Metyrapone/oxazepam
| Combination of | |
|---|---|
| Metyrapone | 11β-Hydroxylase inhibitor |
| Oxazepam | Benzodiazepine (GABAA receptor positive allosteric modulator |
| Clinical data | |
| Other names | EMB-001; EMB001; EMB-001C; EMB001C |
| Routes of administration | Oral[1] |
Metyrapone/oxazepam (developmental code name EMB-001) is a combination of metyrapone, an 11β-hydroxylase inhibitor (and cortisol synthesis inhibitor), and oxazepam, a benzodiazepine and GABAA receptor positive allosteric modulator, which is under development for the treatment of smoking withdrawal, cocaine-related disorders, eating disorders, gambling, post-traumatic stress disorder (PTSD), and other substance-related disorders.[1][2][3][4][5] It is taken orally.[1]
The drug aims to attenuate the enhancing effects of stress on drug-seeking behavior.[4][2][5] It was originally theorized to work by reducing corticosteroid levels (corticosterone in rodents and cortisol in humans), but it might actually work by increasing brain levels of certain neurosteroids, most notably the corticosterone-derived tetrahydrodeoxycorticosterone (THDOC).[5]
EMB-001 is under development by Embera NeuroTherapeutics.[1] As of July 2024, it is in phase 2/3 clinical trials for smoking withdrawal, phase 2 trials for cocaine-related disorders, and the preclinical research stage of development for all other indications.[1]
See also
References
- 1 2 3 4 5 "Metyrapone/oxazepam". AdisInsight. 25 July 2024. Retrieved 26 January 2026.
- 1 2 Young EJ, Radnai L, Prikhodko V, Miller CA (August 2024). "Novel therapeutics in development for the treatment of stimulant-use disorder". Current Opinion in Neurobiology. 87 102898. doi:10.1016/j.conb.2024.102898. PMID 39096558.
When reversed through upregulation or GABA agonism, drug-induced hyperlocomotion and drug-seeking behavior are attenuated in preclinical studies [45,46]. Embera NeuroTherapeutics has found that the combination of two FDA-approved medications targeting the HPA axis and GABA, the cortisol synthesis inhibitor metyrapone and the benzodiazepine oxazepam, respectively, reduced cocaine but not food self-administration in rats [47]. Interestingly, a similar reduction was not seen with administration of metyrapone or oxazepam alone. Embera has formulated this combination in EMB-001 and showed in a Phase 1 study that it reduced cocaine intake and craving over a six-week period, as compared to placebo [48]. The two targets are both potentially problematic as metyrapone can induce adrenal insufficiency, and benzodiazepines, such as oxazepam, have abuse potential. However, efficacious doses of each, when combined, may be low enough to be tolerated. Embera states it is also pursuing disorders associated with methamphetamine, cannabis, tobacco, gambling, eating, and post-traumatic stress with EMB-001. Unfortunately, it is difficult to determine how active the EMB-001 program is, given that the results of the cocaine-use-disorder Phase 1 trial were published in 2012 without publicly available information on follow-up trials to date. However, Embera's website indicates they received funding for a Phase II trial in 2019.
- ↑ Butelman ER, Kreek MJ (December 2017). "Medications for substance use disorders (SUD): emerging approaches". Expert Opinion on Emerging Drugs. 22 (4): 301–315. doi:10.1080/14728214.2017.1395855. PMC 6276123. PMID 29057665.
- 1 2 Harmey D, Griffin PR, Kenny PJ (November 2012). "Development of novel pharmacotherapeutics for tobacco dependence: progress and future directions". Nicotine & Tobacco Research. 14 (11): 1300–1318. doi:10.1093/ntr/nts201. PMC 3611986. PMID 23024249.
Table 3 highlights examples of FDA-approved medications for other indications that are undergoing clinical assessment as potential smoking-cessation agents. As can be seen, repurposing strategies are now being widely adopted. For example, EMB-001 is in development by Embera Neuro Therapeutics Inc. for smoking cessation. EMB-001 is a combination of two FDA-approved medications: the benzodiazepine oxazepam and the cortisol-synthesis inhibitor metyrapone. This combination of drugs was recently shown to decrease intravenous nicotine self-administration in rats in a manner similar to varenicline (Goeders et al., 2012), with this drug combination hypothesized to act by attenuating the known stimulatory effects of stress on nicotine consumption (Goeders et al., 2012).
- 1 2 3 Goeders NE, Guerin GF, Schmoutz CD (2014). "The combination of metyrapone and oxazepam for the treatment of cocaine and other drug addictions". Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Advances in Pharmacology. Vol. 69. pp. 419–479. doi:10.1016/B978-0-12-420118-7.00011-1. ISBN 978-0-12-420118-7. PMID 24484984.