Circulating endocannabinoid concentrations and sexual arousal in women.

The Journal of Sexual Medicine - Click here to go back to the homepage

“Several lines of evidence point to the potential role of the endocannabinoid system in female sexual functioning. These include results from studies describing the subjective effects of exogenous cannabinoids on sexual functioning in humans and the observable effects of exogenous cannabinoids on sexual functioning in other species, as well as results from studies investigating the location of cannabinoid receptors in the brain and periphery, and the effects of cannabinoid receptor activation on neurotransmitters implicated in sexual functioning. While these lines of research suggest a role for the endocannabinoid system in female sexual functioning, no studies investigating the relationship between concentrations of endogenous cannabinoids (i.e., arachidonoylethanolamide [AEA] and 2-arachidonoylglycerol [2-AG]) and sexual functioning have been conducted in any species.

AIM:

To measure circulating endocannabinoid concentrations in relation to subjective and physiological indices of sexual arousal in women (N = 21).

METHODS:

Serum endocannabinoid (AEA and 2-AG) concentrations were measured immediately prior to, and immediately following, viewing of neutral (control) and erotic (experimental) film stimuli in a repeated measures design. Physiological sexual arousal was measured via vaginal photoplethysmography. Subjective sexual arousal was measured both continuously and noncontinuously. Pearson’s correlations were used to investigate the relationships between endocannabinoid concentrations and sexual arousal.

MAIN OUTCOME MEASURES:

Changes in AEA and 2-AG concentrations from pre- to post-film and in relation to physiological and subjective indices of sexual arousal.

RESULTS:

Results revealed a significant relationship between endocannabinoid concentrations and female sexual arousal, whereby increases in both physiological and subjective indices of sexual arousal were significantly associated with decreases in AEA, and increases in subjective indices of sexual arousal were significantly associated with decreases in 2-AG.

CONCLUSIONS:

These findings support the hypothesis that the endocannabinoid system is involved in female sexual functioning, with implications for furthering understanding of the biological mechanisms underlying female sexual functioning.”

https://www.ncbi.nlm.nih.gov/pubmed/22462722

https://www.jsm.jsexmed.org/article/S1743-6095(15)33996-5/fulltext

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Lower circulating endocannabinoid levels in children with autism spectrum disorder.

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“The endocannabinoid system (ECS) is a major regulator of synaptic plasticity and neuromodulation. Alterations of the ECS have been demonstrated in several animal models of autism spectrum disorder (ASD). In some of these models, activating the ECS rescued the social deficits. Evidence for dysregulations of the ECS in human ASD are emerging, but comprehensive assessments and correlations with disease characteristics have not been reported yet.

METHODS:

Serum levels of the main endocannabinoids, N-arachidonoylethanolamine (AEA or anandamide) and 2-arachidonoylglycerol (2-AG), and their related endogenous compounds, arachidonic acid (AA), N-palmitoylethanolamine (PEA), and N-oleoylethanolamine (OEA), were analyzed by liquid chromatography/tandem mass spectrometry in 93 children with ASD (age = 13.1 ± 4.1, range 6-21; 79% boys) and 93 age- and gender-matched neurotypical children (age = 11.8 ± 4.3, range 5.5-21; 79% boys). Results were associated with gender and use of medications, and were correlated with age, BMI, and adaptive functioning of ASD participants as reflected by scores of Autism Diagnostic Observation Schedule (ADOS-2), Vineland Adaptive Behavior Scale-II (VABS-II), and Social Responsiveness Scale-II (SRS-2).

RESULTS:

Children with ASD had lower levels (pmol/mL, mean ± SEM) of AEA (0.722 ± 0.045 vs. 1.252 ± 0.072, P < 0.0001, effect size 0.91), OEA (17.3 ± 0.80 vs. 27.8 ± 1.44, P < 0.0001, effect size 0.94), and PEA (4.93 ± 0.32 vs. 7.15 ± 0.37, P < 0.0001, effect size 0.65), but not AA and 2-AG. Serum levels of AEA, OEA, and PEA were not significantly associated or correlated with age, gender, BMI, medications, and adaptive functioning of ASD participants. In children with ASD, but not in the control group, younger age and lower BMI tended to correlate with lower AEA levels. However, these correlations were not statistically significant after a correction for multiple comparisons.

CONCLUSIONS:

We found lower serum levels of AEA, PEA, and OEA in children with ASD. Further studies are needed to determine whether circulating endocannabinoid levels can be used as stratification biomarkers that identify clinically significant subgroups within the autism spectrum and if they reflect lower endocannabinoid “tone” in the brain, as found in animal models of ASD.”

https://www.ncbi.nlm.nih.gov/pubmed/30728928

https://molecularautism.biomedcentral.com/articles/10.1186/s13229-019-0256-6

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Antimicrobial potential of endocannabinoid and endocannabinoid-like compounds against methicillin-resistant Staphylococcus aureus.

