Cannabis sativa and Skin Health: Dissecting the Role of Phytocannabinoids

Abstract

The use of Cannabis sativa is currently recognized to ease certain types of chronic pain, reduce chemotherapy-induced nausea, and improve anxiety. Nevertheless, few studies highlighted the therapeutic potential of C. sativa extracts and related phytocannabinoids for a variety of widespread skin disorders including acne, atopic dermatitis, psoriasis, pruritus, and pain. This review summarized the current evidence on the effects of phytocannabinoids at the cutaneous level through the collection of in vitro, in vivo, and clinical studies published on PubMed, Scopus, Embase, and Web of Science until October 2020. Phytocannabinoids have demonstrated potential anti-inflammatory, antioxidant, anti-aging, and anti-acne properties by various mechanisms involving either CB₁/₂-dependent and independent pathways. Not only classical immune cells, but also several skin-specific actors, such as keratinocytes, fibroblasts, melanocytes, and sebocytes, may represent a target for phytocannabinoids. Cannabidiol, the most investigated compound, revealed photoprotective, antioxidant, and anti-inflammatory mechanisms at the cutaneous level, while the possible impact on cell differentiation, especially in the case of psoriasis, would require further investigation. Animal models and pilot clinical studies supported the application of cannabidiol in inflammatory-based skin diseases. Also, one of the most promising applications of non-psychotropic phytocannabinoids is the treatment of seborrheic disorders, especially acne. In conclusion, the incomplete knowledge of the role of the endocannabinoid system in skin disorders emerged as an important limit for pharmacological investigations. Moreover, the limited studies conducted on C. sativa extracts suggested a higher potency than single phytocannabinoids, thus stimulating new research on phytocannabinoid interaction.

Key words

Cannabis sativa - Cannabaceae - phytocannabinoids - skin diseases - acne - psoriasis - CBD

Abbreviations

[C]_max : maximum concentration

2-AG: sn-2-arachidonylglycerol

5HT: serotonin receptor

A: adenosine receptor

AEA: N-arachidonoylethanolamine, anandamide

Akt: protein kinase B (PKB)

ASK: apoptosis signal-regulating kinase

AUC: area under the curve

BACH1: transcription factor BTB and CNC homology 1

C. sativa : Cannabis sativa L.

CB: cannabinoid receptor

CBC: cannabichromene

CBCV: cannabichromevarin

CBD: cannabidiol

CBDA: cannabidiolic acid

CBDV: cannabidivarin

CBDVA: cannabidivarinic acid

CBE: cannabielsoin

CBG: cannabigerol

CBGA: cannabigerolic acid

CBGV: cannabigerovarin

CBL: cannabicyclol

CBM: cannabinoid-based medicine

CBN: cannabinol

CBND: cannabinodiol

CBT: cannabitriol

CCL: C-C motif chemokine ligand

CGRP: calcitonin gene-related peptide

CREB: cAMP-response element-binding protein

CXCL: C – X-C motif chemokine ligand

DNFB: dinitrofluorobenzene

DNMT1: DNA (cytosine-5)-methyltransferase 1

DOR: δ-opioid receptor

ECM: extracellular matrix

EGCG: epigallocatechin-3-gallate

FABP: fatty acid-binding protein

GABA: γ-aminobutyric acid

GlyR: glycine receptor

GPCR: G protein-coupled receptor

GPR: putative cannabinoid receptor

HO-1: heme oxygenase-1

HPV: human papillomavirus

ID₅₀ : infective dose

IFNγ : interferon gamma

IKKα/IKB: inhibitor of nuclear factor kappa-B kinase complex – subunit alpha

IL-: interleukin-

JKN: c-Jun N-terminal kinase

K: keratin

Keap-1: Kelch ECH associating protein 1

LTB: lymphotoxin-beta

MAPK: mitogen-activated protein kinase

MCP-2: monocyte chemoattractant protein 2 (CCL8)

MMP-: matrix metallopeptidase-

MOR: µ-opioid receptor

NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells

NK: natural killer

NLRP3: NLR family pyrin domain containing 3

NRF-2: nuclear factor erythroid 2-related factor 2

PBQ: parabenzoquinone

PI3K: phosphoinositide 3-kinase or phosphatidylinositol 3-kinases

p-IκB: phosphor-nuclear factor of kappa B inhibitor

PKA: protein kinase A

PPAR: peroxisome proliferator-activated receptor

PUFA: polyunsaturated fatty acids

Ref-1: redox effector factor 1

ROS: reactive oxygen species

TGase5: transglutaminase 5

THCV: tetrahydrocannabivarin

THCVA: tetrahydrocannabivarinic acid

TIMP: tissue inhibitor of metalloproteinases

TLR: toll-like receptor

T_max : the amount of time that a drug is present at the maximum concentration

TPA: tissue polypeptide antigen

TRP: transient receptor potential

TRPA: transient receptor potential channel, ankyrin subtype

TRPM: transient receptor potential channel, melastatin subtype

TRPV: transient receptor potential channel, vanilloid subtype

VEGF: vascular endothelial growth factor

α2-AR: α2-adrenergic receptor

Δ⁸-THC: (−)-Δ⁸-trans-tetrahydrocannabinol

Δ⁹-THC: THC, (−)-Δ⁹-trans-tetrahydrocannabinol
 

Introduction

Cannabis sativa L. is an herbaceous plant, which is generally found in temperate and tropical regions of the world [1]. Since ancient times, this plant has been an important source of fibers for the preparation of ropes, textiles, or paper. Among the different human applications, a special mention should be made of the therapeutic use of C. sativa, which finds its roots in traditional Chinese medicine about 5000 years ago as a remedy for pain and inflammation [2]. Today, the major clinical evidence shows that C. sativa is a valuable support to ease certain types of chronic pain, to reduce chemotherapy-induced nausea, and to improve anxiety [3].

Nevertheless, old and recent evidence suggests the extension of C. sativa benefits to dermatological disorders. The first Western observations on topical use were recorded at the end of the 19th century for the reduction of itching [4]. Subsequently, several studies have evaluated the cutaneous effects of this plant, focusing mainly on the individual cannabinoids.

Cannabinoids are a group of bioactive compounds, classified as endocannabinoids (physiologically synthesized in our organism), phytocannabinoids (produced by plants), or synthetic cannabinoids (artificially synthesized in laboratories), according to their source.

The endocannabinoids act as neuro- or immunomodulatory agents in humans and interact with several targets in a specific context-dependent way, thanks to their lipophilic nature [5]. Phytocannabinoids have different affinities toward human receptors; furthermore, the biological effects are often the result of the interaction with several molecular targets [3].

The biological activities of phytocannabinoids include the psychoactive effects of C. sativa, and other adverse effects of recreational use, which have been extensively reviewed [6]. Nevertheless, phytocannabinoids can significantly influence skin biology and may also potentially exert therapeutic activities.

This review aims to collect the existing scientific evidence of the beneficial effects of phytocannabinoids from C. sativa at the cutaneous level, focusing on the effects on peculiar cell types in the skin, such as keratinocytes, fibroblasts, melanocytes, and sebocytes. A specific effort was conducted to document the relevance of single phytocannabinoids for the bioactivity of whole extracts.

Molecular targets of phytocannabinoids

C. sativa synthesizes an abundant number of secondary metabolites exhibiting the typical C₂₁ terpenophenolic skeleton, called “cannabinoids” or more specifically “phytocannabinoids”. Some biological effects of phytocannabinoids are connected to the modulation of the endocannabinoid system, through a class of GPCRs, CB₁, and CB₂ [7] differently distributed in various cell types, including human keratinocytes, melanocytes, dermal fibroblasts, and myoepithelial cells [8]. Other receptors involved in the biological activities of C. sativa are the TRP channels, in particular TRPV1 and the PPARs [9]. The main recognized regulatory pathways modulated by phytocannabinoids are described below.

GPCRs

Both CB₁ and CB₂ are expressed in different skin structures, such as the epidermal layer, sebaceous glands, and hair follicles, and their regulation is involved in inflammatory processes, cell proliferation, and sebum production [7]. Although these receptors are found at the cutaneous level, CB₁ is preferentially expressed in the central nervous system, in particular in presynapses of GABA-ergic and glutamatergic neurons [10]. In contrast, CB₂ expression is predominantly diffused in immune cells, such as monocytes, lymphocytes, and NK cells [11]. CB₁ and CB₂ belong to a sub-group of a class A GPCRs able to bind lipid-derived endogenous ligands, such as AEA anandamide and 2-AG [12]. High ligand lipophilicity is required for ligand binding to CB₁ or CB₂. In the skin, CB₁ is preferentially localized in the stratum spinosum and granulosum of keratinocyte layers of the epidermis, while CB₂ is found in basal keratinocytes, and sebaceous and follicle epithelial cells. Among additional class A GPCRs that have been implicated in various phytocannabinoid actions, there are adenosine (A_1A, A_2A), α2-adrenergic (α2-AR) serotonin (5HT_1A, 5HT_2A, 5HT_3A), µ- and δ-opioid (MOR and DOR) receptors, GPR55, and GPR18 [5].

