By Genester Wilson-King, MD FACOG
I recently participated as a speaker at the Society of Cannabis Clinicians’ inaugural conference on cannabis. I was asked a question from the audience about THC, testosterone, and opioid suppression. I wasn’t satisfied with my answer so I wanted to write a more well-rounded response.
Opioid addiction suppresses testosterone production in some men. The healthcare professional who asked the question was using cannabis to treat a patient who was dealing with opioid addiction. Testosterone production is slow to resume after opioid addiction. It is very difficult for men to live with low testosterone, which is referred to as hypogonadism. The clinician gave testosterone (low dose) to the patient to alleviate his symptoms.
The impacts of opioids on the endocrine system are well known. A 2015 review study stated that “opioids appear to affect each of the pituitary hormone pathways” and “the most commonly reported and substantial effect was hypogonadism in both sexes.” Therefore, opioid suppression of testosterone is well established. This suppression persists for some time (months). The researchers concluded, “More research is needed to determine which opioids are more likely to cause endocrine dysfunction and which patients need to be screened and treated. Also unknown is the length of time to development of hormonal changes after starting opioid therapy and if cessation of opioid therapy can result in normalization of hormones.”
The doctor who posed the question made a good point. He was seeking help in counseling patients in this situation. Patients want to know how long they need to endure low testosterone levels. The symptoms include decreased libido, erectile dysfunction, loss of muscle mass, fatigue, depression, and more. I don’t blame this physician for wanting to help these patients. Kudos to him! The doctor uses cannabis to manage patients with opioid addiction to help them discontinue or decrease their dose of opioids.
Does THC suppress testosterone and how can patients be assisted through the period of hypogonadism?
A 2023 study aimed to determine whether THC (Δ9-tetrahydrocannabinol) and CBD (cannabidiol), the two major and best-studied cannabinoids present in cannabis, can directly impact the steroidogenic function and germ cell lineage of the human adult testicles. Testicles were exposed to CBD, THC, CBD/THC (1:1) for either 48 hours continuously or nine days.
There were no adverse effects ascertained that impact testosterone production, the overall tissue morphology, and the number of proliferating cells, or mRNA expression of genes encoding proteins involved in germ cell differentiation, meiosis, or Sertoli and Leydig functions after 24 hours of exposure.
Researchers found that exposure to cannabis-derived cannabinoids THC and CBD did not have immediate direct effects on testicular testosterone production and germ cells ex vivo. Further studies are needed to examine the effects of chronic and indirect exposure.
The Role of the ECS
The endocannabinoid system is a key modulator for reproductive functions in males and females. Most, if not all, molecular components of the ECS are present in the male reproductive system. Endocannabinoid signals are thought to regulate the homeostasis of the hypo-thalamus-pituitary-gonadal (HPG) axis and “critical testicular physiology, including spermatogenesis and the functions of Leydig and Sertoli cells” according to recent research.
The Lim paper breaks this down in detail. The reproductive systems of mammals possess all the necessary proteins to both create and break down endocannabinoid molecules. The endocannabinoid (ECB) system plays a role in regulating the HPG axis through the activation of the cannabinoid CB1 receptor signaling at multiple stages:
- ECBs inhibit the release of GnRH (Gonadotropin-Releasing Hormone) in the hypothalamus.
- The reduction in GnRH levels, in turn, leads to a decrease in the release of LH (Luteinizing Hormone) and FSH (Follicle-Stimulating Hormone) in the adenohypophysis, where the CB1 receptor may have an influence.
- ECBs also directly affect Leydig and Sertoli cells, leading to a reduction in testosterone release and influencing spermatogenesis.
