Rare Phytocannabinoids Exert Anti-Inflammatory Effects on Human Keratinocytes via the Endocannabinoid System and MAPK Signaling Pathway


“Increasing evidence supports the therapeutic potential of rare cannabis-derived phytocannabinoids (pCBs) in skin disorders such as atopic dermatitis, psoriasis, pruritus, and acne. However, the molecular mechanisms of the biological action of these pCBs remain poorly investigated.

In this study, an experimental model of inflamed human keratinocytes (HaCaT cells) was set up by using lipopolysaccharide (LPS) in order to investigate the anti-inflammatory effects of the rare pCBs cannabigerol (CBG), cannabichromene (CBC), Δ9-tetrahydrocannabivarin (THCV) and cannabigerolic acid (CBGA). To this aim, pro-inflammatory interleukins (IL)-1β, IL-8, IL-12, IL-31, tumor necrosis factor (TNF-β) and anti-inflammatory IL-10 levels were measured through ELISA quantification. In addition, IL-12 and IL-31 levels were measured after treatment of HaCaT cells with THCV and CBGA in the presence of selected modulators of endocannabinoid (eCB) signaling. In the latter cells, the activation of 17 distinct proteins along the mitogen-activated protein kinase (MAPK) pathway was also investigated via Human Phosphorylation Array.

Our results demonstrate that rare pCBs significantly blocked inflammation by reducing the release of all pro-inflammatory ILs tested, except for TNF-β. Moreover, the reduction of IL-31 expression by THCV and CBGA was significantly reverted by blocking the eCB-binding TRPV1 receptor and by inhibiting the eCB-hydrolase MAGL. Remarkably, THCV and CBGA modulated the expression of the phosphorylated forms (and hence of the activity) of the MAPK-related proteins GSK3β, MEK1, MKK6 and CREB also by engaging eCB hydrolases MAGL and FAAH.

Taken together, the ability of rare pCBs to exert an anti-inflammatory effect in human keratinocytes through modifications of eCB and MAPK signaling opens new perspectives for the treatment of inflammation-related skin pathologies.”


“Overall, this proof of concept, which shows that in inflamed human keratinocytes, rare pCBs can indeed interact with specific eCB system elements, opens new perspectives for possible treatments of inflammation-related skin diseases. Incidentally, such interactions between pCBs and eCB system seems to hold therapeutic potential well beyond the skin, such as possible treatments reported for autism spectrum disorders and cancer”


“Effects of Rare Phytocannabinoids on the Endocannabinoid System of Human Keratinocytes”


Cannabidiol and Cannabigerol Exert Antimicrobial Activity without Compromising Skin Microbiota


“Cannabidiol (CBD) and cannabigerol (CBG) are two pharmacologically active phytocannabinoids of Cannabis sativa L. Their antimicrobial activity needs further elucidation, particularly for CBG, as reports on this cannabinoid are scarce. We investigated CBD and CBG’s antimicrobial potential, including their ability to inhibit the formation and cause the removal of biofilms.

Our results demonstrate that both molecules present activity against planktonic bacteria and biofilms, with both cannabinoids removing mature biofilms at concentrations below the determined minimum inhibitory concentrations. We report for the first time minimum inhibitory and lethal concentrations for Pseudomonas aeruginosa and Escherichia coli (ranging from 400 to 3180 µM), as well as the ability of cannabinoids to inhibit Staphylococci adhesion to keratinocytes, with CBG demonstrating higher activity than CBD. The value of these molecules as preservative ingredients for cosmetics was also assayed, with CBG meeting the USP 51 challenge test criteria for antimicrobial effectiveness. Further, the exact formulation showed no negative impact on skin microbiota.

Our results suggest that phytocannabinoids can be promising topical antimicrobial agents when searching for novel therapeutic candidates for different skin conditions. Additional research is needed to clarify phytocannabinoids’ mechanisms of action, aiming to develop practical applications in dermatological use.”


“This report compares CBD and CBG’s antimicrobial effectiveness and further cements phytocannabinoids’ potential to be used as antimicrobial agents. Both molecules’ antimicrobial capacity strongly depends on the target microorganism, namely whether it is Gram-negative or Gram-positive. Nonetheless, we were able to determine MICs for all tested strains, including S. pyogenesE. coli, and P. aeruginosa. It is of note that CBG revealed a stronger antimicrobial effect than CBD, particularly in the challenge test and in the antibiofilm assay. Further studies are needed to understand these discrepancies, as they may be connected to structural differences, receptor-binding affinity, or another mechanism other than a receptor-mediated one. Since no significant impact on the skin microbiota was observed and given its current widespread use, both CBD and CBG might be considered safe. Thus, we can assume that the development of topical formulations with active concentrations of CBG and/or CBD might represent a promising approach to tackle skin conditions where microorganisms and inflammation play a fundamental role, including psoriasis, atopic dermatitis, and acne.”


