleep, allodynia, and pain-related disability. Pain relief was maintained without dose escalation or toxicity for one year with some mild side effects, commonly gastrointestinal, that were more prevalent than in the placebo group [21]. In a case report of three patients who self-initiated topical cannabidiol use for epidermolysis bullosa, one patient was weaned off oral opioid analgesics and all three reported decreased pain, faster wound healing, and decreased blistering [22]. Additionally, in a prospective case series, three patients with pyoderma gangrenosum were administered topical medical cannabis [14]. The patients reported considerable analgesia with onset of 3–5 min after application, with a 66.5%, 73.4%, and 65% reduction in mean pain scores for each patient (the latter score was not statistically significant). Two of three patients were already being treated with opioids for pain relief, and both of these patients demonstrated statistically significant reductions in opioid utilisation when treated with topical cannabis [14].

Itch

Itch is a feature of a diverse array of both cutaneous and non-dermatologic conditions, including atopic eczema, allergic contact dermatitis, hepatic or renal failure, autoimmune disorders, neurologic disorders, and psychiatric disorders [23]. The pathophysiology of itch is complex, and may involve diverse mediators, including histamine, interleukin-31, leukotriene B4, and substance P [23, 24].

The endocannabinoid system has been shown to play a role in the reduction in itch responses in animal models through CB1 receptor-dependent mechanisms. In an acute allergenic mouse model induced by subcutaneous administration of mast-cell degranulator compound 48/80, decreased scratching was documented when the endogenous cannabinoid AEA was increased (by inhibiting or knocking out FAAH) [25]. This anti-pruritic effect was blocked by the deletion or antagonism of the CB1 receptor [25]. It should be noted, however, that FAAH types (FAAH1 and FAAH2) are expressed differently in mice compared to humans and may have varied affinities towards cannabinoids [4]. Further targeted studies are required to elucidate the effects of these differences on the aforementioned study’s findings. Cannabinoid receptor agonists tend to decrease scratching, while antagonists tend to increase scratching [25, 26]. In one study, the CB1 receptor antagonist rimonabant was administered to mice by injection and was found to increase scratching [27]. The pruritic effect of rimonabant was not reversed by pre-treatment with an H1 antihistamine, but was absent in CB1 receptor knockout mice, indicating that the itch response was modulated through a neuronal rather than an immunological mechanism [27]. THC injection has also been shown to reduce the scratching response in mice through a CB1 receptor-dependent mechanism [25]. In addition, there is evidence that cannabinoids may be effective in the treatment of the inflammation caused by allergic contact dermatitis, and potentially the itch that is associated with such inflammation. In a 2,4-dinitrofluorobenzene (DNFB)-induced mouse model of allergic contact dermatitis, topical THC (30 μg in 20 μL acetone; 30 min; applied before, 24 h and 48 h after DNFB challenge) attenuated allergic ear swelling, myeloid immune cell infiltration, and inflammatory cytokine production independent of CB1 or CB2 receptors [28]. Intraperitoneal injection of 5 to 10 mg/kg N-palmitoylethanolamine (PEA), an endogenous compound shown to enhance the activity of endocannabinoids, has also been shown to reduce ear inflammation after DNFB injection in this mouse model, likely through stimulating TRPV1 [29, 30].

In a human study, histamine was administered to patients to induce itch, then a cannabinoid receptor agonist, HU210, was delivered via skin patch (50 mM, 24 h) or dermal microdialysis (5 mM, 30 min) [31]. Subjective reports of itch as well as vascular responses such as skin blood flow and flare were attenuated by HU210 through a histamine-independent mechanism [31]. In addition, the topical application of 0.3% PEA twice daily for 4–6 weeks was shown to reduce itch by an average of 86.4% in 14 of 22 patients with prurigo, lichen simplex, or pruritis [32]. Topical PEA application has also been shown to decrease symptoms of atopic eczema and uremic pruritis in open-label studies [3, 29, 33, 34].

