Impact on male fertility
Marijuana, consisting of dried leaves and flowers from the marijuana plant (Cannabis
sativa), is smoked to release the psychoactive cannabinoid compound called delta-9-
tetrahydrocannabinol (THC). In the 1990s, it was found that cannabinoid compounds are also naturally synthesized by the human body from fatty acid derivatives, termed
endogenous cannabinoids or endocannabinoids (Devane et al, 1992) (Felder et al, 1992).
The two most well-studied endocannabinoids are arachidonoylethanolamine (AEA), also
known as anandamide, and 2-arachidonoylglycerol (2-AG). Endocannabinoids may
modulate several pathophysiologic processes including neuropathic pain, mood disorders,
movement disorders such as Parkinson's and Huntington's disease, disease processes such
as cancer, atherosclerosis, and obesity, as well as reproductive functions (Pacher et al,
2006) (Schuel et al, 2002). Endocannabinoid receptors are found on numerous cells
including neurons, immune cells, vascular endothelial and muscle cells, (Howlett et al,
2002) as well as on human testes (Schuel et al, 2002) (Munro et al, 1993), and the head
and middle pieces of sperm (Rossato et al, 2005).
Human studies consistently conclude that THC negatively affects male reproductive
physiology (Table 2). There are observed disruptions in the hypothalamic-pituitarytesticular axis with marijuana users having decreased levels of luteinizing hormone (LH)
(Vescovi et al, 1992) (Cone et al, 1986) . When investigating testosterone levels, chronic
and exclusive marijuana smokers were found to have significantly lower plasma
testosterone compared to age matched controls who had never used marijuana and the
reduction was dose dependent (Kolodny et al, 1974). Over one-third of the chronic
exclusive marijuana smokers studied by Kolodny et al had oligospermia (Kolodny et al,
1974) likely resulting from decreased LH levels which reduce testosterone secretion, and
in turn reduces spermatogenesis. Activation of the endocannabinoid receptors on sperm
by either anandamide or THC has also been reported to reduce sperm motility in a dose
dependent manner and inhibit the capacitation-induced acrosomal reaction (Schuel et al, 2002) (Rossato et al, 2005) (Whan et al, 2006). However, Schuel et al (2002) found a
biphasic effect at different concentrations of anandamide. Sperm were inhibited at higher
levels but hyperactivated at lower levels of anandamide. Reductions in sperm motility
may be due to an anandamide or THC-induced inhibition of sperm mitochondrial activity
which initiates sperm apoptosis (Badawy et al, 2009) (Rossato et al, 2005). Interestingly,
when THC was added to neat sperm, mitochondrial respiration was less affected
suggesting that cells which secrete components of seminal fluid may also secrete
unidentified factors that protect against THC’s inhibitory actions toward sperm (Badawy
et al, 2009).
In addition, normal operation of the endocannabinoid signaling systems requires rapid
release and rapid removal of endocannabinoids (Piomelli et al, 1998). THC has a long
half-life ranging from 24-36 hours as it is lipid soluble which allows it to enter fatty
tissue that then acts as a reservoir to slowly release THC back into the blood. Studies
with rats have shown that after THC administration with approximately 0.06% and 0.02%
of the administered dose concentrates in brain and testis, respectively (Nahas et al, 2002).
The presence of such doses of THC in the testis may over stimulate endocannabinoid
receptors and contribute to altered sperm motility and male infertility.