Cannabidiol mediates epidermal terminal differentiation and redox homeostasis through aryl hydrocarbon receptor (AhR)-dependent signaling

Home Page: Journal of Dermatological Science

“Background: Cannabidiol, a non-psychoactive phytocannabinoid, has antioxidant and anti-inflammatory activity in keratinocytes. However, the signaling pathway through which cannabidiol exerts its effect on keratinocytes or whether it can modulate keratinocyte differentiation has not been fully elucidated yet.

Objective: We investigated whether cannabidiol modulates epidermal differentiation and scavenges reactive oxygen species through the aryl hydrocarbon receptor (AhR) in keratinocytes and epidermal equivalents.

Methods: We investigated the cannabidiol-induced activation of AhR using AhR luciferase reporter assay, qRT-PCR, western blot, and immunofluorescence assays. We also analyzed whether keratinocyte differentiation and antioxidant activity are regulated by cannabidiol-induced AhR activation.

Results: In both keratinocytes and epidermal equivalents, cannabidiol increased both the mRNA and protein expression of filaggrin, involucrin, NRF2, and NQO1 and the mRNA expression of the AhR target genes, including CYP1A1 and aryl hydrocarbon receptor repressor. Additionally, cannabidiol showed antioxidant activity that was attenuated by AhR knockdown or co-administration with an AhR antagonist. Moreover, cannabidiol increased the ratio of OVOL1/OVOL2 mRNA expression, which is a downstream regulator of AhR that mediates epidermal differentiation. In addition to increased expression of barrier-related proteins, cannabidiol-treated epidermal equivalent showed a more prominent granular layer than the control epidermis. The increased granular layer by cannabidiol was suppressed by the AhR antagonist.

Conclusion: Cannabidiol can be a modulator of the AhR-OVOL1-filaggrin axis and AhR-NRF2-NQO1 signaling, thus indicating a potential use of cannabidiol in skin barrier enhancement and reducing oxidative stress.”



Cannabinoid Compounds as a Pharmacotherapeutic Option for the Treatment of Non-Cancer Skin Diseases


“The endocannabinoid system has been shown to be involved in various skin functions, such as melanogenesis and the maintenance of redox balance in skin cells exposed to UV radiation, as well as barrier functions, sebaceous gland activity, wound healing and the skin’s immune response.

In addition to the potential use of cannabinoids in the treatment and prevention of skin cancer, cannabinoid compounds and derivatives are of interest as potential systemic and topical applications for the treatment of various inflammatory, fibrotic and pruritic skin conditions. In this context, cannabinoid compounds have been successfully tested as a therapeutic option for the treatment of androgenetic alopecia, atopic and seborrhoeic dermatitis, dermatomyositis, asteatotic and atopic eczema, uraemic pruritis, scalp psoriasis, systemic sclerosis and venous leg ulcers. This review provides an insight into the current literature on cannabinoid compounds as potential medicines for the treatment of skin diseases.”


“Based on the current publications, it can be summarised that cannabinoid compounds have great potential in the treatment of skin diseases, both as topical applications and as systemic medications.”


The Modulation of Blue-Light-Induced Inflammation, Intracellular Lipid Secretion, and Oxidative Stress in Sebocytes with Cannabidiol

“Light-induced skin damage leads to cellular or molecular dysfunction, thus potentially causing different skin issues (e.g., skin aging, seborrheic dermatitis and pigmentation). Blue light, a potent visible light that was previously adopted for promoting skin regeneration, draws considerable concerns in the past several years due to their potential damage to the skins. In this work, we investigated the roles of blue light in skewing the functions of sebocytes – the major cells that compose the sebaceous gland – an important “active” neuro-immuno-endocrine organ in maintaining skin functions.

For therapeutically purposes, we employed cannabidiol (CBD), a clinically used non-psychotropic phytocannabinoid, to revert blue-light-induced sebocytes dysfunctions, including intracellular lipid secretion, inflammation, reactive oxygen species (ROS) secretion, and cell cycles. At the cellular level, CBD reduced the blue-light-enhanced intracellular lipid secretion, decreased inflammation, down-regulated intracellular ROS production, and restored the skewed cell cycles in the sebocytes. In the intracellular mechanism, CBD inhibited the blue-light-induced pro-apoptotic activity through rebalance BCL-2/BAX expression and down-regulated the NF-κB p65 pathway.

