The plant Cannabis sativa, better known as marijuana, has long been used Most studies on the endocannabinoid system focus on these two. Marijuana has the highest consumption rate among all of the illicit drugs used in the USA, and its popularity as both a recreational and medicinal drug is. After several decades of research, scientists studying the effects of marijuana made several important discoveries. Not only did they identify the active ingredient.
Endocannabinoid System The Cannabis and
It was medical marijuana laws that changed the legal status of cannabis nationwide, opening the doors for an adult-use market and creating a path towards full legalization. Cannabis patients across the country have used the plant to treat a growing number of medical conditions. In Colorado alone, there are nine different qualifying conditions for a medical card: How does cannabis address so many different conditions?
How does the body interact with the plant to produce these medicinal effects? What research has been to done to demonstrate the efficacy of medicinal cannabis?
The endocannabinoid system is essential to human health because it maintains homeostasis in the body. Research into the endocannabinoid system has increased in recent years as scientists begin to reveal how complex and important this system is to our bodies. By understanding the endocannabinoid system and how it interacts with cannabis, patients and consumers can become more informed about their health and can ask their caregivers, doctors, or budtenders better questions.
Put simply, the endocannabinoid system is responsible for maintaining homeostasis in the body. If homeostasis is successful, life continues; if unsuccessful, disaster or death ensues. Endocannabinoid receptors are found throughout the body on the surface of cells in the brain, organs, tissues, and glands. These receptors are embedded in cell membranes and produce varying reactions when stimulated by cannabinoids. Cannabinoids come from two distinct places — the body, which produces naturally occurring endocannabinoids, and the cannabis plant, which produces phytocannabinoids.
The third part of the ECS is metabolic enzymes. Metabolic enzymes act like a natural referee in that they destroy endocannabinoids once they are used and no longer useful to the body. This self-regulating system ensures the interaction only happens when needed and therefore keeps the workings of the endocannabinoid system relatively quiet to the conscious brain, unlike, the hormonal system, which can keep the chemicals around longer than the interaction.
Because homeostasis is so important to health, all vertebrates and invertebrates are known to have an ECS. This discovery was quickly followed up with further evidence by Dr. Raphael Mechoulam, the famous chemist who discovered THC.
With less than 30 years of research, the endocannabinoid system is one of the less studied systems in the body. Currently, restrictions on cannabis research limit what scientists can examine in terms of furthering our understanding of how cannabis interacts with the endocannabinoid system. When someone uses cannabis medicinally they are keying into these natural mechanisms which sometimes are deficient and need supplementation.
Glycolysis combined with oxidative phosphorylation also provides fuel for many other energy-dependent processes including capacitation and the acrosome reaction [ ]. Disturbing the ECS homeostasis will subsequently adversely affect these energy-dependent processes with implications for gaining fertilizing potential. The ECS is important in keeping the spermatozoa from undergoing capacitation before reaching of the oocyte [ 47 ]. This is essential in preventing the spermatozoa from undergoing untimely capacitation in an unusual location.
The fact that the process of capacitation is inhibited by cannabinoids means that this effect can be extrapolated to marijuana. CB1 receptor activation prevents the acrosome reaction from occurring [ 47 , 67 , 75 ]. Similar inhibitory findings were observed for both the spontaneous and induced AR after in vitro treatment of spermatozoa with either therapeutic or recreational concentrations of THC [ ].
Fertilizing ability of spermatozoa also appears to be affected as hyperactivated motility, necessary for penetration of zona pellucida, as well as hemizona binding were negatively affected in AEA-treated spermatozoa. Spermatozoa can also be cytogenetically affected by marijuana as Zimmermann et al. In both males and females, arousability and sexual behavior appear to be modulated by ECBs. It is well established that a group of oxytocinergic neurons containing CB1 receptors in the paraventricular nucleus of the hypothalamus PVN regulate erectile function and copulatory behavior of males [ ].
The use and effect of cannabis on sexual function are extremely controversial and more than likely subject-specific. Anecdotal aphrodisiac-like properties of cannabis as described by some users are likely the result of altered perceptual processing of the sexual encounter. In one study, acute use of marijuana has been shown to increase sexual drive, but chronic use of marijuana was reported to decrease libido in males [ ]. These sentiments were echoed by Abel who stated that a lesser amount of cannabis can enhance sexual activity, but larger quantities may impede sexual motivation [ ].
Besides, similar dose effects were reported by American Indian men who were chronic cannabis users [ ]. It was also shown in a rat model that marijuana use was associated with impotence [ ]. Results from studies on non-human primates suggest that cannabinoids have a predominant detrimental effect on male sexual motivation and erectile function [ ]. Various other studies however report that cannabis intensified arousal and enhanced sexual pleasure in men [ , ].