 Scientific Reports

“Infections caused by antibiotic-resistant strains of Staphylococcus aureus have reached epidemic proportions globally. Staphylococcal biofilms are associated with increased antimicrobial resistance and are generally less affected by host immune factors. Therefore, there is an urgent need for novel agents that not only aim at multidrug-resistant pathogens, but also ones that will act as anti biofilms. In the present study, we investigated the antimicrobial activity of the endocannabinoid (EC) anandamide (AEA) and the endocannabinoid-like (EC-like), arachidonoyl serine (AraS) against methicillin resistant S. aureus strains (MRSA). We observed a strong inhibition of biofilm formation of all tested MRSA strains as well as a notable reduction of metabolic activity of pre-formed MRSA biofilms by both agents. Moreover, staphylococcal biofilm-associated virulence determinants such as hydrophobicity, cell aggregation and spreading ability were altered by AEA and AraS. In addition, the agents were able to modify bacterial membrane potential. Importantly, both compounds prevent biofilm formation by altering the surface of the cell without killing the bacteria. Therefore, we propose that EC and EC-like compounds may act as a natural line of defence against MRSA or other antibiotic resistant bacteria. Due to their anti biofilm action these agents could also be a promising alternative to antibiotic therapeutics against biofilm-associated MRSA infections.”

https://www.ncbi.nlm.nih.gov/pubmed/30523307

https://www.nature.com/articles/s41598-018-35793-7

“Antimicrobial activity of Cannabis sativa, Thuja orientalis and Psidium guajava leaf extracts against methicillin-resistant Staphylococcus aureus.”  https://www.ncbi.nlm.nih.gov/pubmed/30120078

“Antimicrobial Activity of Cannabis sativa L.”  https://www.scirp.org/journal/PaperInformation.aspx?PaperID=18123

“Characterization and antimicrobial activity of essential oils of industrial hemp varieties (Cannabis sativa L.).” https://www.ncbi.nlm.nih.gov/pubmed/19969046

“Antimicrobial studies of the leaf of cannabis sativa L.”   https://www.ncbi.nlm.nih.gov/pubmed/16414764

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The endocannabinoid system: Overview of an emerging multi-faceted therapeutic target.

Prostaglandins, Leukotrienes and Essential Fatty Acids Home

“The endocannabinoids anandamide (AEA) and 2-arachidonoylglyerol (2-AG) are endogenous lipid mediators that exert protective roles in pathophysiological conditions, including cardiovascular diseases. In this brief review, we provide a conceptual framework linking endocannabinoid signaling to the control of the cellular and molecular hallmarks, and categorize the key components of endocannabinoid signaling that may serve as targets for novel therapeutics. The emerging picture not only reinforces endocannabinoids as potent regulators of cellular metabolism but also reveals that endocannabinoid signaling is mechanistically more complex and diverse than originally thought.”

https://www.ncbi.nlm.nih.gov/pubmed/30553404

https://www.plefa.com/article/S0952-3278(18)30176-5/fulltext

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Cannabinoid receptor agonists reduce the short-term mitochondrial dysfunction and oxidative stress linked to excitotoxicity in the rat brain.

Neuroscience

“The endocannabinoid system (ECS) is involved in a considerable number of physiological processes in the Central Nervous System.

Recently, a modulatory role of cannabinoid receptors (CBr) and CBr agonists on the reduction of the N-methyl-d-aspartate receptor (NMDAr) activation has been demonstrated. Quinolinic acid (QUIN), an endogenous analog of glutamate and excitotoxic metabolite produced in the kynurenine pathway (KP), selectively activates NMDAr and has been shown to participate in different neurodegenerative disorders.

Since the early pattern of toxicity exerted by this metabolite is relevant to explain the extent of damage that it can produce in the brain, in this work we investigated the effects of the synthetic CBr agonist WIN 55,212-2 (WIN) and other agonists (anandamide or AEA, and CP 55,940 or CP) on early markers of QUIN-induced toxicity in rat striatal cultured cells and rat brain synaptosomes.

WIN, AEA and CP exerted protective effects on the QUIN-induced loss of cell viability. WIN also preserved the immunofluorescent signals for neurons and CBr labeling that were decreased by QUIN. The QUIN-induced early mitochondrial dysfunction, lipid peroxidation and reactive oxygen species (ROS) formation were also partially or completely prevented by WIN pretreatment, but not when this CBr agonist was added simultaneously with QUIN to brain synaptosomes.