PPARs

Some phytocannabinoids can activate the transcriptional activity of PPARs and these effects can be blocked by the use of PPARs antagonists. The general activation of PPARα and PPARγ isoforms is associated with some of the neuroprotective, antinociceptive, antiproliferative, anti-inflammatory, and metabolic properties of cannabinoids. The mechanism of action is still not clear, but the metabolic conversion to active PPARs interactors has been suggested [13]. A possible mechanism enhancing this interaction is the active transport of cannabinoids to the nucleus by FABPs [14]. Recent findings have shown that some phytocannabinoids can be transported to the interior of the cell by these proteins, and, therefore, they could be delivered for PPARs activation [15]. At the cutaneous level, the expression of PPARγ has been reported in fibroblasts, keratinocytes, melanocytes, and sebocytes, in the latter case related also to lipid biosynthesis [8]. Phytocannabinoids can bind PPARγ, enhancing the related transcriptional activity and inducing apoptotic effects [16], but little information is known about the interaction between PPARα and phytocannabinoids, while the potential involvement of the PPARβ/δ isotype remains unknown.

TRP channels

TRP is a family of ion channels that are strictly involved in different cutaneous processes such as itch, temperature and pain perception, barrier homeostasis, inflammation, and regulation of hair follicles and sebaceous glands [17]. In humans, 27 TRP channels have been identified and divided into 6 subfamilies. Phytocannabinoids have shown activities on TRP channels from 3 different subfamilies: TRPV (vanilloid), TRPA (ankyrin), and TRPM (melastatin). To date, 6 types of TRP channels of the aforementioned 3 subfamilies have been identified as targets of phytocannabinoids: TRPV1, TRPV2, TRPV3, TRPV4, TRPM8, and TRPA1 [18], [19]. TRPM8 is expressed in sensory neurons and is involved in cold perception, while TRPV1, TRPV4, and especially TRPV3 are connected to mechanical and heat-evoked pain and are found in keratinocytes and epithelial cells of human hair follicles. TRPV1 and TRPV2 are diffused in sensory neurons and immune cells and participate in pain sensation and inflammation. Lastly, TRPA1 can be found in keratinocytes and melanocytes, in which it regulates pro-inflammatory processes and melanin synthesis, therefore being involved in photoprotective mechanisms [17].

GlyR

Glycine is an important neurotransmitter in the human central nervous system, and GlyRs are relevant targets for central cannabinoid action. One phytocannabinoid, CBD, has already been shown to reduce the peripherical inflammatory and neuropathic pain by potentiating GlyRs [20], [21]. In mice, topical application of glycine accelerates skin barrier recovery [22]. GlyRs are also expressed in human keratinocytes and could have a role in epidermal permeability and barrier homeostasis [23].

Phytocannbinoids

Up to 120 cannabinoids have been identified so far and classified into 11 classes: Δ⁹-THC, Δ⁸-THC, CBG, CBN, CBD, CBND, CBC, CBE, CBL, CBT, and miscellaneous types [24]. However, the proportion among different classes is dependent on growing conditions, geographical area, plant processing methods, and plant variety/chemotype [25]. The most important classes of phytocannabinoids active at the cutaneous level are summarized below ([Fig. 1]).

Fig. 1 Chemical structures of the main phytocannabinoids investigated at cutaneous level.

Tetrahydrocannabinol (Δ⁹-THC and Δ⁸-THC) types

The Δ⁹-THC type is the most abundant, representing 17.3% of the total phytocannabinoid content, and together with Δ⁸-THC type, which derives from an acidic isomerization of Δ⁹-THC [26], are recognized as the psychoactive substances of C. sativa. Δ⁹-THC is a partial agonist at both cannabinoid receptors: CB₁, a modulator of psychoactive effects, and CB₂, a modulator of immunological and anti-inflammatory pathways. Different studies have shown that Δ⁹-THC acts as an agonist of PPARγ, TRPA1, TRPV2, TRPV3, and TRPV4, and as an antagonist of TRPM8. Furthermore, Δ⁹-THC can modulate the activity of µ/δ opioid- and GlyRα1/α3 receptors [27]. THCV is the homolog of THC characterized by a propyl chain instead of a pentyl chain.

CBD type

CBD is a non-psychotropic phytocannabinoid, and the CBD type class is the third most abundant in C. sativa, after Δ⁹-THC and CBG [28]. This molecule has a low binding affinity for CB₁ and CB₂ receptors [29], [30], [31], but through the modulation of multiple targets, it reduces pain, inflammation, and anxiety and displays potential antitumor activities [32]. Despite the low affinity in vitro, a recent meta-analysis concluded that CBD may affect CB₁ receptor activity in vivo via an indirect mechanism [33], [34], [35]. Also, CBD can reduce the uptake of anandamide at the cellular level, but at concentrations far from those relevant for a physiological effect in vivo [18], and antagonize GPR55 [36], [37], [38] and GPR18 [39].

Outside of the endocannabinoid system, the mechanisms by which CBD possibly mediates anti-inflammatory and immunosuppressive effects include the activity at the A_1A adenosine receptor [40], the inhibition of the equilibrative nucleoside transporter [40], [41], and the activation of strychnine-sensitive α ₁ and α ₁ β Glyrs [20], [21], [42]. CBD interacts differently with the serotonin receptors, as a full agonist, a weak agonist, and a noncompetitive antagonist (respectively for 5HT_1A, 5HT_2A, and 5HT_3A) [43], [44]. In vitro, CBD has been reported by numerous studies to activate the TRPV1, TRPV2, and TRPA1 channels [18], [45], [46], while antagonizing TRPM8 in vitro [47]. In vivo, CBD shows possible activity at the TRPV1 channels in mice and rats and the TRPA1 channels in rats [48]. In addition, CBD acts as an agonist of PPARγ receptors and as an allosteric modulator of µ/δ opioid receptors [49] and GlyRα1/α3 receptors [20], [21]. CBDV is the homolog of CBD with the propyl chain.

CBG type

CBG has been the first compound to be isolated in a pure form from the resin of C. sativa. Many novel cannabinoids belonging to the CBG-type have been reported recently [50], most of them isolated from the buds of the mature female plant of a high-potency variety of C. sativa [51], [52], [53]. As opposed to CBD, CBG acts as a partial agonist for CB₁ and CB₂, but in common they share a weak affinity for these receptors [54] and the inhibition of anandamide uptake [55]. CBG is an agonist of TRP channel receptors (TRPA1, TRPV1, and TRPV2) and an antagonist of TRPM8, TRPV4 [19], [55], and 5HT_1A receptors [56]. CBGV is the homolog of CBG with the propyl chain.

CBC type

CBC was discovered in 1966 [57] as an agonist of CB₂ receptors [58] and is recognized as one of the strongest TRPA1 agonists among the phytocannabinoids, together with CBD and CBN [55]. It also displays agonism to TRPV3 and TRPV4 channels [19] and antagonism for TRPM8. CBC is also able to increase anandamide levels by inhibiting its uptake [55].

CBN type

Seven cannabinol derivatives, which are aromatized derivatives of THC, have been described. CBN is commonly found in the aged plant of C. sativa or in related products, in which the concentration increases during storage [50]. Compared to Δ⁹-THC, CBN shows a higher and lower affinity for CB₂ and CB₁ receptors, respectively [59].

A wider and detailed comparison of the molecular mechanisms of phytocannabinoids and their specific affinities towards human receptors can be found in recently published reviews [25], [27].

Almost all the works concerning the cutaneous effects of phytocannabinoids are based on the study of pure or isolated compounds. The scientific data were collected and commented below, divided according to the evidence on cellular models, in vivo or human.

Search Strategy

This review aimed to collect in vitro, in vivo, and clinical evidence of the role of phytocannabinoids and C. sativa extracts in skin health, as well as their use against skin diseases.

A systemic search of electronic databases, including PubMed, Scopus, Embase, and Web of Science, was conducted in October 2020, for papers reporting in vitro, in vivo, or clinical evidence of the effects of phytocannabinoids at a cutaneous level, using the following search terms: (“cannabis” OR “cannabichromene” OR “cannabidiol” OR “cannabigerol” OR “cannabicyclol” OR “cannabinol” OR “cannabidivarin” OR “tetrahydrocannabinol”) AND (“skin” OR “keratinocytes” OR “fibroblasts”). In a second step, duplicate articles were removed, and the references listed in the remaining ones were sifted through to identify documents that might have eluded the primary search. The search limit was the English language, whereas no limit was applied for the year of publication. This review includes only published articles and does not consider unpublished works or non-peer-reviewed articles.

Preclinical and clinical studies concerning the effects of C. sativa extracts or phytocannabinoids found in the plant on skin pathophysiology were considered eligible. Full titles and abstracts were checked for adherence to the eligibility criteria. Then, full texts were carefully read and checked for inclusion by all the authors. Papers including results obtained from the combination of extracts from plants other than C. sativa or phytocannabinoids together with other non-C. sativa molecules, except for specific pharmacological formulations, were out of the scope of the present review.

Relevant information (the type of phytocannabinoid, type of evidence, details about the model, dose/concentration, presence/absence of a positive control, schematic results, and biological context) was extrapolated from articles and summarized in a table propaedeutic to the text of the article.

In vitro Evidence

Several in vitro researches on cannabinoids described their biological activity ([Fig. 2]) and mechanisms of action in skin cells, like keratinocytes, fibroblasts, melanocytes, and sebocytes ([Table 1]). The role of CB₁/₂-dependent or independent signaling was considered in most of the studies, which regarded inflammation and oxidative stress, proliferation, differentiation, and migration.

Fig. 2 Summary of the main in vitro pharmacological actions of phytocannabinoids in keratinocytes, sebocytes, melanocytes, and fibroblasts.

Table 1 Summary table of in vitro and in vivo skin studies conducted with phytocannabinoids.