Di Marzo and coworkers reported that THC weakens sexual drive by interfering with the production of testosterone [ ]. Similarly, it was also showed in another recent study that chronic cannabis consumption can cause vascular ED in young habitual cannabis users through its effect on endothelial function [ ].
However, no link between frequency of cannabis use and trouble keeping an erection was reported in a study where men were screened for the use of cannabis and its sexual effects [ ]. Despite marijuana use being implicated to cause reduced libido, gynecomastia, and erectile disorders [ ], no properly controlled study has been performed in humans to substantiate these speculations.
It is beyond doubt that recreational and medicinal marijuana usage will increase and become even more prevalent. Given the deep involvement of the ECS in the regulation of male reproduction and the direct impact of exogenous cannabinoids on the homeostasis of the ECS, the potential thread represented by marijuana on the finely tuned events associated with male fertilizing ability must definitely be considered [ 4 , 82 ].
Surprisingly, very few studies have explored the direct effect of marijuana on male fertility. This can mainly be ascribed to legislation and ethical considerations making it virtually impossible to pursue in vivo human studies. The current body of knowledge pertaining to this topic mainly consists of a number of earlier human studies and more recently animal, in vitro, and retrospective studies. Despite these limitations, it is clear that marijuana and its compounds can influence male fertility at multiple levels.
A number of studies have attributed dysregulation of the HPG axis, and in specific reduction in a key hormone such as LH, which, in turn, can affect testosterone and spermatogenesis to marijuana. It appears as if marijuana can actually affect semen parameters and sperm function by acting through both the cannabinoid and vanilloid receptors. Furthermore, sexual health has also been linked to marijuana as it seems to have an effect on erectile function. With the change in legislation and decriminalization of marijuana use, as well as the fact that some studies report conflicting and contradictory findings, it is paramount that more clinical studies should be undertaken to examine the effects of marijuana use in greater detail.
Despite that human studies are currently few and limited by their observational nature, the existing proof substantiates the claim that marijuana use has a detrimental effect on male reproductive potential [ ]. Of interest would also be to explore the confounding effects of marijuana use on tobacco smokers as a recent study revealed that cigarette smokers are greater abusers of cannabis, whilst cigarette smoking males of infertile couples showed lower ejaculate volumes despite higher testosterone levels [ ].
All the above findings underline the fact that clinicians should include questions on marijuana usage while evaluating infertility in males. Health professionals should definitely also keep the association and potential impact of marijuana on male fertility in mind when prescribing medical marijuana. The authors declare that they have no relevant financial and competing interests. Capsule We highlight the latest evidence regarding the effect of marijuana use on male fertility and provide a detailed insight into its significance in the male reproductive system.
Marijuana and its compounds can influence male fertility at multiple levels by acting through both the cannabinoid and vanilloid receptors. National Center for Biotechnology Information , U. J Assist Reprod Genet. Published online Aug Author information Article notes Copyright and License information Disclaimer. Received May 19; Accepted Jul This article has been cited by other articles in PMC.
Abstract Marijuana has the highest consumption rate among all of the illicit drugs used in the USA, and its popularity as both a recreational and medicinal drug is increasing especially among men of reproductive age. Introduction Once a social taboo, medical, spiritual, and even recreational marijuana use is now increasingly accepted. General pharmacobiology of marijuana Marijuana consists of dried leaves and flowers from the plant Cannabis sativa and is also known under numerous street names, including weed, pot, grass, , hashish, joint, dope, and many more.
The endocannabinoid system—a brief overview The ECS consists of the endogenous endocannabinoid ligands, their congeners, the biosynthetic and hydrolyzing enzymes involved in the metabolism of these ligands, their transporter proteins, and receptors [ 15 , 16 ].
The endocannabinoids Endocannabinoids are endogenous lipids that mimic various actions of THC [ 4 ]. The cannabinoid receptors Two subtypes of cannabinoid receptors CB1 and CB2 have been described as of yet, both of which belong to the family of transmembrane spanning G-protein coupled receptors GPCRs [ 31 ]. CB2 receptors CB2 receptors, which are also GPCRs, are mainly expressed in the immune system and peripheral cells as well as in neuronal cells [ 32 , 48 ].
The endocannabinoid system and male reproduction The presence of the ECS has been demonstrated in various cell types that are involved in male reproduction. ECS and the hypothalamus-pituitary-gonadal axis A fully functional HPG axis is needed to properly orchestrate and maintain the process of spermatogenesis [ 55 ]. Open in a separate window. Marijuana, phytocannabinoids, and male reproduction It is to be expected that exogenous cannabinoids, such as those present in marijuana, compete with endocannabinoids for binding on the cannabinoid receptors.
