Masturbation to Orgasm Stimulates the Release of the Endocannabinoid 2-Arachidonoylglycerol in Humans.

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

“Endocannabinoids are critical for rewarding behaviors such as eating, physical exercise, and social interaction. The role of endocannabinoids in mammalian sexual behavior has been suggested because of the influence of cannabinoid receptor agonists and antagonists on rodent sexual activity. However, the involvement of endocannabinoids in human sexual behavior has not been studied.

AIM:

To investigate plasma endocannabinoid levels before and after masturbation in healthy male and female volunteers.

OUTCOMES:

Plasma levels of the endocannabinoids 2-arachidonoylglycerol (2-AG), anandamide, the endocannabinoid-like lipids oleoyl ethanolamide and palmitoyl ethanolamide, arachidonic acid, and cortisol before and after masturbation to orgasm.

METHODS:

In study 1, endocannabinoid and cortisol levels were measured before and after masturbation to orgasm. In study 2, masturbation to orgasm was compared with a control condition using a single-blinded, randomized, 2-session crossover design.

RESULTS:

In study 1, masturbation to orgasm significantly increased plasma levels of the endocannabinoid 2-AG, whereas anandamide, oleoyl ethanolamide, palmitoyl ethanolamide, arachidonic acid, and cortisol levels were not altered. In study 2, only masturbation to orgasm, not the control condition, led to a significant increase in 2-AG levels. Interestingly, we also found a significant increase of oleoyl ethanolamide after masturbation to orgasm in study 2.

CLINICAL TRANSLATION:

Endocannabinoids might play an important role in the sexual response cycle, leading to possible implications for the understanding and treatment of sexual dysfunctions.

STRENGTHS AND LIMITATIONS:

We found an increase of 2-AG through masturbation to orgasm in 2 studies including a single-blinded randomized design. The exact role of endocannabinoid release as part of the sexual response cycle and the biological significance of the finding should be studied further. Cannabis and other drug use and the attainment of orgasm were self-reported in the present study.

CONCLUSION:

Our data indicate that the endocannabinoid 2-AG is involved in the human sexual response cycle and we hypothesize that 2-AG release plays a role in the rewarding consequences of sexual arousal and orgasm.”

https://www.ncbi.nlm.nih.gov/pubmed/29110806

http://www.jsm.jsexmed.org/article/S1743-6095(17)31443-1/fulltext

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Characterization of endocannabinoids and related acylethanolamides in the synovial fluid of dogs with osteoarthritis: a pilot study.

 Image result for bmc veterinary research

“Cannabis-based drugs have been shown to be effective in inflammatory diseases.

A number of endocannabinoids including N- arachidonoylethanolamide (anandamide, AEA) and 2-arachidonyl glycerol (2-AG) with activity at the cannabinoidreceptors (CBR) CBR1 and CBR2, have been identified. Other structurally related endogenous fatty acid compounds such as oleoylethanolamide (OEA) and palmitoyl ethanolamide (PEA) have been identified in biological tissues.

These compounds do not bind to CBR but might be involved in facilitating the actions of directly acting endocannabinoids and thus are commonly termed “entourage” compounds due to their ability to modulate the endocannabinoid system.

The aim of this study was to evaluate the presence of endocannabinoids and entourage compounds in the synovial fluid of dogs with osteoarthritis subjected to arthrotomy of the knee joint. Cytokines and cytology were studied as well.

AEA, 2-AG, OEA and PEA were all present in the synovial fluid of arthritic knees and in the contralateral joints; in addition, a significant increase of OEA and 2AG levels were noted in SF from OA knees when compared to the contralateral joints.

The identification and quantification of endocannabinoids and entourage compounds levels in synovial fluids from dogs with OA of the knee is reported for the first time. Our data are instrumental for future studies involving a greater number of dogs. Cannabinoids represent an emerging and innovative pharmacological tool for the treatment of OA and further studies are warranted to evaluate the effectiveness of cannabinoids in veterinary medicine.”

https://www.ncbi.nlm.nih.gov/pubmed/29110674

“The ECS can be exploited as a potential therapeutic option for OA. We have demonstrated the presence of AEA, 2-AG, OEA and PEA in the SF of dogs with OA. Our data open the avenue to future studies involving a higher number of dogs and aimed at defining the role played by these compounds in OA of the dogs. Both plant-derived and synthetic agonists of CBRs represent an emerging and innovative pharmacological tool for the treatment of OA. ” https://bmcvetres.biomedcentral.com/articles/10.1186/s12917-017-1245-7

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[Cannabinoid receptor system regulates ion channels and synaptic transmission in retinal cells].