Phytocannabinoids	Evidence	Details about the model	Concentration/dose	Positive control	Schematic results	Biological context	Ref.
Preclinical research
Δ9-THC, CBD, CBG, CBN, and olivetol	In vivo	CDI male mice; PBQ-induced writhing and TPA-induced ear erythema		Acetylsalicylic acid and trifluoperazine	CBD, CBN, and olivetol ↓ erythema (topical administration) and writhing (oral administration) with the strongest inhibitory potency (< 10 mg/kg); CBN was only marginally active; Δ9-THC was fully active only at doses > 10 mg/kg	Skin inflammation and pain	[82]
CBD	In vitro	HaCaT keratinocytes and HDF fibroblasts cells, TNF-α induction	0.05 – 5 µM in HaCaT cells, 0.1 – 2.5 µM in HDF cells	EGCG, resveratrol, and quercetin	In keratinocytes: ↓NF-κB; ↓ MMP-9; CBD was able to downregulate 15 TNF-α-induced genes. In fibroblasts: no inhibition of NF-κB; CBD impaired gene expression of 11 TNF-α-induced genes	Potential effect against inflammatory skin diseases	[64]
CBD	In vitro	Normal human dermal fibroblasts (NHDF) and normal human epidermal keratinocytes (NHEK)	CBD 0.1 – 0.2 µg/mL	//	↓ metalloprotease inhibitors TIMP1/2 and the expression of collagen in fibroblasts; ↓ LPS-induced IL-6 expression in fibroblasts, but not in keratinocytes	Wound healing	[66]
Δ8-THC	In vivo/ ex vivo	Human skin samples from abdominoplasty surgery; male and female hairless IAF and Hartley guinea pigs	Ex vivo: the highest concentration of THC in any diffusion sample was 0.77 µg/mL; In vivo: 1 mg/kg was infused for 30 s and application of a TTS patch in guinea pigs	//	Similar permeability of Δ8-THC in human and guinea pig	Permeability study	[71]
CBD	In vitro/ in vivo	NHEK, HaCaT; six-month-old female BALB/cByJRj mice	10 µM for 24 h in vitro; 0.1 – 10% in vivo (topically, 1/day for 5 days)	//	↑ skin thickness, K16, and K17, but not pro-inflammatory cytokines in vivo; ↑NRF-2 and HO expression trough ↓ BACH1 in vitro	Inflammatory skin diseases	[65]
CBD	In vitro	Fibroblast (CCD-25Sk) 2D and 3D culture models; UV-A 20 J/cm2 and UV-B 200 mJ/cm2 irradiation	4 uM	//	↓ UV-induced collagen degradation in 2D and 3D fibroblast models through PI3K/Akt pathway; ↓ lipid peroxidation; ↓ NF-κB pathway, ↑ PPARγ expression	//	[67]
CBD	In vitro	Human epidermal melanocytes	6 µM	Forskolin 5 µM/PMA	↑ melanin levels through tyrosinase activation, ↑ p-CREB, ↑ p-p38, p-p42/44, but not p-JNK; the mechanism was cAMP/PKA-independent and CB-1 dependent	Hypopigmented skin disorder	[68]
CBD	In vitro	Human keratinocytes (CDD 1102 KERTr) exposed to UV-A (30 J/cm2) and UV-B (60 mJ/cm2)	1 µM	//	↑ NF-κB and NRF-2 activity (physiological conditions); ↓ NF-κB, NLRP3, MAPK, ↑NRF-2, and HO-1 expression, ↓ ASK and Ref-1 (during irradiation)	//	[63]
CBD (ethosomal formulation)	In vivo	CD1 nude mice, patch for 24 h; ICR mice, patch or 2 – 73 h and carrageenan paw edema	//	//	↓ paw edema; transdermal absorption; detection in the plasma (0.67 µg/mL at the steady state); accumulation in the hip skin (37.43 µg/cm2), abdominal skin (110.07 µg/cm2), and underlaying muscle (11.54 µg/cm2)	//	[84]
CBD	In vitro	SZ95 (sebocytes)	1 – 10 µM	//	↓ lipogenesis vs. arachidonic acid and testosterone; ↓ proliferation; ↓ TNF-α expression and NF-κB activation induced by TLR2 and TLR4 agonists; ↑ intracellular Ca2+ levels through TRPV4 agonism; ↑ cAMP through A 2α agonism	//	[69]
Δ9-THC	In vivo/ in vitro	Wildtype vs, CB1/2 knock-out mice, DNFB-induced dermatitis model; primary keratinocytes and macrophages from mice	30 µg (in vivo), 0.1 – 1 µM (in vitro)	//	↓ ear dermatitis and IFNγ in vivo; ↓ pro-allergenic chemokines CCL2, CCL8, CXCL10 through CB1/2-independent mechanisms in IFNγ-activated keratinocytes; ↓ macrophage migration in co-culture experiments	Atopic dermatitis	[74]
Δ9-THC	In vivo/ in vitro	CB1 and CB2 receptor-deficient mice; melanoma cells	5 – 10 µM (in vitro), 5 mg/kg (in vivo)	//	The growth of murine melanomas was not affected by CB1/2 depletion; Δ9-THC (5 – 10 µM) ↓ cancer growth through anti-inflammatory activity (↓ infiltration of immune cells) and not CB1/2-dependent mechanisms	Melanoma	[75]
Δ8-THC	In vivo/ ex vivo	Rat vs. human skin models	Two formulations containing 26.5 mg/g Δ8-THC were tested in vivo and in cell diffusion test	//	Δ8-THC is 13-fold more permeable in rat than human skin and accumulates in the epidermis	Permeability study	[71]
CBC, CBDV, CBG, CBGV, THCV	In vitro	SZ95 (sebocytes)	0 – 10 µM	//	CBC ↓ basal and AA-induced lipid synthesis; CBG ↑ basal lipid synthesis and ↓ anandamide inhibitory effect	//	[69]
CBD, CBDA, CBDV, CBDVA, CBC, CBG, CBGA, CBGV, THCV, THCVA	In vitro	HaCaT keratinocytes stimulated with poly-(I : C)	1 – 20 µM	//	CBD: ↓ MCP-2, IL6-, TNF-α, IL-8, ↑ anandamide levels; CBDA, CBDV, CBDVA: no effect on MCP-2; CBC, CBG: ↓ MCP-2, IL-6, IL-8; CBGA: no effect on MCP-2 protein levels; CBGV: ↓ MCP-2 (only at 10 µM); THCV: ↓ MCP-2, IL-6. THCVA: no effect on MCP-2 protein levels.	Allergic contact dermatitis (ACD)	[79]
CBD, CBDV, CBG	In vitro	HaCaT and HNEK keratinocytes; TPA- and calcium-induced differentiation in HaCaT	0.1 – 0.5 – 1.0 µM	Endogenous cannabinoid AEA (anandamide)	↓ keratinocyte differentiation by increasing the general methylation state of genes	Skin diseases involving proliferation and differentiation unbalance	[77]
Δ8-THC, CBD, CBN	In vitro	Human skin samples from abdominoplasty surgery; diffusion cell test	Δ8-THC formulation: 9.09 mg/mL drug solution in propylene glycol : water : ethanol (9 : 1 : 1) or 16.67 mg/mL in propylene glycol : water : ethanol (1 : 1 : 1); CBD and CBN formulations: saturated solutions in mineral oil (7 : 3 propylene glycol : water or 4 : 5 : 4 propylene glycol : water : ethanol)	//	Δ8-THC accumulated in skin tissue; CBN and CBD exhibited 10-fold higher permeability	Permeability study	[73]
CBD, CBDV, CBCV, CBC, THCV, THC	In vivo	Croton oil-induced ear edema in mice	Dose range of 0.1 – 1 µmol/cm2	Indomethacin 0.1 – 1 µmol/cm2	↓edema; Δ8-THC, Δ8-THCV, and Δ9-THC were more effective (ID50 = 0.46 – 0.55 µmol/cm2) than CBD, CBC, CBDV, CBCV (ID50 > 2 µmol/cm2), but only slightly less potent than indomethacin	//	[83]
Δ9-THC, CBD, CBN, CBG (the phytocannabinoids THC, CBD, CBN, and CBG were isolated from a hexane extract of C. sativa, grown domestically under controlled hydroponic conditions. Structures were verified by NMR spectroscopy.)	In vitro	The principal cells selected for use in these experiments were HPV-16 E6/E7 transformed human skin keratinocytes (ATCC; CRL-2309 KERTr). The antiproliferative effect was measured after 72 h of exposure.	//	//	↓ proliferation by CB1- and TRPV1-independent mechanisms (2.0 < IC50s < 2.9 µM)	//	[78]
Δ9-THC	Ex vivo	Wildtype and CB-1−/− or TRPV-1−/− mice; rat skin explants	0.1 – 100 µM	Anandamide	↓ CGRP release via CB1 (low conc.) or TRPV1 (high conc.)	Nociception	[76]
CBD	In vitro	Primary keratinocytes from healthy vs. psoriasis patients	4 µM	//	↓ oxidation in healthy keratinocytes, but only partially in psoriasis keratinocytes; CBD accumulated in membranes, especially after UV stimulation in psoriatic cells	Psoriasis and oxidative stress	[61]
CBD	In vitro	Primary keratinocytes and melanocytes	1, 4, 8 µM	//	↓ cell mortality (vs. UV-B irradiation)	UV damage	[60]
CBD	In vitro	CDD 1102 KERTr human keratinocytes	4 µM	//	↓ lipid peroxidation, ROS, cell mortality (vs. UV and H202); the effect correlated with membrane protection through the restoration of PUFA composition	Skin protection against oxidative stress (UV, ROS)	[62]

The most investigated nonpsychotropic cannabinoid at the cutaneous level was CBD. The antioxidant effect of CBD was recently evaluated against UV or hydrogen peroxide models of cellular oxidation. CBD (4 µM) was able to rescue keratinocytes and melanocytes from UV-B-induced cytotoxicity [60]. The cytoprotective mechanism was deepened in keratinocytes by Skrzydlewska et al. [61], [62], who ascribed it to the preservation of antioxidant defenses, the protection of plasma membrane, and the modulation of the endocannabinoid system. The authors correlated the accumulation of CBD at the membrane level with the reduction of markers of lipid peroxidation (malondialdehyde, 8-isoprostanes), the preservation of antioxidant proteins (thioredoxin, reduced glutathione, catalase) and lipophilic vitamins (A, E), and the restoration of PUFA composition [61], [62]. Moreover, CBD reduced the level of endocannabinoids (anandamide, palmitoylethanolamide) in irradiated keratinocytes from healthy donors, while it increased the expression of CB receptors. Notably, the effect was controversial in irradiated cells from psoriatic patients, in which CBD tended to increase the oxidative status and exerted opposite effects on the endocannabinoid system (increased anandamide levels and decreased CB₂ expression). The authors had taken into consideration the confounding factors related to the different basal conditions of healthy and psoriatic keratinocytes and the impact of UV irradiation per se on the endocannabinoid system [61]. However, this work has opened the investigation on the use of CBD as an antioxidant for psoriasis.