Table 1 Effect of marijuana use on reproductive hormones in males. LH Similar to the effects of marijuana on FSH levels, inconclusive findings are also reported in the literature with regards to its effects on LH. Testosterone There have been contradictory results as far as the effect of marijuana on testosterone levels is concerned. Estrogen To investigate the possible estrogenic effects of marijuana smoke condensate MSC and cannabinoids, a study was conducted on human breast cancer cells.
Effect on reproductive organs Not many reports are available on the direct and physical effects of marijuana use on the reproductive organs of men. Effect on sperm parameters and function As the ECS is so deeply involved in the regulation of the male reproductive system, a number of studies have investigated the effect of cannabis on various sperm parameters.
Table 2 Effect of marijuana and cannabinoids on human sperm parameters and function. Effect on libido and sexual function In both males and females, arousability and sexual behavior appear to be modulated by ECBs. Conclusion It is beyond doubt that recreational and medicinal marijuana usage will increase and become even more prevalent. Conflict of interests The authors declare that they have no relevant financial and competing interests. Footnotes Capsule We highlight the latest evidence regarding the effect of marijuana use on male fertility and provide a detailed insight into its significance in the male reproductive system.
Contributor Information Stefan S. Bifulco M, Pisanti S. Medicinal use of cannabis in Europe: Effects of cannabinoids on spermatogenesis in mice. Cannabinoids reduce fertility of sea urchin sperm. The manifold actions of endocannabinoids on female and male reproductive events. Front Biosci Landmark Ed ; The insults of illicit drug use on male fertility. Management of substance abuse: Accessed 11 Feb National survey on drug use and health: Department of Health and Human Services.
Accessed 18 Feb Ann N Y Acad Sci. The cannabinoid system and male reproductive functions. Shamloul R, Bella AJ. Impact of cannabis use on male sexual health. Some practice-relevant aspects of the pharmacokinetics of THC. The therapeutic potential of cannabis. Sugiura T, Waku K. Isolation and structure of a brain constituent that binds to the cannabinoid receptor.
Meccariello R, Battista N. Updates in reproduction coming from the endocannabinoid system. The endocannabinoid system in vertebrate male reproduction: Regulation of male fertility by the endocannabinoid system. Katona I, Freund TF. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease.
Enzymatic pathways that regulate endocannabinoid signaling in the nervous system. Beltramo M, Piomelli D. Carrier-mediated transport and enzymatic hydrolysis of the endogenous cannabinoid 2-arachidonylglycerol. Why do cannabinoid receptors have more than one endogenous ligand?
Endocannabinoid metabolic pathways and enzymes. Biochemistry and pharmacology of endovanilloids. Lewis SE, Maccarrone M. Endocannabinoids, sperm biology and human fertility.
Structure and function of fatty acid amide hydrolase. Biosynthesis and inactivation of endocannabinoids: Endocannabinoids as regulators of transient receptor potential TRP channels: International Union of Pharmacology.
Classification of cannabinoid receptors. Molecular characterization of a peripheral receptor for cannabinoids. Involvement of Gi in the inhibition of adenylate cyclase by cannabimimetic drugs. Pharmacology of cannabinoid receptors. Annu Rev Pharmacol Toxicol. Cannabinoid receptor agonists inhibit Ca current in NG neuroblastoma cells via a pertussis toxin-sensitive mechanism. Structure of a cannabinoid receptor and functional expression of the cloned cDNA.
International Union of Basic and Clinical Pharmacology. Cannabinoid receptors and their ligands: Cannabinoid receptors in the human brain: Cannabinoid receptor localization in brain.
Localisation and function of the endocannabinoid system in the human ovary. Modulation of ATP-mediated contractions of the rat vas deferens through presynaptic cannabinoid receptors. Cannabinoid CB1 receptors are expressed in the mouse urinary bladder and their activation modulates afferent bladder activity. Localization of cannabinoid receptor mRNA in rat brain.
Expression of cannabinoid receptor 1 in mouse testes. The CB 2 cannabinoid receptor regulates human sperm cell motility. Human sperm express cannabinoid receptor Cb1, the activation of which inhibits motility, acrosome reaction, and mitochondrial function. J Clin Endocrinol Metab. Anandamide activity and degradation are regulated by early postnatal aging and follicle-stimulating hormone in mouse Sertoli cells. GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current.
