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Enclomiphene Citrate and Cannabis: Full Interaction Profile

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At a glance

  • Drug / enclomiphene citrate, an oral SERM with no FDA-approved product [3]
  • Approved product label / none exists [3]
  • Possible overlap / CB1 receptors in the hypothalamus and pituitary influence gonadotropin release, while enclomiphene blocks estrogen receptors in the pituitary [1][3]
  • Enzyme data / CBD potentially inhibits CYP3A4/5/7; THC and CBD inhibit CYP2D6 and CYP2C19 [2]
  • Pharmacokinetics / peak 2 to 3 hours, half-life about 10 hours, mainly fecal excretion [3]
  • Most frequent side effects / headache, hot flushes, nausea, muscle spasm [4]

Is there a documented interaction?

Enclomiphene has no FDA-approved product, and FDA's June 8, 2022 advisory-committee materials state that no FDA-approved drugs contain enclomiphene as an active ingredient [3]. With no approved label, there is no label interaction section.

Clomiphene citrate is a mixture of enclomiphene and zuclomiphene. It is approved for ovulatory dysfunction in women and is used off-label in men. It is related to enclomiphene but is not the same drug, and its label does not cover enclomiphene [3][5].

What enclomiphene does, and where cannabis could meet it

Enclomiphene blocks estrogen receptors in the pituitary. Estrogen normally suppresses the pituitary-testis axis, so blocking those receptors makes the pituitary release more LH and FSH, which tells the testes to make more testosterone and keep making sperm [3]. In two phase 3 studies against AndroGel 1.62%, LH and FSH rose with enclomiphene and fell with testosterone gel [6].

Oral enclomiphene peaks 2 to 3 hours after a dose and has a half-life of about 10 hours. Its main metabolite is 4-hydroxy enclomiphene, and it is excreted mainly in feces [3]. Doses studied were 6.25, 12.5 and 25 mg once daily in a 6-week phase 2 trial [7], and 12.5 mg daily, up-titrated to 25 mg at week 6 if morning testosterone stayed below 300 ng/dL, in the phase 3 protocols [8]. No dose is FDA-approved [3].

Cannabinoid CB1 receptors are expressed in the hypothalamus and the pituitary gland, and their activation modulates the hypothalamic-peripheral endocrine axes, including gonadotropin release [1]. That is a possible overlap in hormone regulation, not a measured interaction.

What the cannabinoid enzyme data show

Qian and colleagues reviewed laboratory and clinical data on cannabis-drug interactions through March 2019 [2]. CBD potentially inhibits CYP3A4/5/7, and THC and CBD inhibit several other enzymes, including CYP2D6 and CYP2C19, in laboratory analyses [2]. Clinical studies suggest CBD inhibits CYP2C19 and that various cannabis products inhibit CYP2C9 [2]. The review did not identify clinical studies suggesting cannabinoids influence drug transporters [2]. These findings are about cannabinoids in general, and whether they matter for enclomiphene has not been tested.

Side effects documented with enclomiphene

The most frequent side effects in phase 3 and EMA data were headache, hot flushes, nausea and muscle spasm. Reasons for stopping included blurred vision, muscle spasm, headache and aggression [4]. FDA listed cardiac and thromboembolic events, raised estradiol, raised PSA, raised hematocrit, and no long-term safety data [3].

Frequently asked questions

Can I use cannabis while taking enclomiphene?
Enclomiphene has no approved label, so there is no label interaction section [3]. There are two theoretical points of contact: cannabinoid CB1 receptors in the hypothalamus and pituitary, which influence gonadotropin release [1], and CBD's potential inhibition of CYP3A4/5/7 seen in laboratory work [2]. Neither has been shown to affect enclomiphene.
Does CBD interact with enclomiphene?
CBD potentially inhibits CYP3A4/5/7, and THC and CBD inhibit CYP2D6 and CYP2C19, in a systematic review of cannabis-drug interactions [2]. That review did not study enclomiphene, so any effect on it is unknown.
Is enclomiphene FDA-approved?
No. FDA issued a complete response letter to the sponsor in 2015, and EMA refused marketing authorisation in January 2018 [3][9]. For compounding, FDA lists enclomiphene citrate as a bulk substance under evaluation, which is not an approval and does not establish safety or effectiveness [10].
What side effects were reported with enclomiphene?
Headache, hot flushes, nausea and muscle spasm were most frequent, with blurred vision, muscle spasm, headache and aggression among reasons for stopping [4]. FDA also listed cardiac and thromboembolic events, raised estradiol, PSA and hematocrit, and a lack of long-term safety data [3].

References

  1. Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006;27(1):73-100. The emerging role of the endocannabinoid system in endocrine regulation and energy balance
  2. Qian Y, Gurley BJ, Markowitz JS. The Potential for Pharmacokinetic Interactions Between Cannabis Products and Conventional Medications. J Clin Psychopharmacol. 2019;39(5):462-471. The Potential for Pharmacokinetic Interactions Between Cannabis Products and Conventional Medications
  3. U.S. Food and Drug Administration. FDA advisory committee presentation on enclomiphene citrate, June 8, 2022. FDA advisory committee presentation on enclomiphene citrate
  4. ClinicalTrials.gov. Study NCT01739595 (ZA-302), enclomiphene citrate in men with secondary hypogonadism. ClinicalTrials.gov NCT01739595
  5. U.S. National Library of Medicine, DailyMed. Clomid (clomiphene citrate) tablets, Cosette prescribing information. Clomid (clomiphene citrate) tablets, Cosette label
  6. Kim ED, McCullough A, Kaminetsky J. Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement. BJU Int. 2016;117(4):677-85. Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement
  7. Wiehle R, Cunningham GR, Pitteloud N, Wike J, Hsu K, Fontenot GK, et al. Testosterone Restoration by Enclomiphene Citrate in Men with Secondary Hypogonadism: Pharmacodynamics and Pharmacokinetics. BJU Int. 2013;112(8):1188-200. Testosterone Restoration by Enclomiphene Citrate in Men with Secondary Hypogonadism: Pharmacodynamics and Pharmacokinetics
  8. ClinicalTrials.gov. Study NCT01532414 (ZA-301), enclomiphene citrate in overweight men with secondary hypogonadism. ClinicalTrials.gov NCT01532414
  9. European Medicines Agency. Questions and answers on the refusal of marketing authorisation for EnCyzix (enclomifene). EMA questions and answers on EnCyzix refusal
  10. U.S. Food and Drug Administration. Bulk drug substances nominated for compounding: category list including enclomiphene citrate. FDA bulk drug substances category list
Evidence overview for Enclomiphene Citrate and Cannabis: Full Interaction Profile