The same group evaluated also the antioxidant and anti-inflammatory activity of CBD (1 µM) at the transcriptional level in keratinocytes, pointing out the role of the transcription factors NRF-2 and NF-κB, and their interplay [63]. In physiological conditions, CBD enhanced the activity of NF-κB and NRF-2, acting, respectively, on the upstream proteins IKKα/p-IKB and p62/Keap-1. The results suggested the concomitance of antioxidant and pro-inflammatory activity; on the contrary, after UV-A or UV-B irradiation, CBD revealed mostly antioxidant and anti-inflammatory properties, despite the production of TNF-α being elevated: in fact, CBD enhanced the phosphorylation of NRF-2 and the expression of the NRF-2-dependent proteins heme oxygenase 1 (HO-1) and thioredoxin reductase; moreover, the cytoprotective proteins ASK and Ref-1, elevated by UV irradiation, were normalized.

From the inflammatory point of view, CBD inhibited the inflammasome NLRP3, the levels of MAPKs, and the translocation of p52 (NF-κB). Despite the interplay between NF-κB and NRF-2 being still not clear in the scientific literature, the authors asserted the plausibility of the hypothesis that the activation of NRF-2 impaired the activity of NF-κB, according to their data and the literature. On the other hand, our group [64] excluded that CBD (1 µM) may act on NRF-2 translocation, which resulted in impairment after UV-B irradiation in human keratinocytes, while we confirmed the anti-inflammatory effect of CBD in TNF-α-challenged cells. In particular, CBD was able to interfere with NF-κB activity (IC₅₀ = 2.85 µM), affecting the NF-κB-dependent protease MMP-9 in a significant manner (IC₅₀ = 5 µM) but not VEGF and IL-8. In qPCR arrays, TNF-α treatment induced the upregulation of 26 genes including chemokines (e.g., CXCL8/IL-8 and CXCL10), interleukins (e.g., IL17C and IL1B), TNF family members (e.g., TNF and LTB), and other genes such as VEGFA, while the treatment with CBD was able to downregulate 15 of those genes. Different from keratinocytes, NF-κB and inflammatory mediators (MMP-9 and IL-8) were not influenced by CBD in human dermal fibroblasts. However, CBD impaired gene expression, similar to what was observed in keratinocytes. In fact, TNF-α upregulated 16 genes involved in wound healing and inflammation; in particular, the most upregulated ones were ECM enzymes (e.g., MMP-1 and MMP-9), cytokines (e.g., CXCL11, CXCL2, and IL-6), growth factors and signal transducers, while CBD treatment downregulated 11 of those genes.

In line with previous works [63], [64], Casares et al. [65] selected NRF-2 as a possible target of CBD for skin protection. This work was performed on human keratinocytes and confirmed that CBD (10 µM) may act as a weak inducer of NRF-2 (in comparison to sulforaphane, a known NRF-2 activator) and added new information on the mechanism of action. CBD strongly enhanced the expression of HO-1 and other antioxidant genes, but this effect was not sustained by strong NRF-2 activation. Moreover, the increase of HO-1 expression was observed even in Keap-1 knock-out cells and paralleled with the prevention of ROS generation, thus leading the authors to investigate ROS- and NRF-2-independent ways for HO-1 expression by CBD. Consequently, BACH1, another important transcription factor involved in oxidative stress and HO-1 expression, was pointed out as a potential target: CBD induced a strong degradation of this transcription factor. Since BACH1 represses p62 expression, its degradation by CBD paralleled with enhanced levels of p62, which, in turn, may stabilize NRF-2 competing with Keap-1. This mechanism was recognized as an indirect way for the weak induction of NRF-2 by CBD. A direct consequence of HO-1 induction is the promotion of cell survival and resilience to oxidative stress, useful in pathological conditions characterized by the occurrence of skin lesions.

This indication is also sustained by other authors, who focused on the wound healing properties of CBD [66]. The cannabinoid (in the concentration range of 0.1 – 0.2 µg/mL, corresponding to 0.3 – 0.6 µM) impaired the matrix metalloprotease inhibitors TIMP1/2 and the expression of collagen in fibroblasts, while keratinocytes were less influenced. Consequently, the observed effect was in favor of the degradation of the ECM. Similarly, CBD inhibited LPS-induced IL-6 expression in fibroblasts, but not in keratinocytes, thus exhibiting a potential anti-inflammatory activity.

Another work reported opposite effects on collagen turnover in fibroblasts [67]. CBD (4 µM) was able to prevent UV-induced collagen degradation in 2D and 3D fibroblast models. The biological mechanism was attributed to the activation of the PI3K/Akt pathway, which is also involved in cell proliferation. Of note, in line with the fact that CBD may act as stabilizer and weak inducer of NRF-2 [65], this work confirmed the protective effect of CBD against lipid peroxidation. Moreover, CBD exerted an anti-inflammatory effect acting on the NF-κB pathway, which correlated with the increase of PPARγ expression.

As previously mentioned, most of the authors focused on the role of CBD for keratinocyte and fibroblast functions. Hwang et al. [68] demonstrated that CBD may also influence melanogenesis. In particular CBD 6 µM was able to increase melanin levels in melanocytes through tyrosinase activation. The effect was independent from cAMP and the related PKA activation (forskolin was used as a positive control), although the downstream transcription factor, CREB, was equally phosphorylated. A possible explanation was attributed to the activation of MAPKs (p38, p42/44, but not JNK). Moreover, the biological activity was CB₁-dependent, since CB₁ silencing counteracted CBD-induced melanogenesis.

A specific work regarding the role of cannabinoids against acne was conducted by Olah et al. [69], [70]. The authors had previously investigated the effect of CBD (1 – 10 µM) in sebocytes: the compound inhibited lipogenesis, counteracting acne-inducing agents, such as arachidonic acid and testosterone; moreover, CBD suppressed the proliferation of sebocytes in the absence of cytotoxicity and impaired TNF-α expression induced by TLR2 and TLR4 agonists (LPS and lipoteichoic acid, respectively). The main mechanism of all the aforementioned effects was recognized in the increase of intracellular Ca²⁺ levels through TRPV4 agonism. In addition, the activation of A2α receptor was revealed as another fundamental anti-inflammatory mechanism, again ascribed to cAMP elevation and consequent NF-κB impairment. In a following work on sebocytes [69], the same authors compared the evidence on CBD with experiments on other cannabinoids (CBC, CBDV, CBG, CBGV, THCV), thus revealing a differential effect on lipogenesis. CBDV, THCV, and CBC impaired basal lipogenesis, resembling CBD, while CBG and CBGV slightly induced it with an opposite effect. However, following acne-like phenotype induction by arachidonic acid, all compounds were able to impair lipogenesis, with CBDV, CBC and, especially, THCV being the most effective ones. THCV (0.1 µM) was further selected for anti-inflammatory assessment, thus revealing the inhibition of LPS-induced expression of IL-8, IL-6, TNF-α, IL-1α, and IL-1β. The mechanism behind the differential functions of cannabinoids in basal lipogenesis was not verified; however, the authors suggested the involvement of the CB₂/PPARγ pathway in the activity of CBG and CBGV, which would resemble the lipogenic effect of endocannabinoids (anandamide and 2-AG), contrarily to CBD. As a consequence, several cannabinoids (CBG-like) may be of interest against dry skin conditions (xerosis, skin aging), while others (CBD-, THC-, CBC-like) may counteract seborrheic disturbs.

The second most investigated cannabinoid is THC, in the isoforms Δ⁸-THC and Δ⁹-THC. Despite the pharmacological equivalence among the 2 isoforms, Δ⁸-THC is usually preferred for the higher stability. Three works investigated the permeability of Δ⁸-THC [71], [72], [73] in skin explants from animals and humans. Valiveti et al. measured a similar permeability coefficient in human skin and hairless guinea pig skin after the application of 0.77 µg/mL (around 2.5 µM), thus sustaining the validity of the in vivo models for THC studies: transdermal flux was found to be 649 and 717 ng/cm²/h with a lag period of 12.4 and 13.2 h, respectively. The permeability was further confirmed in vivo, using a transdermal patch system. On the contrary, Touitou et al. underlined a great difference in the diffusion of Δ⁸-THC among human and rat skin: Δ⁸-THC was 13-fold more permeable in the latter [71]. Moreover, the cannabinoid accumulated in the upper epidermis.