Characterization of the endocannabinoid system in human spermatozoa and involvement of transient receptor potential vanilloid 1 receptor in their fertilizing ability. Pistis M, Melis M. From surface to nuclear receptors: Normal testicular function and spermatogenesis. The central cannabinoid receptor inactivation suppresses endocrine reproductive functions. Biochem Biophys Res Commun. The inhibitory effect of anandamide on luteinizing hormone-releasing hormone secretion is reversed by estrogen.
Retrograde endocannabinoid signaling reduces GABAergic synaptic transmission to gonadotropin-releasing hormone neurons. Alcohol inhibits luteinizing hormone-releasing hormone release by activating the endocannabinoid system. The role of endocannabinoids in the regulation of luteinizing hormone and prolactin release.
Follicle-stimulating hormone activates fatty acid amide hydrolase by protein kinase A and aromatase-dependent pathways in mouse primary Sertoli cells. Follicle-stimulating hormone-induced aromatase in immature rat Sertoli cells requires an active phosphatidylinositol 3-kinase pathway and is inhibited via the mitogen-activated protein kinase signaling pathway. Anat Rec Hoboken ; 2: N-Acylethanolamines in human reproductive fluids. Quantitative analysis of anandamide and related acylethanolamides in human seminal plasma by ultra performance liquid chromatography tandem mass spectrometry.
Evidence that anandamide-signaling regulates human sperm functions required for fertilization. Molecular characterization of a phospholipase D generating anandamide and its congeners. Anandamide modulates human sperm motility: Rimonabant SR induces metabolism and acquisition of fertilizing ability in human sperm. Endocannabinoid system in frog and rodent testis: Endocannabinoid control of sperm motility: Characterization of the endocannabinoid system in boar spermatozoa and implications for sperm capacitation and acrosome reaction.
Endocannabinoids, sperm functions and energy metabolism. A new role of anandamide in human sperm: CB1 activity in male reproduction: Endocannabinoids as biomarkers of human reproduction. Function of cannabinoid receptors in the neuroendocrine regulation of hormone secretion. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Acute effects of smoking marijuana on hormones, subjective effects and performance in male human subjects.
Chronic effects of marihuana smoking on luteinizing hormone, follicle-stimulating hormone and prolactin levels in human males. Depression of plasma testosterone levels after chronic intensive marihuana use. N Engl J Med. Plasma testosterone levels before, during and after chronic marihuana smoking. Marihuana, chemistry, biochemistry and cellular effects. Hypothalamic-pituitary-adrenal axis activity and early onset of cannabis use.
Effects of deltatetrahydrocannabinol on the hypothalamic-pituitary control of luteinizing hormone and follicle-stimulating hormone secretion in adult male rats. Inhibition of gonadotropin by delta9-tetrahydrocannabinol: Immunocytochemical demonstration of CB1 cannabinoid receptors in the anterior lobe of the pituitary gland.
Serum testosterone concentrations in cannabis and opiate users. The effect of marihuana delta 9—tetrahydrocannabinol on the secretion of sex hormones in the mature male rhesus monkey. The effects of delta9-tetrahydrocannabinol and cannabidiol on the metabolism of gonadal steroids in the rat. Estrogenic effects of marijuana smoke condensate and cannabinoid compounds.
Effects of cannabinoids given orally and reduced appetite on the male rat reproductive system. Population-based case—control study of recreational drug use and testis cancer risk confirms an association between marijuana use and nonseminoma risk. Effects of cannabis on sex hormones and testicular enzymes of the rodent. Subchronic toxicity of cannabis leaves on male albino rats.
Testicular toxicity in cannabis extract treated mice: Testicular degeneration and necrosis induced by chronic administration of cannabis extract in dogs. Effects of chronic bhang cannabis administration on the reproductive system of male mice. Chakravarty I, Ghosh JJ. Influence of cannabis and deltatetrahydrocannabinol on the biochemistry of the male reproductive organs.
Pharmacokinetics of THC in brain and testis, male gametotoxicity and premature apoptosis of spermatozoa. Changes in human spermatozoa associated with high dose marihuana smoking. Modifiable and non-modifiable risk factors for poor sperm morphology. Energetic metabolism and human sperm motility: Effects of deltatetrahydrocannabinol, the primary psychoactive cannabinoid in marijuana, on human sperm function in vitro. Effects of cannabinoids on sperm morphology. Hall W, Degenhardt L.
Adverse health effects of non-medical cannabis use. Cannabinoids inhibit the respiration of human sperm.
Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility
The legal cannabis movement started in San Francisco in the. While decades of Cannabis prohibition will ferociously debate this claim, this system does indeed exist. It's known as the Endocannabinoid. Find out how the endocannabinoid system produces the body balance In order to consume medical cannabis in a responsible and efficient.