cannabidiol and palmidrol

An increasing number of studies have investigated the adverse effect profile of oral cannabinoids; however, few studies have provided sufficient data on the tolerability of topical cannabinoids in human participants.. To assess the tolerability profile of several commercial topical formulations containing cannabidiol (CBD) and palmitoylethanolamide (PEA) on the skin of healthy human participants.. Three human clinical trials and one in vitro study were conducted. The potential for skin irritation, sensitization and phototoxicity of several products, were assessed via patch testing on healthy human skin. The products assessed included two formulations containing CBD and PEA, one containing hemp seed oil and four concentrations of CBD alone. Ocular toxicity was tested using a traditional hen's egg chorioallantoic membrane model with three CBD, PEA and hemp seed oil formulations.. There was no irritation or sensitization of the products evident via patch testing on healthy participants. Additionally, mild phototoxicity of a hemp seed oil product was found at the 48-h time point compared with the negative control. The in vitro experiment demonstrated comparable effects of cannabinoid products with historically nonirritating products.. These specific formulations of CBD- and PEA-containing products are nonirritating and nonsensitizing in healthy adults, and further encourage similar research assessing their long-term safety and efficacy in human participants with dermatological diseases. There are some limitations to the study: (i) external validity may be limited as formulations from a single manufacturer were used for this study, while vast heterogeneity exists across unregulated, commercial CBD products on the market; and (ii) products were assessed only on normal, nondiseased human skin, and therefore extrapolation to those with dermatological diseases cannot be assumed.

Topics: Administration, Topical; Amides; Cannabidiol; Cannabis; Chorioallantoic Membrane; Dermatitis, Irritant; Dermatitis, Phototoxic; Ethanolamines; Humans; In Vitro Techniques; Palmitic Acids; Plant Extracts; Single-Blind Method

We aimed to examine, for the first time, the effect of cannabidiol (CBD) and palmitoylethanolamide (PEA) on the permeability of the human gastrointestinal tract in vitro, ex vivo, and in vivo.. Flux measurements of fluorescein-labeled dextrans 10 (FD10) and fluorescein-labeled dextrans 4 (FD4) dextran across Caco-2 cultures treated for 24 hours with interferon gamma (IFNγ) and tumour necrosis factor alpha (TNFα) (10 ng·mL-1) were measured, with or without the presence of CBD and PEA. Mechanisms were investigated using cannabinoid receptor 1 (CB1), cannabinoid receptor 2 (CB2), transient receptor potential vanilloid 1 (TRPV1), and proliferator activated receptors (PPAR) antagonists and protein kinase A (PKA), nitric oxide synthase, phosphoinositide 3-kinases, extracellular signal-regulated kinases (MEK/ERK), adenylyl cyclase, and protein kinase C (PKC) inhibitors. Human colonic mucosal samples collected from bowel resections were treated as previously stated. The receptors TRPV1, PPARα, PPARδ, PPARγ, CB1, CB2, G-coupled protein receptor 55 (GPR55), G-coupled protein receptor 119 (GPR119), and claudins-1, -2, -3, -4, -5, -7, and -8 mRNA were measured using multiplex. Aquaporin 3 and 4 were measured using enzyme-linked immunosorbent assay (ELISA). A randomized, double-blind, controlled-trial assessed the effect of PEA or CBD on the absorption of lactulose and mannitol in humans taking 600 mg of aspirin. Urinary concentrations of these sugars were measured using liquid chromatography mass spectrometry.. In vitro, PEA, and CBD decreased the inflammation-induced flux of dextrans (P < 0.0001), sensitive to PPARα and CB1 antagonism, respectively. Both PEA and CBD were prevented by PKA, MEK/ERK, and adenylyl cyclase inhibition (P < 0.001). In human mucosa, inflammation decreased claudin-5 mRNA, which was prevented by CBD (P < 0.05). Palmitoylethanolamide and cannabidiol prevented an inflammation-induced fall in TRPV1 and increase in PPARα transcription (P < 0.0001). In vivo, aspirin caused an increase in the absorption of lactulose and mannitol, which were reduced by PEA or CBD (P < 0.001).. Cannabidiol and palmitoylethanolamide reduce permeability in the human colon. These findings have implications in disorders associated with increased gut permeability, such as inflammatory bowel disease.

Topics: Adolescent; Adult; Amides; Anti-Inflammatory Agents, Non-Steroidal; Caco-2 Cells; Cannabidiol; Cell Membrane Permeability; Double-Blind Method; Ethanolamines; Follow-Up Studies; Gastrointestinal Tract; Humans; Inflammation; Inflammatory Bowel Diseases; Male; Middle Aged; Palmitic Acids; Young Adult

Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest that inhibition of anandamide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia.