Cannabis’ impact on male fertility is related to semen parameters and does not affect testosterone levels. Preclinical studies show adverse effects on hormone levels that does not translate to the human experience. Cannabis is reported to reduce sperm count and concentration, induce abnormalities in sperm morphology, reduce sperm motility and viability, and inhibit capacitation (the process that enables the sperm to penetrate the oocyte for fertilization). However, subsequent studies have shown that these changes apparently don’t affect fertility. Eisenberg and colleagues did a retrospective study in 2018 based on the findings from the National Survey of Family Growth. The results showed no statistically significant impact of cannabis use on the time to conceive a baby. This illustrates that study findings do not always exhibit clinical impact. It does not mean the study findings are incorrect, it just means further study is needed.
A 2008 study was done based on the premise that female rats are more sensitive than males to many behavioral effects of cannabinoids, as evidenced by preclinical studies. The purpose of their study was to determine if “sex differences in the antinociceptive and motoric effects of Δ9 -tetrahydrocannabinol (THC) are due to activational effects of gonadal steroid hormones.”
They took male and female gonadectomized rats and created arms of the study:
- Gonadectomized rats with Hormone Therapy (HT)
- Gonadectomized rats and no HT
- During vaginal estrus
- Diestrus
THC was given to each of the gonadectomized groups with HT or no HT. THC’s effects were also compared between gonadally intact females tested during vaginal estrus vs. diestrus. The results indicated that any adverse effect (e.g. locomotor suppression, antinociception) was less significant in the HT-treated groups (estradiol and testosterone). Perhaps the hormones provided a protective effect?
It seems THC had an impact on the behavior in the estrous group as opposed to the diestrous group. The presence or absence of hormones is influential in one way or the other. I haven’t seen a study that has shown a direct effect of THC suppressing testosterone.
The above studies are a few papers looking at THC and its influence on testosterone levels. It is not meant to be a thorough search. The conference attendee had a second part of their question I wanted to address.
How does someone treat testosterone suppression while weaning off opioids and initiating other therapies (including cannabis)?
Treating hypogonadism is best managed based on the patient’s age. That’s because age determines who will or won’t respond well to a certain treatment method. People assigned male at birth under the age of 40 can increase their testosterone levels by stimulating the actions of the Sertoli and Leydig cells. This can be done using Clomid or HCG (if you can find an affordable source).
Patients 50 and older are probably going to end up on testosterone if its production does not resume after an appropriate length of time. Their Sertoli and Leydig cells are not as responsive to exogenous stimulators as people 40 and under are. Between 40 and 50 years of age, try Clomid or HCG and assess its effectiveness. If it is ineffective, testosterone can always be supplemented.
I understand the position healthcare professionals find themselves in when faced with a patient who is tired of feeling unwell and looks to them for solutions. My best advice is to be open and transparent about the treatment options and let the patient make an informed decision.
To the optimal well-being of all!
References
- · Demarest SP, Gill RS, Adler RA. Opioid endocrinopathy. Endocr Pract. 2015 Feb;21(2):190-8. doi: 10.4158/EP14339.RA. Erratum in: Endocr Pract. 2015 May;21(5):559. PMID: 25536970.
- · da Silva, J., Dochez-Arnault, J., Desdoits-Lethimonier, C., Dejucq-Rainsford, N., & Gely-Pernot, A. (2023). The Acute Exposure of Human Adult Testis Tissue to Cannabinoids THC and CBD Does Not Impact Testosterone Production Nor Germ Cell Lineage. The World Journal of Men’s Health
- · Lim, J., Squire, E., & Jung, K. M. (2023). Phytocannabinoids, the Endocannabinoid System and Male Reproduction. The World Journal of Men’s Health, 41(1), 1.
- · Kasman AM, Thoma ME, McLain AC, Eisenberg ML. Association between use of marijuana and time to pregnancy in men and women: findings from the National Survey of Family Growth. Fertil Steril. 2018 May;109(5):866-871. doi: 10.1016/j.fertnstert.2018.01.015. Epub 2018 Mar 16. PMID: 29555335.
- · Craft, R. M., & Leitl, M. D. (2008). Gonadal hormone modulation of the behavioral effects of Δ9-tetrahydrocannabinol in male and female rats. European journal of pharmacology, 578(1), 37-42.