The CB2 Cannabinoid Receptor Helps Regulate Sperm Development, and Disrupting It Alters the Timeline | Research

The takeaway

Research in mice showed that the CB2 receptor plays a role in regulating the timing of spermatogenesis, with both overactivation and blocking of the receptor disrupting the normal sperm development cycle.

Men concerned about cannabis effects on fertility and reproductive biology researchers.

Both activating and blocking CB2 disrupted normal sperm development timing

What the researchers found

Researchers discovered that the CB2 cannabinoid receptor is involved in the normal process of sperm cell development (spermatogenesis) in mice.

Activating CB2 with a specific agonist (JWH133) mimicked the effects of retinoic acid on gene expression in spermatogonia (sperm precursor cells), upregulating genes needed for meiosis (c-Kit, Stra8, Prdm9) through epigenetic modifications to histone markers.

When young mice were given prolonged JWH133 treatment, they showed accelerated onset of spermatogenesis. Conversely, blocking CB2 with an antagonist delayed sperm cell maturation. Both over- and under-stimulation of CB2 disrupted the normal temporal progression of the spermatogenic cycle.

The findings suggest that proper CB2 signaling is important for maintaining the correct timing of sperm development, and cannabis use could potentially deregulate this process.

Why it matters

This is the first study to show that CB2 receptor signaling can regulate spermatogenesis through epigenetic mechanisms similar to retinoic acid. Since cannabis activates cannabinoid receptors, this provides a mechanism by which cannabis use could affect male fertility.

The numbers in context

JWH133 treatment upregulated H3K4me3 and downregulated H3K9me2 at meiotic gene promoters. Prolonged JWH133 accelerated spermatogenesis onset in immature mice. CB2 antagonist delayed germ cell differentiation.

How the study worked

In vitro: spermatogonia were treated with JWH133 (CB2 agonist) or retinoic acid, and epigenetic modifications and gene expression were measured. In vivo: immature mice received prolonged JWH133 or CB2 antagonist treatment, and spermatogenic progression was assessed.

What this study cannot tell us

This was a mouse study, and the specific timing and regulation of spermatogenesis differs between mice and humans. The CB2 agonist used (JWH133) is more selective than THC, which activates both CB1 and CB2. Whether THC from cannabis produces the same effects through CB2 was not directly tested.

How to read the evidence

This is an animal study combining in vitro epigenetic analysis with in vivo developmental assessment, providing preliminary mechanistic evidence.

When this study was published

Published in 2016. Research on cannabinoid effects on male fertility continues to develop.

The bigger picture

Male fertility concerns related to cannabis use have been debated for decades. This study identifies a specific receptor (CB2) and mechanism (epigenetic regulation of meiotic gene expression) through which cannabinoids could affect sperm development, adding molecular detail to the clinical observations.

Questions still open

Does chronic cannabis use in humans affect spermatogenesis through this CB2 mechanism? Are the effects reversible after cannabis cessation?

Common questions

Can cannabis affect sperm production?

This study found that the CB2 cannabinoid receptor helps regulate the timing of sperm development in mice, and disrupting CB2 signaling (either too much or too little) altered the spermatogenic cycle. Since THC activates cannabinoid receptors, chronic cannabis use could potentially affect this process, though human evidence remains limited.

Is this effect reversible?

The study did not directly test reversibility. However, since the effects involve the timing of an ongoing biological process (spermatogenesis takes about 74 days in humans), removal of the disrupting factor would theoretically allow the cycle to normalize over subsequent rounds of sperm production.

Read the original research

Type 2 cannabinoid receptor contributes to the physiological regulation of spermatogenesis.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 30(4), 1453-63

View on PubMed ↗Publisher’s paper ↗

Citation

Di Giacomo, Daniele; De Domenico, Emanuela; Sette, Claudio; Geremia, Raffaele; Grimaldi, Paola. (2016). Type 2 cannabinoid receptor contributes to the physiological regulation of spermatogenesis.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 30(4), 1453-63. https://doi.org/10.1096/fj.15-279034