Image result for Sheng Li Xue Bao. journal

“Endocannabinoid receptor system is extensively expressed in the vertebrate retina. There are two types of cannabinoid receptors, CB1 and CB2. Activation of these two receptors by endocannabinoids N-arachidonoylethanolamide (anandamine, AEA) and 2-arachidonyl glycerol (2-AG) regulates multiple neuronal and glial ion channels, thus getting involved in retinal visual information processing. In this review, incorporating our results, we discuss the modulation of cannabinoid CB1 and CB2 receptors on retinal neuronal and glial ion channels and retinal synaptic transmission.”

https://www.ncbi.nlm.nih.gov/pubmed/29063116

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Human bone marrow mesenchymal stem cells secrete endocannabinoids that stimulate in vitro hematopoietic stem cell migration effectively comparable to beta adrenergic stimulation.

Experimental Hematology Home

“Granulocyte Colony-Stimulating Factor (G-CSF) is a well-known hematopoietic stem cell (HSC) mobilizing agent used in both allogeneic and autologous transplantation. However, a proportion of patients or healthy donors fail to mobilize sufficient number of cells. New mobilization agents are therefore needed.

Endocannabinoids (eCBs) are endogenous lipid mediators generated in the brain and peripheral tissues and activate the cannabinoid receptors (CB1, CB2). We suggest that eCBs may act as mobilizers of hematopoietic stem cells (HSC) from the BM under stress conditions as beta adrenergic receptors (Adrβ).

This study demonstrates that bone marrow (BM) mesenchymal stem cells (MSCs) secrete anandamide (AEA) and 2-arachidonylglycerol (2-AG), and peripheral blood (PB) and BM microenvironment contain AEA and 2-AG. 2-AG levels are significantly higher in PB of the G-CSF treated group when compared to BM plasma. BM mononuclear cells (MNCs) and CD34+HSCs, express CB1, CB2 and Adrβ subtypes. CD34+HSCs had higher CB1 and CB2 receptor expression in G-CSF untreated and treated groups when compared to MSCs. MNCs but not MSCs expressed CB1 and CB2 receptors based on qRT-PCR and flow cytometry (FC). AEA and 2-AG stimulated HSC migration was blocked by eCB receptor antagonists in in vitro migration assay.

In conclusion, components of the eCB system and their interaction with Adrβ subtypes were demonstrated on HSCs and MSCs of G-CSF treated and untreated healthy donors in vitro, revealing that eCBs might be potential candidates to enhance or facilitate G-CSF-mediated HSC migration under stress conditions in a clinical setting.”

https://www.ncbi.nlm.nih.gov/pubmed/29030083

http://www.exphem.org/article/S0301-472X(17)30813-5/fulltext

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Cannabinoid CB1 Discrimination: Effects of Endocannabinoids and Catabolic Enzyme Inhibitors.

Journal of Pharmacology and Experimental Therapeutics

“An improved understanding of the endocannabinoid system has provided new avenues of drug discovery and development toward the management of pain and other behavioral maladies. Exogenous cannabinoid type-1 (CB1) receptor agonists such as Δ9-tetrahydrocannabinol are increasingly utilized for their medicinal actions; however, their utility is constrained by concern regarding abuse-related subjective effects. This has led to growing interest in the clinical benefit of indirectly enhancing the activity of the highly labile endocannabinoids N-arachidonoylethanolamine (anandamide; AEA) and/or 2-arachidonoylglycerol (2-AG) via catabolic enzyme inhibition. The present studies were conducted to determine whether such actions can lead to CB1 agonist-like subjective effects, as reflected in the presence or absence of CB1-related discriminative-stimulus effects in laboratory subjects. Squirrel monkeys (n=8) that discriminated the CB1 full agonist AM4054 (0.01 mg/kg) from vehicle were used to study, first, inhibitors of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MGL) alone or in combination [FAAH (URB597, AM4303); MGL (AM4301); FAAH/MGL (AM4302)] and, second, the ability of the endocannabinoids AEA and 2-AG to produce CB1 agonist-like effects when administered alone or after enzyme inhibition. Results indicate that CB1-related discriminative-stimulus effects were produced by combined, but not selective, inhibition of FAAH and MGL, and that these effects were non-surmountably antagonized by low doses of rimonabant. Additionally, FAAH- or MGL-inhibition revealed CB1-like subjective effects produced by AEA, but not 2-AG. Taken together, the present data suggest that therapeutic effects of combined, but not selective, enhancement of AEA or 2-AG activity via enzyme inhibition may be accompanied by CB1 receptor-mediated subjective effects.”