These findings support a neuroprotective and modulatory role of cannabinoids in the early toxic events elicited by agents inducing excitotoxic processes.”

https://www.ncbi.nlm.nih.gov/pubmed/25446347

https://www.sciencedirect.com/science/article/abs/pii/S0306452214009737?via%3Dihub

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Anandamide Effects in a Streptozotocin-Induced Alzheimer’s Disease-Like Sporadic Dementia in Rats.

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“Alzheimer’s disease (AD) is characterized by multiple cognitive deficits including memory and sensorimotor gating impairments as a result of neuronal and synaptic loss.

The endocannabinoid system plays an important role in these deficits but little is known about its influence on the molecular mechanism regarding phosphorylated tau (p-tau) protein accumulation – one of the hallmarks of AD -, and on the density of synaptic proteins.

Thus, the aim of this study was to investigate the preventive effects of anandamide (N-arachidonoylethanolamine, AEA) on multiple cognitive deficits and on the levels of synaptic proteins (syntaxin 1, synaptophysin and synaptosomal-associated protein, SNAP-25), cannabinoid receptor type 1 (CB1) and molecules related to p-tau degradation machinery (heat shock protein 70, HSP70), and Bcl2-associated athanogene (BAG2) in an AD-like sporadic dementia model in rats using intracerebroventricular (icv) injection of streptozotocin (STZ).

This study showed, for the first time, that the administration of an endocannabinoid can prevent AD-like effects induced by STZ, boosting further investigations about the modulation of endocannabinoid levels as a therapeutic approach for AD.”

“Altogether, our results showed, for the first time, that the administration of an endocannabinoid can prevent cognitive, synaptic and histopatological AD-like alterations induced by STZ, thus prompting endocannabinoids as a candidate therapeutic target in AD.”  https://www.frontiersin.org/articles/10.3389/fnins.2018.00653/full
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Endocannabinoid Virodhamine is an Endogenous Inhibitor of Human Cardiovascular CYP2J2 Epoxygenase.

 Biochemistry

“The human body contains endogenous cannabinoids (endocannabinoids) that elicit similar effects as Δ9-tetrahydrocanabinol, the principal bioactive component of cannabis.

The endocannabinoid virodhamine (O-AEA) is the constitutional isomer of the well-characterized cardioprotective and anti-inflammatory endocannabinoid anandamide (AEA).

The chemical structures of O-AEA and AEA contain arachidonic acid (AA) and ethanolamine, however AA in O-AEA is connected to ethanolamine via an ester linkage whereas AA in AEA is connected through an amide linkage. We show that O-AEA is found at 9.6 fold higher levels than AEA in porcine left ventricle and is involved in regulating blood pressure and cardiovascular function.

On a separate note, the cytochrome P450 (CYP) epoxygenase CYP2J2 is the most abundant CYP in the heart where it catalyzes the metabolism of AA and AA-derived eCBs to bioactive epoxides that are involved in diverse cardiovascular functions. Herein, using competitive binding studies, kinetic metabolism measurements, molecular dynamics and wound healing assays we have shown that O-AEA is an endogenous inhibitor of CYP2J2 epoxygenase.

Together, the role of O-AEA as an endogenous eCB inhibitor of CYP2J2 may provide a new mode of regulation to control the activity of cardiovascular CYP2J2 in vivo and suggests a potential cross talk between the cardiovascular endocannabinoids and cytochrome P450 system.”

https://www.ncbi.nlm.nih.gov/pubmed/30285425

https://pubs.acs.org/doi/10.1021/acs.biochem.8b00691

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Cannabis sativa: A comprehensive ethnopharmacological review of a medicinal plant with a long history.

Journal of Ethnopharmacology

“Cannabis sativa L. (C. sativa) is an annual dioecious plant, which shares its origins with the inception of the first agricultural human societies in Asia. Over the course of time different parts of the plant have been utilized for therapeutic and recreational purposes, for instance, extraction of healing oils from seed, or the use of inflorescences for their psychoactive effects. The key psychoactive constituent in C. sativa is called Δ-9-tetrahydrocannabinol (D9-THC). The endocannabinoid system seems to be phylogenetically ancient, as it was present in the most primitive vertebrates with a neuronal network. N-arachidonoylethanolamine (AEA) and 2-arachidonoyl glycerol (2-AG) are the main endocannabinoids ligands present in the animal kingdom, and the main endocannabinoid receptors are cannabinoid type-1 (CB1) receptor and cannabinoid type-2 (CB2) receptor.