Similarly, Stinchcomb et al. compared the permeability of Δ⁸-THC with CBN and CBD [73]; in line with the previous work [71], they observed the accumulation of Δ⁸-THC in skin tissue, while CBN and CBD exhibited 10-fold higher permeability. THC accumulation in the epidermis suggests its preferential interaction with keratinocytes. Gaffal et al. [74] exploited this possibility in in vitro studies on skin allergy: Δ⁹-THC (0.1 – 1 µM) suppressed the secretion of pro-allergenic chemokines (CCL2, CCL8, CXCL10) by IFNγ -activated wild type and Cnr1/2 ^–/– (murine CB_1/2 receptor genes) keratinocytes cultured from the respective knock-out mice. The inhibitory effect resulted in the impairment of macrophage migration in co-culture experiments with IFNγ -activated keratinocytes. These results indicated that Δ⁹-THC decreased the production of chemokines in a CB_1/2-independent manner. In line with this evidence, Glodde et al. [75] demonstrated that the growth of murine melanomas is not affected by CB_1/2 depletion; thus Δ⁹-THC (5 – 10 µM) was not able to inhibit the tumor in a CB-dependent manner. However, as reported in the next section devoted to in vivo studies, THC showed anti-cancer activity through anti-inflammatory effects on infiltrating immune cells.

Δ⁹-THC is also well known for its anti-nociceptive effect. Engel et al. [76] validated the effect of Δ⁹-THC in skin explants from rats and mice, pointing out the role of TRPV1 and CB₁ receptors. Δ⁹-THC, in comparison with anandamide, exerted moderate inhibitory activity at low (0.1 µM) and high (100 µM) concentrations on heat and capsaicin-induced calcitonin CGRP release from nociceptive nerve endings in skin. On the contrary, lower (10 nM) and intermediate (1 – 10 µM) concentrations of the cannabinoid were not sufficiently effective on CGRP release. Specific experiments on knock out animals revealed that the inhibitory effect at low concentrations was entirely CB₁-dependent, while, at higher concentrations, TRPV1 desensitization occurred as major mechanism.

Several authors performed a biological comparison among different cannabinoids within the same experimental setting. Due to their common anti-inflammatory properties, cannabinoids were investigated for their potential application in inflammatory-based skin diseases [77], [78], [79]. However, Petrosino et al. [79] observed different behaviors in poly(I : C)-activated keratinocytes, an immunogenic model that mimics viral infection and hypersensitivity through TLR3 and IFNγ induction. CBD, CBC, CBG, and THCV exhibited a concentration-dependent (5 – 20 µM) inhibitory effect on IL-6 and MCP-2, while the respective carboxylic forms (CBDA and CBGA) were inactive. The effect of CBD was further investigated, thus including IL-8 and TNF-α inhibition. The biological activity correlated with anandamide elevation and depended on CB₂ and TRPV1 agonism. Accordingly, further experiments [77] regarded the role of CBD, CBG, and anandamide in keratinocyte differentiation, a fundamental step for skin barrier constitution. CBD inhibited the expression of all the considered differentiation markers (K1, K10, involucrin, TGase5), while CBG decreased the levels of K10 and TGase5, only. Both compounds acted at the epigenetic level by increasing the methylation state of genes via selective DNMT1 up-regulation. All the biological activities were resembled by anandamide, which was found to be directly elevated by CBD in the previously described work [79]. These results indicate that CBD and CBG may counteract inflammation while impairing differentiation in keratinocytes, which is in line with the discussion from Casares et al. [65], who suggested to take into consideration the proliferative potential of CBD at skin level. In fact, although anti-inflammatory, the use of CBD may theoretically result in undesired effects when proliferation or skin barrier alteration occur, such as in plaque psoriasis or atopic dermatitis: in those patients, the differentiation markers like K10 and involucrin are downregulated [80], [81]. On the other hand, the results from Pucci et al. [77] prompted the authors to promote the use of CBD and CBG in skin cancer, which is only apparently contradictory. Indeed, Reichelt et al. clarified the role of K10 in skin papillomas, since Krt10 ^−/− mice exhibited keratinocyte hyperproliferation, but also lower susceptibility to tumors due to the enhancement of skin turnover [22]. Consequently, the inhibition of K10 levels by CBD and CBG may result in skin tumor repression and should require further clinical investigation.

Regarding the context of psoriasis, Wilkinson et al. [78] demonstrated that phytocannabinoids (Δ⁹-THC, CBD, CBG, CBN) may counteract the proliferation of human HPV 16-transformed keratinocytes. The effect was independent from TRPV1 or CB_1/2 agonism and was slightly superior for nonpsychotropic cannabinoids (IC₅₀ ranging from 2.0 and 2.3 µM) than for THC (IC₅₀ = 2.9 µM).

This evidence seems in conflict with the previously mentioned one on the proliferative potential of CBD: on the contrary, in vitro experiments from Casares et al. showed that CBD may up-regulate a cluster of genes involved in differentiation and counteract proliferation, while the in vivo system confirmed an opposite effect with a proliferative profile [65]. As a consequence, the effect of CBD on the proliferative/differentiative balance of epidermis may vary in vitro or in vivo and may depend on the pathological context under study. In particular, the effect of CBD and CBG on differentiation may require further validation against skin cancer, while specific studies are suggested to criticize their role in psoriasis.

In vivo Evidence

In vivo studies on cannabinoids at skin level, collected in [Table 1], are few and mostly focused on the anti-inflammatory and antioxidant properties. As mentioned in the previous section, only a small number of authors translated in vitro evidence to the in vivo level. Casares at al. [65] characterized the antioxidant effect of CBD in human keratinocytes, demonstrating that this compound acts through NRF-2 and BACH1 degradation, thus leading to antioxidant gene expression, such as HO-1. In line with the anti-apoptotic role of HO-1, the authors observed an elevated skin thickness in vivo, due to keratinocyte hyperproliferation, after the topical treatment of BALB/c mice with CBD (0.1 – 10%). In parallel, markers of wound repair, inflammation and proliferation (K16, K17) were increased in the epidermis of mice, but the expression of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) was absent. The results suggested a possible role for CBD in skin protection but underlining a theoretical risk for the treatment of psoriasis.

Formukong et al. [82] evaluated the effect of the oral administration of Δ⁹-THC, CBD, CBG, CBN and the pharmacophore olivetol on PBQ-induced writhing and the topical application of the same compounds on TPA-induced ear erythema. CBD, CBG, and olivetol showed the strongest inhibitory potency (< 10 mg/kg) in both tests, and were more potent than acetylsalicylic acid, used as a positive control in a PBQ-induced writhing test, and trifluoperazione, used as a positive control in TPA-induced ear erythema test. CBN showed only negligible effects; Δ⁹-THC was effective only at doses greater than 10 mg/kg. Notably, the biological effect of individual compounds was not able to clearly explain that of petroleum or ethanolic cannabis extracts.

The anti-inflammatory effect of the topical application of Δ⁹-THC (30 µg) was verified also in the mouse model of DNFB-induced ear contact dermatitis [74]. Δ⁹-THC inhibited the infiltration of monocytes and granulocytes (Gr-1⁺ staining) in the inflamed tissue and the release of IFNγ by hapten-activated T cells ex vivo. The mechanism of action was CB-independent, since Δ⁹-THC acted also in Cnr⁻ /⁻ mice and keratinocytes. Moreover, the inhibitory effect of Δ⁹-THC (5 mg/kg, subcutaneous injection) on immune cell infiltration was also considered responsible for the reduction of melanomas in Cnr⁻ /⁻ mice. In fact, CD45⁺ cells, largely consisting of myeloid derived macrophages and neutrophils, were lowered in tumoral tissues, while the growth of tumors was not inhibited in vitro.

Similarly, Tubaro et al. [83] compared the topical effect of different cannabinoids (CBD, CBDV, CBC, CBCV, THC, THCV) against croton oil-induced ear edema in mice, in the dose range of 0.1 – 1 µmol/cm². Δ⁸-THC, Δ⁸-THCV, and Δ⁹-THC were more effective (ID₅₀ = 0.46 – 0.55 µmol/cm²) than CBD, CBC, CBDV, and CBCV (ID₅₀ > 2 µmol/cm²), while only slightly less potent than indomethacin, used as reference anti-inflammatory compound.

Another in vivo study documented the anti-inflammatory effect of CBD, with a particular focus on its absorption after topical application [84]. The authors enhanced the bioavailability of CBD with an ethosome formulation, which was applied at the abdominal site of ICR mice: in parallel, paw inflammation was induced by carrageen injection. The transdermal absorption was measured after 12 h and 73 h and resulted in 1.37 mg and 2.60 mg, respectively, starting from the administration of 200 mg. CBD was detected in the plasma at the concentration of 0.67 µg/mL (about 2.1 µM) at the steady state (72 h). The treatment strongly reduced the paw edema. In a parallel experiment, the topical administration in CDI nude mice led to the accumulation of CBD in the hip skin (37.43 µg/cm²), abdominal skin (110.07 µg/cm²), and underlying muscle (11.54 µg/cm²) after 24 h.

The bioavailability of CBD also was investigated in healthy dogs following oral or topical administration of 3 formulations (oral microencapsulated oil beads, oral CBD-infused oil, or CBD-infused transdermal cream) with doses of 75 mg or 150 mg. The highest systemic exposure and the best pharmacokinetic profile were observed with the oral CBD-infused oil formulation: the [C]_max in the plasma was 625.3 ng/mL, the T_max was 1 h, and the AUC was 8%, with comparable results for the 2 administered doses [85]. In line with previous works, the authors observed a low bioavailability after oral administration and suggested the study of formulative strategies to avoid first-pass effect by improving the transdermal passage and circumventing skin accumulation.