https://www.ncbi.nlm.nih.gov/pubmed/28947487

http://jpet.aspetjournals.org/content/early/2017/09/25/jpet.117.244392

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Interplay Between n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids and the Endocannabinoid System in Brain Protection and Repair.

 Lipids

“The brain is enriched in arachidonic acid (ARA) and docosahexaenoic acid (DHA), long-chain polyunsaturated fatty acids (LCPUFAs) of the n-6 and n-3 series, respectively. Both are essential for optimal brain development and function. Dietary enrichment with DHA and other long-chain n-3 PUFA, such as eicosapentaenoic acid (EPA), has shown beneficial effects on learning and memory, neuroinflammatory processes, and synaptic plasticity and neurogenesis. ARA, DHA and EPA are precursors to a diverse repertoire of bioactive lipid mediators, including endocannabinoids.

The endocannabinoid system comprises cannabinoid receptors, their endogenous ligands, the endocannabinoids, and their biosynthetic and degradation enzymes. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are the most widely studied endocannabinoids and are both derived from phospholipid-bound ARA. The endocannabinoid system also has well-established roles in neuroinflammation, synaptic plasticity and neurogenesis, suggesting an overlap in the neuroprotective effects observed with these different classes of lipids.

Indeed, growing evidence suggests a complex interplay between n-3 and n-6 LCPUFA and the endocannabinoid system. For example, long-term DHA and EPA supplementation reduces AEA and 2-AG levels, with reciprocal increases in levels of the analogous endocannabinoid-like DHA and EPA-derived molecules. This review summarises current evidence of this interplay and discusses the therapeutic potential for brain protection and repair.”

https://www.ncbi.nlm.nih.gov/pubmed/28875399

https://link.springer.com/article/10.1007%2Fs11745-017-4292-8

“The seed of Cannabis sativa L. has been an important source of nutrition for thousands of years in Old World cultures. Technically a nut, hempseed typically contains over 30% oil and about 25% protein, with considerable amounts of dietary fiber, vitamins and minerals. Hempseed oil is over 80% in polyunsaturated fatty acids (PUFAs), and is an exceptionally rich source of the two essential fatty acids (EFAs) linoleic acid (18:2 omega-6) and alpha-linolenic acid (18:3 omega-3). The omega-6 to omega-3 ratio (n6/n3) in hempseed oil is normally between 2:1 and 3:1, which is considered to be optimal for human health. Hempseed has been used to treat various disorders for thousands of years in traditional oriental medicine.”  http://link.springer.com/article/10.1007%2Fs10681-004-4811-6

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Increased Renal 2-Arachidonoylglycerol Level Is Associated with Improved Renal Function in a Mouse Model of Acute Kidney Injury.

Mary Ann Liebert, Inc. publishers

“Acute kidney injury (AKI) is associated with a significantly increased risk of morbidity and mortality. Ischemia-reperfusion injury (IRI) is a major cause of AKI. In this study, we investigated the role of the endocannabinoid (EC) system in renal IRI using a well-established mouse model.

Results: Renal IRI was associated with significantly increased serum BUN and creatinine, increased tubular damage score, increased expression of renal markers of inflammation and oxidative stress and elevated renal 2-AG content. Pretreatment with JZL184 was associated with a significant increase in renal 2-AG content and there was also improved serum BUN, creatinine and tubular damage score. However, renal expression of inflammation and oxidative stress markers remained unchanged.

Conclusions: This is the first report documenting that renal IRI is associated with an increase in kidney 2-AG content. Further enhancement of 2-AG levels using JZL184 improved indices of renal function and histology, but did not lower renal expression of markers of inflammation and oxidative stress. Further studies are needed to determine the mechanisms responsible for the effects observed and the potential value of 2-AG as a therapeutic target in renal IRI.”