Topics: Acute Disease; Adult; Amides; Amisulpride; Antipsychotic Agents; Arachidonic Acids; Cannabidiol; Double-Blind Method; Drug Therapy, Combination; Endocannabinoids; Ethanolamines; Female; Humans; Male; Oleic Acids; Palmitic Acids; Polyunsaturated Alkamides; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Signal Transduction; Sulpiride; Young Adult

The endocannabinoid system (ECS) is a widespread cell signaling network that maintains homeostasis in response to endogenous and exogenous stressors. This has made the ECS an attractive therapeutic target for various disease states. The ECS is a well-known target of exogenous phytocannabinoids derived from cannabis plants, the most well characterized being Δ

Topics: Amides; Cannabidiol; Cannabis; Endocannabinoids; Ethanolamines; Humans

In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produced long-lasting behavioral alterations such as social withdrawal and cognitive impairment in the social interaction test and in the novel object recognition test, respectively. At the molecular level, an increased cannabinoid receptor type-1 (CB1) mRNA and protein expression, which might be due to reduction in DNA methylation at the gene promoter in the prefrontal cortex (PFC), coincided with deficits in the social interaction test and in the novel object recognition test in MAM rats. Both the schizophrenia-like phenotype and altered transcriptional regulation of CB1 receptors were reversed by peripubertal treatment (from PND 19 to PND 39) with the non-psychotropic phytocannabinoid cannabidiol (30 mg/kg/day), or, in part, by treatment with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day), but not with haloperidol (0.6 mg/kg/day). These results suggest that early treatment with cannabidiol may prevent both the appearance of schizophrenia-like deficits as well as CB1 alterations in the PFC at adulthood, supporting that peripubertal cannabidiol treatment might be protective against MAM insult.

Topics: Amides; Animals; Arachidonic Acids; Cannabidiol; Disease Models, Animal; Endocannabinoids; Ethanolamines; Female; Glycerides; Hippocampus; Interpersonal Relations; Male; Methylazoxymethanol Acetate; Motor Activity; Oleic Acids; Palmitic Acids; Piperidines; Polyunsaturated Alkamides; Prefrontal Cortex; Pregnancy; Prenatal Exposure Delayed Effects; Puberty; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Recognition, Psychology; RNA, Messenger; Schizophrenia

We sought to quantify the anti-inflammatory effects of two cannabinoid drugs, cannabidiol (CBD) and palmitoylethanolamide (PEA), in cultured cell lines and compared this effect with experimentally inflamed explant human colonic tissue. These effects were explored in acutely and chronically inflamed colon, using inflammatory bowel disease and appendicitis explants.. Caco-2 cells and human colonic explants collected from elective bowel cancer, inflammatory bowel disease (IBD) or acute appendicitis resections, and were treated with the following drug treatments: vehicle, an inflammatory protocol of interferon γ (IFNγ) and tumour necrosis factor α (TNFα; 10 ng/ml), inflammation and PEA (10 µM), inflammation and CBD (10 µM), and PEA or CBD alone, CBD or vehicle were added simultaneously with IFNγ. Nine intracellular signalling phosphoproteins were determined by multiplex. Inflammatory cytokine secretion was determined using ELISA. Receptor mechanisms were investigated using antagonists for CB. IFNγ and TNFα treatment increased phosphoprotein and cytokine levels in Caco-2 cultures and colonic explants. Phosphoprotein levels were significantly reduced by PEA or CBD in Caco-2 cultures and colonic explants. CBD and PEA prevented increases in cytokine production in explant colon, but not in Caco-2 cells. CBD effects were blocked by the CB. PEA and CBD are anti-inflammatory in the human colon. This effect is not seen in cultured epithelial cells. Appropriately sized clinical trials should assess their efficacy.

Topics: Acute Disease; Amides; Anti-Inflammatory Agents; Caco-2 Cells; Cannabidiol; Colon; Cytokines; Ethanolamines; Humans; Inflammatory Bowel Diseases; Palmitic Acids; Tumor Necrosis Factor-alpha

Cannabinoids (CBs) have recently been approved to exert broad anti-inflammatory activities in experimental models of multiple sclerosis (MS). It has been demonstrated that these compounds could also have effects on neurodegeneration, demyelination, and autoimmune processes occurring in the pathology of MS. However, the clinical use of CBs is limited by their psychoactive effects. Among cannabinoid compounds, cannabidiol (CBD) and palmitoylethanolamide (PEA) have no psychotropic activities. We induced experimental autoimmune encephalomyelitis (EAE), a model of MS, by injecting myelin oligodendrocyte glycoprotein (MOG) to C57BL/6 mice. We assessed the effects of CBD, PEA, and co-administration of CBD and PEA on neurobehavioral scores, immune cell infiltration, demyelination, axonal injury, and the expression of inflammatory cytokines by using histochemistry methods and real-time RT-PCR. Treatment with either CBD (5mg/kg) or PEA (5mg/kg) during disease onset reduced the severity of the neurobehavioral scores of EAE. This effect of CBD and PEA was accompanied by diminished inflammation, demyelination, axonal damage and inflammatory cytokine expression while concurrent administration of CBD (5mg/kg) and PEA (5mg/kg) was not as effective as treatment with either drug per se. These results suggest that, CBD and PEA, non-psychoactive CBs, attenuate neurobehavioral deficits, histological damage, and inflammatory cytokine expression in MOG-immunized animals. However, there is an antagonistic interaction between CBD and PEA in protection against MOG-induced disease.

Topics: Amides; Animals; Anti-Inflammatory Agents; Axons; Cannabidiol; Drug Therapy, Combination; Encephalomyelitis, Autoimmune, Experimental; Ethanolamines; Female; Interferon-gamma; Interleukin-17; Macrophages; Mice, Inbred C57BL; Microglia; Myelin Sheath; Neuroimmunomodulation; Palmitic Acids; Severity of Illness Index; Spinal Cord; Treatment Outcome; Tumor Necrosis Factor-alpha