Valiveti et al. investigated if the topical application of Δ⁸-THC may account for a different permeability on the basis of the model: they observed a similar permeability for Δ⁸-THC (0.77 µg/mL, i.e., about 2.5 µM) in human and guinea pig skin explants and validated a patch system that guaranteed the transdermal passage of the cannabinoid (4.4 ng/mL at the steady state) in vivo [72].

On the contrary, as mentioned in the in vitro section, Touitou et al. [71] underlined the great differences in the diffusion of Δ⁸-THC in human and rat skin and, again, its accumulation in the upper epidermis, thus remarking how important is the selection of predictable in vivo models for preclinical investigations.

In general, despite the clear anti-inflammatory properties of cannabinoids, there are still few in vivo studies concerning the biological effects in the context of common autoimmune skin disease or skin cancer. From the collection of the studies concerning topical permeability of cannabinoids, the following aspects emerged: 1) the bioavailability of cannabinoids other than THC or CBD is poorly investigated; 2) thanks to the relatively easy diffusion of cannabinoids after topical application, related to their lipophilicity, transdermal delivery is considered preferable to oral administration to reach a systemic effect, both for safety and bioavailability aspects, but innovative formulative strategies are required. However, topical administration has been only partially explored as an advantage to target the epidermis in inflammatory skin diseases, limiting diffusion to other untargeted organs.

Clinical Evidence

Clinical evidence on the therapeutic use of cannabinoids against skin diseases is rare and has been summarized in [Table 2]. Most are anecdotal or observational studies concerning CBD. Chelliah [86] et al. described 3 case reports of self-initiated topical CBD oil use against a rare genetic disease occurring in children, epidermolysis bullosa. Those patients suffer for skin frailty and the consequent lesions, but resolutive treatments are still missing. During the study, family members noted fewer blisters, shorter healing time, and less analgesic need, but these results were not verified in a randomized, double-blind, controlled study. Similarly, other authors reported 3 cases of patients with epidermolysis bullosa, who were prescribed sublingual pharmaceutical preparations of CBD and THC (20 mg/mL and 13 mg/mL, respectively), called CBM oil [87]. The CBM caused improved pain scores and reduced pruritus and the overall analgesic drug intake, but, once again, rigorous controlled trials were not conducted.

Table 2 Summary table of cutaneous clinical studies conducted with phytocannabinoids.

Phytocannabinoids	Evidence	Details about the model	Concentration/dose	Positive control	Schematic results	Biological context	Ref.
CBD oil	Clinical	Observational study (3 case reports)			↓ healing time; ↓ analgesic need	Epidermolysis bullosa	[86]
CBD in a formulation called Permetrex (a pure synthetic form of CBD was manufactured for topical delivery and formulated)	Phase I clinical trial	Open-label, single-arm, 28-day evaluation of the safety of 5% BTX 1503 in moderate to severe acne (n = 23)	5% formulation of CBD applied twice daily to the entire face.	//	↓ acne lesions	Treatment of acne	[88]
CBD, THC	Clinical	3 case reports	Sublingual pharmaceutical preparation of CBD and THC (20 mg/mL and 13 mg/mL, respectively)	//	↓ pain score; ↓ pruritus; ↓ analgesic drug intake	Epidermolysis bullosa	[87]

Another clinical study regarded the safety and efficacy of CBD-based preparations against skin inflammation. A patented formulation (5% BTX 1503) for topical delivery reached phase II clinical trial against moderate to severe acne, after the first safety and efficacy assessment reported by Spleman et al. [88]. The phase I trial was an open-label and single arm study firstly performed on 20 healthy volunteers and subjects with inflammatory (n = 23) or noninflammatory (n = 20) face lesions, who were treated twice a day. At day 28, safety and efficacy were observed and recorded as preliminary evidence for further clinical trials.

Conclusions

The scientific evidence reported in this review underlines the complexity of the mechanisms regulating the effects of phytocannabinoids at cutaneous level. Data collected in vitro demonstrate that the biological effects of phytocannabinoids involve many different cell populations other than immune cells, whose role is still fundamental in the pathogenesis of numerous skin disorders, such as keratinocytes and sebocytes, implicated in the etiology of psoriasis and atopic dermatitis, and acne and dry skin, respectively.

Most of the evidence concerns isolated phytocannabinoids and, as it can be easily seen from [Table 1] and [2], CBD is the most investigated compound, considering all the clinical and preclinical studies in several fields of application. CBD protects keratinocytes from oxidative damage induced by UV rays and stimulates the production of melanin from melanocytes, thus suggesting multiple photoprotective mechanisms that may be useful for treating skin disorders such as photo-aging or skin aging.

Despite not always being in agreement, data reported herein highlight the general anti-inflammatory effect of CBD, which in addition exploits the concomitant promotion of endogenous antioxidant factors, through the stabilization of NRF-2. The results from preliminary clinical studies and animal models support the anti-inflammatory activity of CBD for the skin; however, due to its inhibitory effects on keratinocyte differentiation, targeted studies are needed to evaluate the possible consequences in diseases such as psoriasis and atopic dermatitis, in which differentiation and proliferation are already dysregulated. It is important to point out that in the only 2 investigations in which C. sativa extract was compared to pure CBD, the extract was superior in terms of anti-inflammatory effects, both in vitro [64] and in vivo [82]. This observation is certainly linked to the plurality of action of different components; in fact, the oral administration of PUFA of C. sativa seeds also seems to have a role in the improvement of clinical symptoms of atopic dermatitis [89], but the involvement of other non-cannabinoid secondary metabolites cannot be excluded [90]. In this context, the topical applications of Δ⁸-THC and Δ⁹-THC also obtained good results in terms of skin inflammation reduction, probably helped by their preferential accumulation in the epidermis, but their intrinsic psychotropic activity limits the development of new dedicated therapeutic solutions.

One of the most promising applications of phytocannabinoids, supported by preclinical and clinical evidence, is the treatment of seborrheic disorders, especially acne. Although only some compounds, such as CBD, CBC, and THCV, reduce lipogenesis in vitro, a clinical study conducted with a mixture of phytocannabinoids (a cream based on C. sativa seed extract) confirmed the reduction of sebum and erythema, even if the actual composition in phytocannabinoids of the formulation was not fully described [91]. In addition, a hexane extract from C. sativa seeds reduced the inflammatory markers of keratinocytes challenged by Propionibacterium acnes in vitro, one of the main etiological agents of acne, demonstrating also a direct antimicrobial effect [92].

In conclusion, phytocannabinoids possess a great potential for the treatment of several cutaneous pathological conditions, ranging from photo-aging and inflammatory diseases to seborrheic and autoimmune disorders. However, this review suggests that the biological plausibility for the use of phytocannabinoids in human diseases still needs explanations. Only few molecular mechanisms peculiar to phytocannabinoids have been causally associated with the improvement of skin diseases. In particular, the action on PPARs, GlyRs, and TRP channels was rarely considered in comparison with CB receptor modulation. In analogy, whole extracts have been sometimes reported to exert a wider and more potent bioactivity than single phytocannabinoids, but their targets were only partially discovered. Moreover, despite the promising evidence found in the preclinical field, the small number of rigorous clinical studies, the lack of data on safety and data specifically related to C. sativa extracts and their intrinsic complexity limit the understanding of the real benefits for human skin.

Contributorsʼ Statement

Conception and design: G. Martinelli, A. Magnavacca, M. Fumagalli, E. Sangiovanni, S. Piazza, M. DellʼAgli; search: G. Martinelli, A. Magnavacca, M. Fumagalli, E. Sangiovanni, S. Piazza; interpretation of the literature: E. Sangiovanni, S. Piazza, M. DellʼAgli; drafting: G. Martinelli, A. Magnavacca, M. Fumagalli, E. Sangiovanni, S. Piazza, M. DellʼAgli; critical revision: G. Martinelli, A. Magnavacca, M. Fumagalli, E. Sangiovanni, S. Piazza, M. DellʼAgli.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Acknowledgements

This research was supported by MIUR Progetto di Eccellenza at DiSFeB.