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CB1 and CB2 Receptor Pharmacology.

Advances in Pharmacology

“The CB1 and CB2 cannabinoid receptors (CB1R, CB2R) are members of the G protein-coupled receptor (GPCR) family that were identified over 20 years ago. CB1Rs and CB2Rs mediate the effects of Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive constituent of marijuana, and subsequently identified endogenous cannabinoids (endocannabinoids) anandamide and 2-arachidonoyl glycerol. CB1Rs and CB2Rs have both similarities and differences in their pharmacology. Both receptors recognize multiple classes of agonist and antagonist compounds and produce an array of distinct downstream effects. Natural polymorphisms and alternative splice variants may also contribute to their pharmacological diversity. As our knowledge of the distinct differences grows, we may be able to target select receptor conformations and their corresponding pharmacological responses. This chapter will discuss their pharmacological characterization, distribution, phylogeny, and signaling pathways. In addition, the effects of extended agonist exposure and how that affects signaling and expression patterns of the receptors are considered.”

https://www.ncbi.nlm.nih.gov/pubmed/28826534

http://www.sciencedirect.com/science/article/pii/S1054358917300340?via%3Dihub

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Endocannabinoid Analytical Methodologies: Techniques That Drive Discoveries That Drive Techniques.

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“Identification of the two major endogenous cannabinoid ligands, known as endocannabinoids, N-arachidonoyl-ethanolamine (anandamide, AEA) and 2-arachidonoyl-glycerol (2-AG), opened the way for the identification and isolation of other lipid congeners, all derivatives of fatty acids and related to the Endocannabinoid System. The nomenclature of this anandamide-type class of lipids is evolving as new species are discovered all the time. However, they each fall under the larger umbrella of lipids that are a conjugation of a fatty acid with an amine through and amide bond, which we will refer to as lipoamines. Specific subspecies of lipoamines that have been discovered are the N-acyl-ethanolamides (including AEA), N-acyl-dopamines, N-acyl-serotonins, N-acyl-GABA, N-acyl-taurines, and a growing number of N-acyl amino acids. Emerging data from multiple labs also show that monoacylglycerols (including 2-AG), COX-2 metabolites, and fatty acid esters of hydroxyl fatty acids are interconnected with these lipoamines at both the biosynthetic and metabolic levels. Understanding the molecular relatedness of these lipids is important for studying how they act as signaling molecules; however, a first step in this process hinges on advances in being able to accurately measure them.”

https://www.ncbi.nlm.nih.gov/pubmed/28826532

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Endocannabinoid Transport Proteins: Discovery of Tools to Study Sterol Carrier Protein-2.

Elsevier

“The endocannabinoid (eCB) neurotransmitter system regulates diverse neurological functions including stress and anxiety, pain, mood, and reward. Understanding the mechanisms underlying eCB regulation is critical for developing targeted pharmacotherapies to treat these and other neurologic disorders.

Cellular studies suggest that the arachidonate eCBs, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), are substrates for intracellular binding and transport proteins, and several candidate proteins have been identified. Initial evidence from our laboratory indicates that the lipid transport protein, sterol carrier protein 2 (SCP-2), binds to the eCBs and can regulate their cellular concentrations.

Here, we present methods for evaluating SCP-2 binding of eCBs and their application to the discovery of the first inhibitor lead molecules. Using a fluorescent probe displacement assay, we found SCP-2 binds the eCBs, AEA (Ki=0.68±0.05μM) and 2-AG (Ki=0.37±0.02μM), with moderate affinity. A series of structurally diverse arachidonate analogues also bind SCP-2 with Ki values between 0.82 and 2.95μM, suggesting a high degree of tolerance for arachidonic acid head group modifications in this region of the protein. We also report initial structure-activity relationships surrounding previously reported inhibitors of Aedis aegypti SCP-2, and the results of an in silico high-throughput screen that identified structurally novel SCP-2 inhibitor leads.

The methods and results reported here provide the basis for a robust probe discovery effort to fully elucidate the role of facilitated transport mediated by SCP-2 in eCB regulation and function.”

https://www.ncbi.nlm.nih.gov/pubmed/28750817

http://www.sciencedirect.com/science/article/pii/S007668791730174X?via%3Dihub

 

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