Inflammation

Research over the past few decades has shown that the endocannabinoid system exerts complex immunoregulatory effects [35,36,37]. In both in vitro and in vivo studies, cannabinoids have demonstrated anti-inflammatory effects through modulation of inflammatory mediators and cell functioning [38, 39]. The majority of evidence of anti-inflammatory effects relates to the production of inflammatory cytokines. Cannabinoids have been shown to downregulate multiple inflammatory cytokines both in vitro, including tumour necrosis factor alpha (TNF-α), interleukin-1 alpha (IL-1α), IL-1β, IL-2, IL-6, and interferon gamma (IFN-γ) in a variety of cells (macrophages, monocytes, lymphocytes, and rodent splenic lymphocytes) [3, 8, 38, 40,41,42,43,44,45] in vivo [28, 38, 46]. The mechanism for the inhibition of inflammatory cytokine production varied, with some demonstrating CB1 or CB2 receptor-dependent pathways, while others were through canonical cannabinoid receptor-independent mechanisms [28, 38, 39, 41, 42]. Interestingly, the endocannabinoid 2-AG has been shown to promote or suppress diverse inflammatory mediators. In one study, 2-AG was shown to increase pro-inflammatory cytokines IL-8 and monocyte chemotactic protein (MCP)-1 in the human leukaemia cell line HL-60 [47]. 2-AG has also been shown to increase nitric oxide (NO) production, although the mechanism was unclear [35, 36]. Conversely, 2-AG has been shown to suppress IL-2 expression by Jurkat T cells through PPAR-γ [35, 48, 49]. In contrast, CBD was shown to induce heme oxygenase 1, which plays antioxidant and anti-inflammatory roles in the skin. CBD’s effect was shown both in vitro in normal human epidermal keratinocytes (NHEK) after incubation in 10 μM of CBD for 24 h and in vivo in the skin of female BALB/cByJrj mice with topical application of 0.1%, 1% and 10% CBD once daily for 5 days [50]. The reduced production of inflammatory mediators NO and inducible NO synthase (iNOS) has been corroborated in other studies as well [38, 39]. Cannabinoids have also been shown to downregulate chemokines which recruit immune cells in vitro and in vivo, such as IL-8, chemokine (C–C motif) ligand 2 (CCL2), and CCL8 [3, 9, 40, 44, 46]. Another potential mechanism for cannabinoids’ anti-inflammatory effects includes the modulation of eicosanoids. Treatment of human fibroblast-like synovial cells for 1 h with 10–30 μM of the cannabinoid ajulemic acid (AjA) increased in vitro production of the anti-inflammatory eicosanoid 15-Deoxy-Delta-12,14-prostaglandin J2 (15d-PGJ2) by increasing cyclooxygenase-2 expression and arachidonic acid release [51].

The cannabinoid system also modulates immune functioning through its influence on immune cell activity. A range of in vitro and in vivo studies have demonstrated that cannabinoids can decrease immune cell function and maturation [3]. THC has been shown to suppress the cytolytic activity of natural killer cells and cytotoxic T lymphocytes in vitro [38, 52]. THC also inhibited lymphocyte proliferation and the maturation to mature effector cytotoxic T lymphocytes in vitro [38, 52]. As well, cannabinoid exposure may impair the functional activity of macrophages both in vitro and in vivo [38]. Furthermore, cannabinoids can also alter the interaction between immune cells. Notably, the interaction between macrophages and T lymphocytes has been shown to be suppressed by cannabinoid administration in vivo [38, 39]. Finally, the cannabinoid system may achieve an anti-inflammatory effect through the suppression of immune cell recruitment. In a mouse model for DNFB-induced allergic contact dermatitis, the subcutaneous injection (5 mg/kg) or topical application (30 μg) of THC (30 min before as well as 24 and 48 h after DNFB challenge) reduced granulocyte recruitment to the site of allergic contact, likely through modulation of the chemokine system [9]. In another in vivo study of DNFB-mediated allergic contact inflammation, topical THC (30 μg in 20 μL acetone 30 min before as well as 24 and 48 h after DNFB challenge) limited myeloid immune cell infiltration through a CB1/2-receptor-independent mechanism [28]. In the Hgf-Cdk4R24C melanoma mouse model, daily subcutaneous THC injections (5 mg/kg) also decreased infiltration of pro-tumorigenic macrophages and neutrophils into melanoma tissues [53]. In mice with 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute ear inflammation, the topical application of 100 μg/ear of the cannabinoid receptor agonists WIN55212-2 inhibited leukocyte infiltration and blocked immune cell migration likely through a CB2 receptor-dependent mechanism [54].

The cannabinoid system has also been shown to decrease physical manifestations of inflammation in vivo for multiple disease models. The effect of the local administration of cannabinoids has been investigated in mouse models of inflammation induced by injection of inflammatory substances such as carrageen and arachidonic acid [55, 56]. Cannabidiol and cannabinoid receptor agonists were administered locally through transdermal application of ethosomal carriers or topical application. In three studies of inflammatory mouse models, local cannabinoid administration led to an anti-inflammatory effect as demonstrated by decreased swelling, inflammatory infiltrate, and/or inflammatory mediators [54,55,56]. However, in one ear dermatitis model induced by DNFB, increased ear thickness was correlated with the CB2 ligand 2-AG, and CB2 knockout mice demonstrated decreased ear thickness [47]. Thus the role of the CB2 receptor remains controversial [3]. In another example of the in vivo effect of cannabinoids on inflammation, 20 mg/kg of THC was administered to mice before inducing graft versus host disease. Intraperitoneal injection of THC was found to attenuate the host inflammatory response and improve skin graft survival [29, 57].