Collectively, this study demonstrated that CBD was a potent therapeutic agent for maintaining normal sebocytes functions, thus is a promising drug for skincare purposes, especially considering its effectiveness in restoring the twisted sebocytes behaviors.”



Medical cannabis dimethyl ether, ethanol and butane extracts inhibit the in vitro growth of bacteria and dermatophytes causing common skin diseases

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“Cannabis preparations are gaining popularity among patients with various skin diseases. Due to the lack of scientific evidence, dermatologists remain cautious about their prescriptions. So far, only a few studies have been published about the effects of high-potency cannabis extracts on microorganisms (especially dermatophytes) causing skin problems that affect more than 25% of the worldwide population. Even though, the high-potency cannabis extracts prepared by cold extraction are mostly composed of non-psychoactive tetrahydrocannabinolic acid (THCA) and only low amount of THC, their use in topical treatment can be stigmatized. The in vitro antimicrobial and antifungal activity of two high potent cannabis strains extracted by three solvents traditionally or currently used by cannabis users (ethanol; EtOH, butane; BUT, dimethyl ether; DME) was investigated by broth dilution method. The chemical profile of cannabis was determined by high-performance liquid chromatography with ultraviolet detection and gas chromatography with mass spectrometer and flame ionization detector. The extraction methods significantly influenced chemical profile of extracts. The yield of EtOH extracts contained less cannabinoids and terpenes compared to BUT and DME ones. Most of the extracts was predominantly (>60%) composed of various cannabinoids, especially THCA. All of them demonstrated activity against 18 of the 19 microorganisms tested. The minimal inhibitory concentrations (MICs) of the extracts ranged from 4 to 256 μg/mL. In general, the bacteria were more susceptible to the extracts than dermatophytes. Due to the lower content of biologically active substances, the EtOH extracts were less effective against microorganisms. Cannabis extracts may be of value to treat dermatophytosis and other skin diseases caused by various microorganisms. Therefore, they could serve as an alternative or supportive treatment to commonly used antibiotics.”


“Our research brought new evidence that cannabis extracts may be of value to treat dermatophytosis and other skin diseases caused by various microorganisms and showed that cannabis could serve as an alternative or supportive treatment to commonly used antibiotics.”


Comparison of the in vitro Anti-Inflammatory Effect of Cannabidiol to Dexamethasone

“Background: Cannabidiol (CBD) is a non-psychoactive phytocannabinoid constituent of Cannabis sativa with pain-relieving and anti-inflammatory properties. With the emphasis on natural ingredients in cosmetics, CBD has become a new cosmetic ingredient due to its ability to alleviate inflammation. However, in-depth studies that directly compare the effective mechanism and the therapeutic potential of CBD are still needed.

Purpose: The aim of the present study was to investigate the anti-inflammatory effect of CBD in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and compare it to dexamethasone (DEX).

Methods: RAW264.7 macrophages in the logarithmic growth phase were incubated in the presence or absence of LPS. After that, the production of nitric oxide (NO), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured. A luciferase reporter assay for nuclear factor kappa B (NF-κB) was performed, and the phosphorylation levels of the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways were measured.

Results: The present study indicated that CBD had a similar anti-inflammatory effect to DEX by attenuating the LPS-induced production of NO, IL-6, and TNF-α. However, only CBD attenuated JNK phosphorylation levels, and only DEX attenuated IKK phosphorylation levels.

Conclusion: These results suggested that CBD and DEX exhibit similar anti-inflammatory effects on LPS-induced RAW264.7 macrophages mainly through suppressing the MAPK and NF-κB signaling pathways, but with different intracellular mechanisms. These findings suggested that CBD may be considered a natural anti-inflammatory agent for protecting skin from immune disorders.”


“As alternative and complementary therapies grow in dermatology, plant extracts such as CBD have garnered significant attention in dermatology. The present study provided new insight of CBD against LPS-induced inflammation. Our results suggested that CBD and DEX suppress the LPS-induced activation of the MAPK and NF-κB signaling pathways in RAW264.7 cells through different intracellular components, indicating that the anti-inflammatory biological mechanism of CBD is different from other immuno-suppressants. Because macrophages exert various pro-inflammatory functions through multiple intracellular pathways, further in vivo and in vitro studies are necessary to enrich the theoretical knowledge of CBD and promote its future clinical application.”