AIM OF THE STUDY:

The review aims to provide a critical and comprehensive evaluation, from the ancient times to our days, of the ethnological, botanical, chemical and pharmacological aspects of C. sativa, with a vision for promoting further pharmaceutical research to explore its complete potential as a therapeutic agent.

RESULTS AND CONCLUSIONS:

A detailed comparative analysis of the available resources for C. sativa confirmed its origin and traditional spiritual, household and therapeutic uses and most importantly its popularity as a recreational drug. The result of several studies suggested a deeper involvement of phytocannabinoids (the key compounds in C. sativa) in several others central and peripheral pathophysiological mechanisms such as food intake, inflammation, pain, colitis, sleep disorders, neurological and psychiatric illness. However, despite their numerous medicinal benefits, they are still considered as a menace to the society and banned throughout the world, except for few countries. We believe that this review will help lay the foundation for promoting exhaustive pharmacological and pharmaceutical studies in order to better understand the clinical relevance and applications of non-psychoactive cannabinoids in the prevention and treatment of life-threatening diseases and help to improve the legal status of C. sativa.”

https://www.ncbi.nlm.nih.gov/pubmed/30205181

https://www.sciencedirect.com/science/article/pii/S0378874118316611?via%3Dihub

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Endocannabinoid system, Stress and HPA axis.

European Journal of Pharmacology

“The endocannabinoid system (ECS), which is composed of the cannabinoid receptors types 1 and 2 (CB1 and CB2) for marijuana’s psychoactive ingredient ∆9-tetrahydrocannabinol (∆9-THC), the endogenous ligands (AEA and 2-AG) and the enzymatic systems involved in their biosynthesis and degradation, recently emerged as important modulator of emotional and non-emotional behaviors. In addition to its recreational actions, some of the earliest reports regarding the effects of Cannabis use on humans were related to endocrine system changes. Accordingly, the ∆9-THC and later on, the ECS signaling have long been known to regulate the hypothalamic-pituitary-adrenocortical (HPA) axis, which is the major neuroendocrine stress response system of mammals. However, how the ECS could modify the stress hormone secretion is not fully understood. Thus, the present article reviews current available knowledge on the role of the ECS signaling as important mediator of interaction between HPA axis activity and stressful conditions, which, in turn could be involved in the development of psychiatric disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/30036537

https://www.sciencedirect.com/science/article/pii/S0014299918304138?via%3Dihub

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The Role of Cannabinoids in the Setting of Cirrhosis.

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“Although the mortality rates of cirrhosis are underestimated, its socioeconomic burden has demonstrated a significant global impact. Cirrhosis is defined by the disruption of normal liver architecture after years of chronic insult by different etiologies. Treatment modalities are recommended primarily in decompensated cirrhosis and specifically tailored to the different manifestations of hepatic decompensation. Antifibrogenic therapies are within an active area of investigation.

The endocannabinoid system has been shown to play a role in liver disease, and cirrhosis specifically, with intriguing possible therapeutic benefits. The endocannabinoid system comprises cannabinoid receptors 1 (CB1) and cannabinoid receptor 2 (CB2) and their ligands, endocannabinoids and exocannabinoids.

CB1 activation enhances fibrogenesis, whereas CB2 activation counteracts progression to fibrosis. Conversely, deletion of CB1 is associated with an improvement of hepatic fibrosis and steatosis, and deletion of CB2 results in increased collagen deposition, steatosis, and enhanced inflammation.

CB1 antagonism has also demonstrated vascular effects in patients with cirrhosis, causing an increase in arterial pressure and vascular resistance as well as a decrease in mesenteric blood flow and portal pressure, thereby preventing ascites. In mice with hepatic encephalopathy, CB1 blockade and activation of CB2 demonstrated improved neurologic score and cognitive function.

Endocannabinoids, themselves also have mechanistic roles in cirrhosis. Arachidonoyl ethanolamide (AEA) exhibits antifibrogenic properties by inhibition of HSC proliferation and induction of necrotic death. AEA induces mesenteric vasodilation and hypotension via CB1 induction. 2-arachidonoyl glycerol (2-AG) is a fibrogenic mediator independent of CB receptors, but in higher doses induces apoptosis of HSCs, which may actually show antifibrotic properties. 2-AG has also demonstrated growth-inhibitory and cytotoxic effects.

The exocannabinoid, THC, suppresses proliferation of hepatic myofibroblasts and stellate cells and induces apoptosis, which may reveal antifibrotic and hepatoprotective mechanisms. Thus, several components of the endocannabinoid system have therapeutic potential in cirrhosis.”

https://www.ncbi.nlm.nih.gov/pubmed/29890719

http://www.mdpi.com/2305-6320/5/2/52

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