Cannabinoids have shown promise in animal models of dermatitis. In a mouse model of allergic contact dermatitis, the authors determined that the endocannabinoid system plays a role in reducing allergic inflammation induced by a nickel ear tag [9]. CB1 and CB2 receptor knockout or antagonism led to increased inflammation, whereas CB1/2 receptor agonism decreased inflammation measured by reduced ear swelling. In the same study, a FAAH-deficient mouse model with an excess of the endocannabinoid AEA displayed reduced allergic responses, demonstrating that the endocannabinoid system is protective for allergic contact inflammation [9]. The subcutaneous injection or topical application of THC and six other phytocannabinoids has also been shown to attenuate allergic contact inflammation and swelling, demonstrating a possible role for exogenous cannabinoid administration as treatment [3, 9, 28, 46, 58]. These anti-inflammatory effects make cannabinoids attractive targets as therapies for a wide range of inflammatory conditions, such as atopic or allergic dermatitis, acne, and psoriasis.

Cell Proliferation

A key function of the cutaneous endogenous endocannabinoid system is to manage the appropriate growth, differentiation, and survival of skin cells [2, 59]. Excessive cellular proliferation is involved in a range of dermatologic conditions including acne vulgaris, psoriasis, hair growth disorders, and skin cancer [2]. The proliferation of a range of cell types may be influenced by cannabinoids, including keratinocytes, sebocytes, hair shaft cells, and cutaneous tumour cells [2, 53]. The mechanism for the anti-proliferative effect of cannabinoids seems to be multifactorial, with varied influences on TRPV4, transcriptional repression, and CB1/2 receptors for different cell types [42, 53, 60].

Cannabinoids have demonstrated anti-proliferative effects on keratinocytes in vitro through CB-receptor-independent and epigenetic mechanisms [3, 60, 61]. In one in vitro study, the phytocannabinoids THC, CBD, cannabigerol (CBG), and cannabinol (CBN) demonstrated a concentration-dependent, anti-proliferative effect on HPV-16 E6/E7 transformed human skin keratinocytes after 72 h of incubation through a CB1/CB2-receptor-independent mechanism [61]. An epigenetic study performed on the HaCaT human transformed keratinocyte cell line also found an anti-proliferative effect of CBD and CBG but not cannabidivarin (CBDV) [60]. In another study, 24-h incubation with 10 μM AEA suppressed the proliferation of NHEK and HaCaT keratinocytes in vitro and of keratinocytes in organ culture of full thickness human skin fragments in situ. AEA’s effect was mediated through sequential signalling through CB1 followed by TPRV1 [62].

Cannabinoids have also demonstrated an anti-proliferative effect on the pilosebaceous unit of the skin [2]. AEA and THC (2–20 μM) inhibited the proliferation of hair matrix keratinocytes and hair shaft elongation through a CB1-receptor-mediated mechanism, while 2-AG did not have an effect [2, 63]. Additionally, CBD (10 μM, 24 h) was shown to have a TRPV4-dependent anti-proliferative effect on human immortalized SZ95 sebocytes or human skin organ culture (hSOC) [42]. Similarly, a study investigating five phytocannabinoids suggested that tetrahydrocannabivarin (THCV) also suppressed the proliferation of human SZ95 sebocytes in a dose-dependent manner up to 10 μM after 24, 48, and 72 h treatments, while the effect on proliferation of the four other phytocannabinoids was not mentioned [44]. Interestingly, sebaceous lipogenesis was inhibited by THCV and cannabichromene but increased by CBG and cannabigerovarin in this study [42]. Another study showed a CB2-dependent apoptotic effect on sebocytes of the endocannabinoids AEA and 2-AG [2, 64]. These findings suggest that the use of cannabinoids may be promising for disorders of hair growth and excessive sebum production.

There is some preliminary evidence that the endocannabinoid system has an effect on the proliferation of skin tumour cells. Cannabinoids have been shown to inhibit growth of a range of cancer models (e.g. glioblastoma, thyroid carcinoma, breast cancer) [53, 65, 66]. Cannabinoid receptors have also been shown to be involved in the regulation of cutaneous tumour growth of inoculated melanoma and basal cell cancers in mice [53, 67,68,69,70]. The exact antiproliferative mechanisms are unclear. In one study, daily subcutaneous THC injections (5 mg/kg) inhibited the growth of transplanted HCmel12 melanoma cells in mice in a CB1/CB2-receptor-dependent manner through an antagonistic effect on the pro-inflammatory tumour microenvironment, but had no effect on the growth of melanoma cell lines B16 and HCmel12 in vitro [53].