Terpenes and Cannabinoids in Supercritical CO 2 Extracts of Industrial Hemp Inflorescences: Optimization of Extraction, Antiradical and Antibacterial Activity


“Natural products are increasingly in demand in dermatology and cosmetology. In the present study, highly valuable supercritical CO2 (sCO2) extracts rich in bioactive compounds with antiradical and antibacterial activity were obtained from the inflorescences of industrial hemp. Volatile compounds were analyzed by gas chromatography in tandem with mass spectrometry (GC-MS), while cannabinoids were determined by high performance liquid chromatography (HPLC-DAD). Extraction yields varied from 0.75 to 8.83%, depending on the pressure and temperature applied. The extract obtained at 320 bar and 40 °C with the highest content (305.8 µg mg-1) of cannabidiolic acid (CBDA) showed the best antiradical properties. All tested extract concentrations from 10.42 µg mL-1 to 66.03 µg mL-1 possessed inhibitory activities against E. coliP. aeruginosa, B. subtilis, and S. aureus. The sCO2 extract with the highest content of cannabidiol (CBD) and rich in α-pinene, β-pinene, β-myrcene, and limonene was the most effective. The optimal conditions for sCO2 extraction of cannabinoids and volatile terpenes from industrial hemp were determined. The temperature of 60 °C proved to be optimal for all responses studied, while the pressure showed a different effect depending on the compounds targeted. A low pressure of 131.2 bar was optimal for the extraction of monoterpenes, while extracts rich in sesquiterpenes were obtained at 319.7 bar. A high pressure of 284.78 bar was optimal for the extraction of CBD.”



Cannabidiol Inhibits Inflammation Induced by Cutibacterium acnes-Derived Extracellular Vesicles via Activation of CB2 Receptor in Keratinocytes

“Background: Acne is a common inflammatory skin disease, while cannabidiol (CBD) is a representative non-psychoactive phytocannabinoid which has been proved to exert universal anti-inflammatory properties. This study aimed to explore the effect of CBD on acne inflammation induced by Cutibacterium acnes-derived extracellular vesicles (CEVs) in keratinocytes and reveal the underlying mechanisms.

Results: The expression of inflammatory cytokines (IL-6, IL-8 and TNF-α) in CEVs-stimulated NHEKs was suppressed by CBD. CB2 receptor expression was upregulated by CBD, whereas CEVs-promoted TRPV1 expression was downregulated by CBD. AM630 reversed TNF-α levels inhibited by CBD. Capsazepine exerted an inhibitory effect on CEVs-induced inflammation and had synergistic effect with CBD. The phosphorylation of ERK1/2 and NF-κB p65 and nuclear translocation of NF-κB p65 were induced by CEVs but reduced by CBD.

Conclusion: The results indicated that CBD could inhibit inflammation induced by CEVs in NHEKs, which was mediated by activation of CB2 receptor and enhanced by the TRPV1 antagonist, through inactivation of the MAPK and NF-κB signaling pathways. CBD might be a potential novel strategy for acne treatment in the future.”


“In conclusion, our results provided the evidence that CBD exerted an inhibitory effect on acne inflammation in keratinocytes induced by CEVs, which was mediated by CB2 receptor and through inactivating the MAPK and NF-κB signaling pathways. The TRPV1 antagonist Capsazepine had synergistic effect with CBD, but whether TRPV1 directly mediated the anti-inflammatory action of CBD still remains to be confirmed. Besides, the regulatory effect of CB2 receptor and TRPV1 on the MAPK and NF-κB signaling pathways in the acne model should also be further unraveled. Despite several limitations above, our study proposes the anti-acne property of CBD and a potent novel therapeutic approach for acne.”


Topical cannabidiol (CBD) in skin pathology – A comprehensive review and prospects for new therapeutic opportunities

“Humans have utilised cannabis products in various forms throughout the recorded history. To date, more than 500 biologically active components have been identified in the plants of the Cannabis genus, amongst which more than 100 were classified as phytocannabinoids (exocannabinoids).

The plant genus Cannabis is a member of the plant family Cannabaceae, and there are three primary cannabis species which vary in their biochemical constituents: Cannabis sativa, Cannabis indica and Cannabis ruderalis. There has been a growing level of interest in research on the topical usage of a cannabis-based extract as a safer and more effective alternative to the usage of topical corticosteroids in treating some dermatoses.

Together with the discovery of the cannabinoid receptors on the skin, it has been further illustrated that topical cannabis has anti-inflammatory, anti-itching, analgesics, wound healing and anti-proliferative effects on the skin.”