Phytocannabinoids and Male Fertility: Implications of Cannabis sativa and the Endocannabinoid System in Reproductive Regulation

Abstract

<i>Cannabis sativa</i>, a species within the Cannabaceae family, produces a diverse range of phytochemicals, notably cannabinoids and terpenoids, with significant physiological and pharmacological relevance. Among its phytochemicals, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most studied for their psychoactive and medicinal properties. However, emerging evidence indicates that chronic or excessive exposure to these phytocannabinoids may adversely affect male fertility. This review synthesizes current knowledge on the influence of C. sativa and its constituents on the male reproductive system, with emphasis on spermatogenesis, sperm function, hormonal regulation, and the role of the endocannabinoid system (ECS). Experimental and clinical studies demonstrate that cannabinoids interact with CB1 and CB2 receptors expressed in the testes, epididymis, and spermatozoa, thereby modulating testosterone synthesis, sperm motility, morphology, and capacitation. THC, in particular, disrupts the hypothalamic-pituitary-gonadal (HPG) axis, leading to reduced luteinizing hormone and testosterone levels, impaired mitochondrial activity, and abnormal sperm morphology. Although CBD exhibits anti-inflammatory and antioxidant properties, its long-term impact on reproductive function remains uncertain. The review further highlights the complex interplay between exogenous cannabinoids and the endogenous ECS in maintaining reproductive homeostasis. Understanding these molecular mechanisms is critical for balancing the therapeutic potential of Cannabis-derived products with their reproductive risks. This knowledge could inform safe medicinal applications and contribute to the development of targeted cannabinoid-based therapies for male infertility.