• References

• 1 Small E. Evolution and classification of Cannabis sativa (Marijuana, Hemp) in relation to human utilization. Bot Rev 2015; 81: 189-294
• 2 Bonini SA, Premoli M, Tambaro S, Kumar A, Maccarinelli G, Memo M, Mastinu A. Cannabis sativa: A comprehensive ethnopharmacological review of a medicinal plant with a long history. J Ethnopharmacol 2018; 227: 300-315
• 3 Goncalves J, Rosado T, Soares S, Simao AY, Caramelo D, Luis A, Fernandez N, Barroso M, Gallardo E, Duarte AP. Cannabis and its secondary metabolites: their use as therapeutic drugs, toxicological aspects, and analytical determination. Medicines (Basel) 2019; 6: 31
• 4 Theroux Z, Cropley T. Cannabis and Dr. Piffard–a century ahead of the curve. JAMA Dermatol 2016; 152: 972
• 5 Toth KF, Adam D, Biro T, Olah A. Cannabinoid signaling in the skin: therapeutic potential of the “c(ut)annabinoid” system. Molecules 2019; 24: 918
• 6 Dhadwal G, Kirchhof MG. The risks and benefits of cannabis in the dermatology clinic. J Cutan Med Surg 2018; 22: 194-199
• 7 Sheriff T, Lin MJ, Dubin D, Khorasani H. The potential role of cannabinoids in dermatology. J Dermatolog Treat 2020; 31: 839-845
• 8 Rio CD, Millan E, Garcia V, Appendino G, DeMesa J, Munoz E. The endocannabinoid system of the skin. A potential approach for the treatment of skin disorders. Biochem Pharmacol 2018; 157: 122-133
• 9 Biro T, Toth BI, Hasko G, Paus R, Pacher P. The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities. Trends Pharmacol Sci 2009; 30: 411-420
• 10 Lynn AB, Herkenham M. Localization of cannabinoid receptors and nonsaturable high-density cannabinoid binding sites in peripheral tissues of the rat: implications for receptor-mediated immune modulation by cannabinoids. J Pharmacol Exp Ther 1994; 268: 1612-1623
• 11 Klein TW, Newton C, Larsen K, Lu L, Perkins I, Nong L, Friedman H. The cannabinoid system and immune modulation. J Leukoc Biol 2003; 74: 486-496
• 12 Hurst DP, Schmeisser M, Reggio PH. Endogenous lipid activated G protein-coupled receptors: emerging structural features from crystallography and molecular dynamics simulations. Chem Phys Lipids 2013; 169: 46-56
• 13 Kozak KR, Gupta RA, Moody JS, Ji C, Boeglin WE, DuBois RN, Brash AR, Marnett LJ. 15-Lipoxygenase metabolism of 2-arachidonylglycerol. Generation of a peroxisome proliferator-activated receptor alpha agonist. J Biol Chem 2002; 277: 23278-23286
• 14 Hughes ML, Liu B, Halls ML, Wagstaff KM, Patil R, Velkov T, Jans DA, Bunnett NW, Scanlon MJ, Porter CJ. Fatty Acid-binding proteins 1 and 2 differentially modulate the activation of peroxisome proliferator-activated receptor α in a ligand-selective manner. J Biol Chem 2015; 290: 13895-13906
• 15 Elmes MW, Kaczocha M, Berger WT, Leung K, Ralph BP, Wang LQ, Sweeney JM, Miyauchi JT, Tsirka SE, Ojima I, Deutsch DG. Fatty acid-binding proteins (FABPs) are intracellular carriers for delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD). J Biol Chem 2015; 290: 8711-8721
• 16 Vara D, Morell C, Rodriguez-Henche N, Diaz-Laviada I. Involvement of PPAR gamma in the antitumoral action of cannabinoids on hepatocellular carcinoma. Cell Death Dis 2013; 4: 11
• 17 Caterina MJ. TRP channel cannabinoid receptors in skin sensation, homeostasis, and inflammation. ACS Chem Neurosci 2014; 5: 1107-1116
• 18 De Petrocellis L, Ligresti A, Moriello AS, Allarà M, Bisogno T, Petrosino S, Stott CG, Di Marzo V. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol 2011; 163: 1479-1494
• 19 De Petrocellis L, Orlando P, Moriello AS, Aviello G, Stott C, Izzo AA, Di Marzo V. Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. Acta Physiol (Oxf) 2012; 204: 255-266
• 20 Ahrens J, Demir R, Leuwer M, de la Roche J, Krampfl K, Foadi N, Karst M, Haeseler G. The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-Beta glycine receptor function. Pharmacology 2009; 83: 217-222
• 21 Xiong W, Cui T, Cheng K, Yang F, Chen SR, Willenbring D, Guan Y, Pan HL, Ren K, Xu Y, Zhang L. Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors. J Exp Med 2012; 209: 1121-1134
• 22 Denda M, Fuziwara S, Inoue K. Influx of calcium and chloride ions into epidermal keratinocytes regulates exocytosis of epidermal lamellar bodies and skin permeability barrier homeostasis. J Invest Dermatol 2003; 121: 362-367
• 23 Inoue K, Takei K, Denda M. Functional glycine receptor in cultured human keratinocytes. Exp Dermatol 2015; 24: 307-309
• 24 ElSohly MA, Radwan MM, Gul W, Chandra S, Galal A. Phytochemistry of Cannabis sativa L. Prog Chem Org Nat Prod 2017; 103: 1-36
• 25 Turner SE, Williams CM, Iversen L, Whalley BJ. Molecular pharmacology of phytocannabinoids. Prog Chem Org Nat Prod 2017; 103: 61-101
• 26 Hanus LO, Meyer SM, Munoz E, Taglialatela-Scafati O, Appendino G. Phytocannabinoids: a unified critical inventory. Nat Prod Rep 2016; 33: 1357-1392
• 27 Martínez V, Iriondo De-Hond A, Borrelli F, Capasso R, Del Castillo MD, Abalo R. Cannabidiol and other non-psychoactive cannabinoids for prevention and treatment of gastrointestinal disorders: Useful nutraceuticals?. Int J Mol Sci 2020; 21: 3067
• 28 Elsohly M, Gul W. Constituents of Cannabis sativa . In: Iversen L. ed. Handbook of Cannabis. Oxford, UK: Oxford University Press; 2014: 3-22
• 29 Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 2009; 30: 515-527
• 30 Pertwee RG, Ross RA, Craib SJ, Thomas A. (−)-Cannabidiol antagonizes cannabinoid receptor agonists and noradrenaline in the mouse vas deferens. Eur J Pharmacol 2002; 456: 99-106
• 31 Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 2007; 150: 613-623
• 32 Morales P, Hurst DP, Reggio PH. Molecular Targets of the Phytocannabinoids: A complex Picture. In: Kinghorn AD, Falk H, Gibbons S, Kobayashi J. eds. Phytocannabinoids: Unraveling the complex Chemistry and Pharmacology of Cannabis sativa. Vol 103. Switzerland: Springer International Publishing; 2017: 103-131
• 33 Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol 2015; 172: 4790-4805
• 34 McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Δ(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol 2015; 172: 737-753
• 35 Morales P, Goya P, Jagerovic N, Hernandez-Folgado L. Allosteric modulators of the CB(1) cannabinoid receptor: a structural update review. Cannabis Cannabinoid Res 2016; 1: 22-30
• 36 Sylantyev S, Jensen TP, Ross RA, Rusakov DA. Cannabinoid- and lysophosphatidylinositol-sensitive receptor GPR55 boosts neurotransmitter release at central synapses. Proc Natl Acad Sci U S A 2013; 110: 5193-5198
• 37 Whyte LS, Ryberg E, Sims NA, Ridge SA, Mackie K, Greasley PJ, Ross RA, Rogers MJ. The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. Proc Natl Acad Sci U S A 2009; 106: 16511-16516
• 38 Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol 2007; 152: 1092-1101
• 39 McHugh D, Page J, Dunn E, Bradshaw HB. Δ(9) -Tetrahydrocannabinol and N-arachidonyl glycine are full agonists at GPR18 receptors and induce migration in human endometrial HEC-1B cells. Br J Pharmacol 2012; 165: 2414-2424
• 40 Gonca E, Darici F. The effect of cannabidiol on ischemia/reperfusion-induced ventricular arrhythmias: the role of adenosine A1 receptors. J Cardiovasc Pharmacol Ther 2015; 20: 76-83
• 41 Carrier EJ, Auchampach JA, Hillard CJ. Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci U S A 2006; 103: 7895-7900
• 42 Xiong W, Cui T, Cheng K, Yang F, Chen SR, Willenbring D, Guan Y, Pan HL, Ren K, Xu Y, Zhang L. Cannabinoids suppress inflammatory and neuropathic pain by targeting alpha3 glycine receptors. J Exp Med 2012; 209: 1121-1134
• 43 Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 2005; 30: 1037-1043
• 44 Yang KH, Galadari S, Isaev D, Petroianu G, Shippenberg TS, Oz M. The nonpsychoactive cannabinoid cannabidiol inhibits 5-hydroxytryptamine3A receptor-mediated currents in Xenopus laevis oocytes. J Pharmacol Exp Ther 2010; 333: 547-554
• 45 Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, Moriello AS, Davis JB, Mechoulam R, Di Marzo V. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 2001; 134: 845-852
• 46 Iannotti FA, Hill CL, Leo A, Alhusaini A, Soubrane C, Mazzarella E, Russo E, Whalley BJ, Di Marzo V, Stephens GJ. Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci 2014; 5: 1131-1141
• 47 De Petrocellis L, Vellani V, Schiano-Moriello A, Marini P, Magherini PC, Orlando P, Di Marzo V. Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J Pharmacol Exp Ther 2008; 325: 1007-1015
• 48 Maione S, Piscitelli F, Gatta L, Vita D, De Petrocellis L, Palazzo E, de Novellis V, Di Marzo V. Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action. Br J Pharmacol 2011; 162: 584-596
