Role of the endocannabinoid system (ECS) and effect of plant cannabinoids in reproduction and development

Summary

Testicles and spermatogenesis
Both animal and human studies show the presence of the ECS in male gonads (CB1, CB2, GPR55, TRPV1, DAGL, NAPE-PLD, MAGL, FAAH1, FAAH2, ABDH2, AEA, 2AG, OEA and PEA) and suggest a regulatory role in testicular (patho-)physiology and spermatogenesis. Animal studies suggest a gonadotoxic/spermatoxic effect of plant cannabinoids such as THC and CBD but it should be noted that the used doses are very high for human standards. In humans, THC may have a small negative effect on sperm motility. On the other hand, among sub-fertile men, THC/cannabis seems to actually increase sperm count. Also, according to the WHO, men (with a history of) smoking cannabis are actually less likely to be infertile.

Ovaries and ovulation
Both animal and human studies show the presence of the ECS in female gonads (CB1, CB2, GPR55, NAPE-PLD, MAGL, FAAH and AEA) and suggests a regulatory role in oocyte maturation and ovulation. Animal studies suggest a negative effect of THC on successful full-term pregnancies but it should be noted that the used doses are very high for human standards. In humans, THC may actually accelerate oocyte maturation and prove useful in some aspects of in vitro fertilization. 

Sex drive
In animal studies AEA, 2AG and CB1 were found to be involved in sexual motivation. In humans 2AG is involved in sexual arousal. In animals the effects of cannabis/THC on female receptiveness is ambiguous but human studies suggest cannabis may improve sexual satisfaction in women.

Pregnancy and placenta
Both animal and human studies show a strong influence of the ECS in placental formation and physiology (CB1, CB2, TRPV1, MAGL, FAAH, NAPE-PLD, AEA, 2AG and NADA). Animal studies and studies with human placental cell lines suggest a negative effect of THC on placental development but it should be noted that the used doses are very high for human standards.

Fetal development
Animal studies suggest a strong influence of the ECS on fetal development (CB1, CB2, TRPV1, MAGL, FAAH, 2AG, AEA and omega 3 fatty acids). Various animal studies suggest a negative effect of both THC and CBD on fetal development but it should be noted that the used doses are very high for human standards and the animal models are quite far removed from the human situation. Interestingly, at sub-micromolar concentrations, THC and CBD may actually be beneficial for fetal development. Studies with human-derived cultured neurons suggest continuous exposure to THC may negatively affect brain development.

Lactation
Human milk contains several endocannabinoids such as AEA, PEA, OEA, DHEA, 2AG, 2OG and 2PG and others. THC can be detected in breast milk up to 6 days after last reported cannabis use.

Neonatal development
Animal studies show that the ECS is involved in normal neonatal development (CB1, CB2, DAGL, MAGL, 2AG) and that THC may negatively affect neonatal brain development. It should be noted that the doses of THC used are very high for human standards.

Adolescence
Animal studies show that the ECS is active during adolescent development and that THC consumption during adolescence (but not in adulthood) can induce long-term behavioral changes reminiscent of schizophrenia or depression although it should be noted that the doses of THC used in animal research are very high for human standards. Interestingly, with the same dose of THC, adolescent rats can have ±50% higher plasma and adipose tissue concentrations than adults but ±50% lower brain concentrations. Also, some adolescent THC effects are gender-specific. In humans, adolescents report feeling less stoned or anxious than adults and show less cognitive impairment than adults after consuming cannabis. Also, where adults show satiation after cannabis consumption, adolescents tend to want to consume more.

Adult brain
Animal studies show the involvement of the ECS in adult neurogenesis (CB1). CBD did not impair learning but increased adult neurogenesis, whereas THC reduced learning without affecting adult neurogenesis. In humans, adult cannabis use does not seem to affect hippocampal neuroanatomy. 

Transgenerational effects
In animals there is some evidence that THC use before pregnancy may affect the behavior of adult offspring, suggesting epigenetic effects of THC may exist.

Epidemiological studies
Several cohort studies suggest that cannabis exposure during pregnancy can negatively impact birth weight or increase the chance of requiring neonatal intensive care treatment. However, other cohort studies contradict these findings and find that potential effects of cannabis use during pregnancy are clinically unimportant.

Overall, a picture emerges that the ECS is involved in all major stages of reproduction and development and that manipulation of the ECS with plant cannabinoids/cannabis is potentially disruptive. However, most animal studies use very high concentrations of cannabis/THC or other cannabinoids for human standards and consequently overstress the disruptive effect of cannabinoids on development. In line with this, human studies still indicate cannabis use as a risk factor in reproduction and development but also that this risk is relatively light in comparison with the use of alcohol or tobacco. 

Apart from the potential effect of cannabinoids on reproduction and development it is good to realize that pesticides used during cannabis cultivation may also have a negative effect on reproduction (Leung et al., 2019).

Literature:
Leung, M.C.K., Silva, M.H., Palumbo, A.J., Lohstroh, P.N., Koshlukova, S.E., and DuTeaux, S.B. (2019). Adverse outcome pathway of developmental neurotoxicity resulting from prenatal exposures to cannabis contaminated with organophosphate pesticide residues. Reprod. Toxicol. Elmsford N.