In mice with nonmelanoma malignant tumours generated by inoculation of PDV.C57 keratinocyte tumour cells, local administration of synthetic CB1/CB2 agonist WIN-55,212-2 or the selective CB2 agonist JWH-133 through a surgically implanted pump inhibited growth of tumour cells [2, 68]. In another study, oral administration of THC (15 mg/kg) for 20 days to mice with CHL-1 melanoma xenografts resulted in the activation of cytotoxic autophagy of melanoma cells and inhibited melanoma growth [71]. However, one study demonstrates that cannabinoids are involved in ultraviolet B-induced inflammation and skin carcinogenesis in mice, suggesting that the effects of cannabinoids may be more complex [3, 72]. Indeed, some controversial data showed that CB1 promoted the growth of human A375 and 501 Ml melanoma cell lines [73]. These studies indicate that cannabinoids may be beneficial for their anti-proliferative effects in tumour cells in addition to keratinocytes, sebocytes, and hair matrix cells. Further studies are required, however, to resolve existing controversies.

Fibrosis

There is a wide spectrum of fibrotic skin diseases, including scleroderma, morphea, mixed connective tissue disease, nephrogenic fibrosing dermopathy, scleromyxedema, scleredema, eosinophilic fasciitis, and secondary to chemical or physical agent exposure [74]. The pathogenesis of dermal fibrosis is characterized by increased fibroblast numbers or activity resulting in augmented collagen deposition. A number of cytokines are also involved in fibrosis, with increased pro-fibrotic cytokines such as transforming growth factor-β (TGF-β) and IL-4, and decreased anti-fibrotic cytokines such as IFN-γ and TNF-α [74, 75]. The endocannabinoid system plays a role in many of the features of fibrosis, namely proliferation, differentiation, and apoptosis, as well as cytokine and mediator production in the skin [2].

Cannabinoids have demonstrated anti-fibrotic effects in vitro via a non-classical, non-CB1/CB2 receptor-mediated mechanism. Incubation of human diffuse systemic sclerosis (SSc) skin fibroblasts with the cannabinoid receptor agonist WIN55,212-2 for 24 h at 1 and 10 μM led to a reduction in collagen production and pro-fibrotic cytokines (TGF-β and IL-6) [8, 76]. WIN55,212-2 also increased the number of apoptotic cells and inhibited trans-differentiation, key pathophysiologic features of fibrosis. The agonist’s effect was independent of CB1 or CB2 receptors [8, 76]. Interestingly, in another study of human SSc fibroblasts, the CB1 receptor was found to interact with the A2A receptor (A2Ar) to increase collagen production, but A2Ar inhibition in the presence of WIN55,212-2 led to decreased collagen production [77]. In another in vitro study, 24 h of treatment at varying concentrations of the synthetic cannabinoid VCE-004.8 also demonstrated anti-fibrotic effects on the following human and mouse fibroblast cell lines—NIH-3T3, HEK-293T-CB2, normal human dermal fibroblasts, and mouse embryonic fibroblasts [78]. VCE-004.8 inhibited TGF-β-mediated myofibroblast differentiation, collagen synthesis, and fibroblast migration in vitro through a non-classical PPAR-γ-mediated mechanism [78].

Similar findings were noted in scleroderma mouse models created by bleomycin or hypochlorite injections. CB2 knockout or injected CB2 antagonist-treated mice demonstrated increased sensitivity to bleomycin-induced dermal fibrosis, increased dermal thickness, and higher lesional skin leukocyte counts as compared to wild-type mice. The opposite effect was observed with CB2 agonist injection [2, 79, 80]. Another study investigated the anti-fibrotic effect of AjA, a synthetic cannabinoid [8, 81]. AjA is a weak ligand for CB1 and CB2 receptors and is also known to bind to PPAR-γ, which is implicated in pathological fibrosis. In this study, oral AjA (1 mg/kg/day for 4 weeks) prevented development and reduced progression of bleomycin-induced skin fibrosis in mice by stimulating PPAR-γ signalling [8, 81]. In a third study, an injected synthetic cannabinoid inhibited fibrotic features and was dependent on both PPAR-γ and CB2 [78].

There is some controversy regarding the cannabinoid system’s effects on fibrosis. CB1, CB2, and TRPV4 have been found to be over-expressed in cultured lesional fibroblasts from patients with diffuse cutaneous SSc compared with healthy controls [4, 76, 82]. It should be noted that this study has been criticized for its densitometry analyses [4]. In addition, the CB1R agonist ACEA injected intraperitoneally twice daily at 7.5 mg/kg for 4 weeks worsened bleomycin-induced dermal thickening in mice (Goswami above). In CB1 knockout mice, bleomycin-induced dermal thickening as well as T cell and macrophage infiltration were decreased [82, 83]. These studies indicate that cannabinoids may be promising for the treatment of fibrosis, yet there are some conflicting results regarding cannabinoids’ role in fibrosis, especially regarding the CB1R.