• 49 Kathmann M, Flau K, Redmer A, Trankle C, Schlicker E. Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmiedebergs Arch Pharmacol 2006; 372: 354-361
• 50 Elsohly MA, Slade D. Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci 2005; 78: 539-548
• 51 Ahmed SA, Ross SA, Slade D, Radwan MM, Zulfiqar F, ElSohly MA. Cannabinoid ester constituents from high-potency Cannabis sativa . J Nat Prod 2008; 71: 536-542
• 52 Radwan MM, Ross SA, Slade D, Ahmed SA, Zulfiqar F, Elsohly MA. Isolation and characterization of new Cannabis constituents from a high potency variety. Planta Med 2008; 74: 267-272
• 53 Radwan MM, Elsohly MA, Slade D, Ahmed SA, Khan IA, Ross SA. Biologically active cannabinoids from high-potency Cannabis sativa . J Nat Prod 2009; 72: 906-911
• 54 Navarro G, Varani K, Reyes-Resina I, Sánchez de Medina V, Rivas-Santisteban R, Sánchez-Carnerero Callado C, Vincenzi F, Casano S, Ferreiro-Vera C, Canela EI, Borea PA, Nadal X, Franco R. Cannabigerol action at cannabinoid CB1 and CB2 receptors and at CB1–CB2 heteroreceptor complexes. Front Pharmacol 2018; 9: 632
• 55 De Petrocellis L, Ligresti A, Moriello AS, Allara M, Bisogno T, Petrosino S, Stott CG, Di Marzo V. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol 2011; 163: 1479-1494
• 56 Cascio MG, Gauson LA, Stevenson LA, Ross RA, Pertwee RG. Evidence that the plant cannabinoid cannabigerol is a highly potent alpha2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. Br J Pharmacol 2010; 159: 129-141
• 57 Gaoni Y, Mechoulam R. Cannabichromene, a new active principle in hashish. Chemical Communications (London) 1966; 20-21 doi:10.1039/C19660000020
• 58 Udoh M, Santiago M, Devenish S, McGregor IS, Connor M. Cannabichromene is a cannabinoid CB2 receptor agonist. Br J Pharmacol 2019; 176: 4537-4547
• 59 Patil AS, Mahajan UB, Agrawal YO, Patil KR, Patil CR, Ojha S, Sharma C, Goyal SN. Plant-derived natural therapeutics targeting cannabinoid receptors in metabolic syndrome and its complications: a review. Biomed Pharmacother 2020; 132: 110889
• 60 Gohad P, McCoy J, Wambier C, Kovacevic M, Situm M, Stanimirovic A, Goren A. Novel cannabidiol sunscreen protects keratinocytes and melanocytes against ultraviolet B radiation. J Cosmet Dermatol 2020; DOI: 10.1111/jocd.13693.
• 61 Jarocka-Karpowicz I, Biernacki M, Wronski A, Gegotek A, Skrzydlewska E. Cannabidiol effects on phospholipid metabolism in keratinocytes from patients with Psoriasis vulgaris. Biomolecules 2020; 10: 362
• 62 Atalay S, Dobrzynska I, Gegotek A, Skrzydlewska E. Cannabidiol protects keratinocyte cell membranes following exposure to UVB and hydrogen peroxide. Redox Biol 2020; 36: 101613
• 63 Jastrzab A, Gegotek A, Skrzydlewska E. Cannabidiol regulates the expression of keratinocyte proteins involved in the inflammation process through transcriptional regulation. Cells 2019; 8: 827
• 64 Sangiovanni E, Fumagalli M, Pacchetti B, Piazza S, Magnavacca A, Khalilpour S, Melzi G, Martinelli G, DellʼAgli M. Cannabis sativa L. extract and cannabidiol inhibit in vitro mediators of skin inflammation and wound injury. Phytother Res 2019; 33: 2083-2093
• 65 Casares L, Garcia V, Garrido-Rodriguez M, Millan E, Collado JA, Garcia-Martin A, Penarando J, Calzado MA, de la Vega L, Munoz E. Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1. Redox Biol 2020; 28: 101321
• 66 Styrczewska M, Kostyn A, Kulma A, Majkowska-Skrobek G, Augustyniak D, Prescha A, Czuj T, Szopa J. Flax Fiber hydrophobic extract inhibits human skin cells inflammation and causes remodeling of extracellular matrix and wound closure activation. Biomed Res Int 2015; 2015: 862391
• 67 Gegotek A, Atalay S, Domingues P, Skrzydlewska E. The differences in the proteome profile of cannabidiol-treated skin fibroblasts following UVA or UVB irradiation in 2D and 3D cell cultures. Cells 2019; 8: 995
• 68 Hwang YS, Kim YJ, Kim MO, Kang M, Oh SW, Nho YH, Park SH, Lee J. Cannabidiol upregulates melanogenesis through CB1 dependent pathway by activating p38 MAPK and p42/44 MAPK. Chem Biol Interact 2017; 273: 107-114
• 69 Olah A, Markovics A, Szabo-Papp J, Szabo PT, Stott C, Zouboulis CC, Biro T. Differential effectiveness of selected non-psychotropic phytocannabinoids on human sebocyte functions implicates their introduction in dry/seborrhoeic skin and acne treatment. Exp Dermatol 2016; 25: 701-707
• 70 Olah A, Toth BI, Borbiro I, Sugawara K, Szollosi AG, Czifra G, Pal B, Ambrus L, Kloepper J, Camera E, Ludovici M, Picardo M, Voets T, Zouboulis CC, Paus R, Biro T. Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. J Clin Invest 2014; 124: 3713-3724
• 71 Touitou E, Fabin B, Dany S, Almog S. Transdermal delivery of tetrahydrocannabinol. Int J Pharmaceutics 1988; 43: 9-15
• 72 Valiveti S, Hammell DC, Earles DC, Stinchcomb AL. In vitro/in vivo correlation studies for transdermal delta 8-THC development. J Pharm Sci 2004; 93: 1154-1164
• 73 Stinchcomb AL, Valiveti S, Hammell DC, Ramsey DR. Human skin permeation of Delta8-tetrahydrocannabinol, cannabidiol and cannabinol. J Pharm Pharmacol 2004; 56: 291-297
• 74 Gaffal E, Cron M, Glodde N, Tuting T. Anti-inflammatory activity of topical THC in DNFB-mediated mouse allergic contact dermatitis independent of CB1 and CB2 receptors. Allergy 2013; 68: 994-1000
• 75 Glodde N, Jakobs M, Bald T, Tuting T, Gaffal E. Differential role of cannabinoids in the pathogenesis of skin cancer. Life Sci 2015; 138: 35-40
• 76 Engel MA, Izydorczyk I, Mueller-Tribbensee SM, Becker C, Neurath MF, Reeh PW. Inhibitory CB1 and activating/desensitizing TRPV1-mediated cannabinoid actions on CGRP release in rodent skin. Neuropeptides 2011; 45: 229-237
• 77 Pucci M, Rapino C, Di Francesco A, Dainese E, DʼAddario C, Maccarrone M. Epigenetic control of skin differentiation genes by phytocannabinoids. Br J Pharmacol 2013; 170: 581-591
• 78 Wilkinson JD, Williamson EM. Cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis. J Dermatol Sci 2007; 45: 87-92
• 79 Petrosino S, Verde R, Vaia M, Allara M, Iuvone T, Di Marzo V. Anti-inflammatory properties of cannabidiol, a nonpsychotropic cannabinoid, in experimental allergic contact dermatitis. J Pharmacol Exp Ther 2018; 365: 652-663
• 80 Kim JE, Kim JS, Cho DH, Park HJ. Molecular mechanisms of cutaneous inflammatory disorder: atopic dermatitis. Int J Mol Sci 2016; 17: 1234
• 81 Reichelt J, Furstenberger G, Magin TM. Loss of keratin 10 leads to mitogen-activated protein kinase (MAPK) activation, increased keratinocyte turnover, and decreased tumor formation in mice. J Invest Dermatol 2004; 123: 973-981
• 82 Formukong EA, Evans AT, Evans FJ. Analgesic and antiinflammatory activity of constituents of Cannabis sativa L. Inflammation 1988; 12: 361-371
• 83 Tubaro A, Giangaspero A, Sosa S, Negri R, Grassi G, Casano S, Della Loggia R, Appendino G. Comparative topical anti-inflammatory activity of cannabinoids and cannabivarins. Fitoterapia 2010; 81: 816-819
• 84 Lodzki M, Godin B, Rakou L, Mechoulam R, Gallily R, Touitou E. Cannabidiol-transdermal delivery and anti-inflammatory effect in a murine model. J Control Release 2003; 93: 377-387
• 85 Bartner LR, McGrath S, Rao S, Hyatt LK, Wittenburg LA. Pharmacokinetics of cannabidiol administered by 3 delivery methods at 2 different dosages to healthy dogs. Can J Vet Res 2018; 82: 178-183
• 86 Chelliah MP, Zinn Z, Khuu P, Teng JMC. Self-initiated use of topical cannabidiol oil for epidermolysis bullosa. Pediatr Dermatol 2018; 35: e224-e227
• 87 Schrader NHB, Duipmans JC, Molenbuur B, Wolff AP, Jonkman MF. Combined tetrahydrocannabinol and cannabidiol to treat pain in epidermolysis bullosa: a report of three cases. Br J Dermatol 2019; 180: 922-924
• 88 Spleman L, Sinclair R, Freeman M, Davis M, Gebauer K. 1061 The safety of topical cannabidiol (CBD) for the treatment of acne. J Invest Dermatol 2018; 138: S180
• 89 Callaway J, Schwab U, Harvima I, Halonen P, Mykkanen O, Hyvonen P, Jarvinen T. Efficacy of dietary hempseed oil in patients with atopic dermatitis. J Dermatolog Treat 2005; 16: 87-94
• 90 Hill TDM, Cascio MG, Romano B, Duncan M, Pertwee RG, Williams CM, Whalley BJ, Hill AJ. Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism. Br J Pharmacol 2013; 170: 679-692
• 91 Ali A, Akhtar N. The safety and efficacy of 3 % Cannabis seeds extract cream for reduction of human cheek skin sebum and erythema content. Pak J Pharm Sci 2015; 28: 1389-1395
• 92 Jin S, Lee MY. The ameliorative effect of hemp seed hexane extracts on the Propionibacterium acnes-induced inflammation and lipogenesis in sebocytes. PLoS One 2018; 13: e0202933

Publication History

Received: 27 November 2020

Accepted after revision: 09 March 2021

Article published online:
13 April 2021