“New and emerging research from the past several years reveals that tamoxifen, and other Selective Estrogen Receptor Modulators, or SERMS, bind not only to estrogen receptors. They also bind with high affinity to one or both cannabinoid receptors, for CB1 and CB2,” said Wohlschlagel. “Tamoxifen apparently binds to both receptors, as what is called an ‘inverse agonist.’ The possible effects caused by that binding are just beginning to be explored.’”
Tamoxifen, Hormones, Receptors, and the Immune Response
Small doses of cannabis medicines used are much less likely to cause any significant drug interactions, but some patients are using doses much higher than historically common. Because CBD-rich medicines will not cause as much psychoactivity, people can easily use large doses (75 mg CBD per day or more) without feeling any significant side effects. While large doses may be considered generally safe, the potential for side effects and potential interactions with other therapies is increased at these levels.
Tamoxifen and SERMS
Because large doses of cannabinoids like CBD and THC can inhibit metabolism or processing of substances by the liver, reviewing this potential with your healthcare team is important.
Blasco-Benito et al. applied a combination of THC or cannabis drug preparation with tamoxifen to ER positiveT47D cell cultures. Submaximal concentrations of tamoxifen in combination with pure THC and cannabis drug preparation decreased the viability in an additive manner. The additive effects observed between tamoxifen and cannabinoids in cell cultures was not evident in vivo . There are no clinical studies evaluating the effect of cannabinoids on treatment with tamoxifen.
Interactions of cannabinoids with hypothalamic-pituitary-gonadal axis hormones are well documented in animal models. There is evidence that the acute administration of THC lowers serum luteinizing hormone (LH) and gonadotropin-releasing hormone (GnRH) secretion in ovariectomized female and intact male rats [28,29,30]. Lower concentrations of GnRH result in lower circulating estrogen levels. Anandamide produces similar results in both female and male rats . Cannabinoids could modulate the release of GnRH through their effect on hypothalamic GnRH-releasing neurons that have a high density of CB1 and low density of CB2 . Fatty acid amide hydrolase (FAAH) is responsible for anandamide degradation  and estrogens decrease FAAH activity in the mouse uterus . Two studies found a positive correlation between peak plasma anandamide with peak plasma 17β-estradiol, LH, and follicle-stimulating hormone (FSH) levels at ovulation in healthy premenopausal women [35,36]. A possible mechanism responsible for this phenomenon is that increased levels of estrogens at ovulation inhibit FAAH activity and consequently increase endocannabinoid plasma levels .
The text was edited by Kristina Alice Waller.
8.2. Gonadotropin-Releasing Hormone Agonists
In addition to its action on estrogen receptors (ER), tamoxifen (TAM) acts as an inverse agonist at cannabinoid receptors 1 and 2 (CB1 and CB2). The clinical significance of inverse agonist action on cannabinoid receptors is unknown.
Cannabinoid receptor 2 (CB2) crystal structure and mode of action.
6. Cannabinoids and Hormone Receptor-Positive Breast Cancer (Preclinical Evidence)
Cannabinoid receptor 1 (CB1) crystal structure and mode of action.
AIs lower plasma estrogen concentration through the inhibition of the aromatase, which is an enzyme that converts androgens to estrogens in the peripheral tissues. As estrogens are predominantly produced in peripheral tissues of the body in postmenopausal women, AIs are the standard option in the treatment of postmenopausal women with HR+ BC in all settings [58,59]. Takeda et al. reported the modulation of THC-induced BC cell growth by cyclooxygenase and aromatase in the ER positive MCF-7 BC cell line. 17β-Estradiol produced by aromatase interferes with THC-induced cell growth, which is more prominent in low 17β-estradiol environments. THC-mediated BC cell growth is stimulated by co-treatment with AIs. It has therefore been suggested that THC could act as an exacerbating agent when co-treated with estrogen-lowering drugs . There are no clinical studies evaluating the effect of cannabinoids on treatment with AI.