Since heroin is a prodrug (i.e inactive) and must be metabolized into morphine by certain esterase enzymes in order to produce psychoactive effects, would some esterase inhibitors theoretically decrease the amount of stimulation provided by a given dose? And would this be a practical method of treating heroin addiction? Also wondering if the metabolization of prodrugs serves an additional purpose - such as decreasing toxicity - that would render any such treatment too dangerous.

  • $\begingroup$ Although opioid and opiate seem to be interchangeable, even with official sites, they are technically different, whereby opiates include heroin as it is extracted from the opium poppy, and opioids include oxycodone etc. as they are opiate-like synthetics created in a lab. $\endgroup$ Jan 17 at 10:45
  • $\begingroup$ @ChrisRogers thanks for clarifying! $\endgroup$
    – Rider
    Jan 17 at 17:41
  • $\begingroup$ "Esterase" is a huge category of enzymes, not a particular enzyme; this question seems to treat it as one. $\endgroup$
    – Bryan Krause
    Jan 17 at 21:18
  • $\begingroup$ @BryanKrause noted, thank you. Question has been updated to reflect this. $\endgroup$
    – Rider
    Jan 18 at 1:15

1 Answer 1


Heroin (also called diacetyl morphine) is synthesized from crude morphine via a process called acetylation. This process adds two acetyl groups to the morphine molecule.

Due to this addition of acetyl groups, heroin is relatively non-polar in comparison to morphine, meaning that it has higher fat solubility and more readily and completely passes through the blood-brain barrier. However, the addition of these acetyl groups renders heroin an inactive prodrug, which must be metabolized within the body in order to produce psychotropic effects.

Once ingested, heroin is metabolized sequentially: An enzyme called butyrylcholinesterase (BChE) breaks down heroin into its primary metabolite - the chemical 6-monoacetylmorphine (6-MAM) - by removing one of these acetyl groups via hydrolysis, then further transforms this primary metabolite into morphine by removing the other acetyl group.

Both morphine and 6-MAM are active drugs, so once this enzymatic deacetylation has occurred, the euphoric effects of ingesting heroin can be observed; specifically, an increase in dopamine in the striatum, where the brain's "reward system" is located. This increase in dopamine is a development and maintenance factor for heroin addiction.

Recent research has identified a number of chemicals that selectively inhibit the function of BChE and "significantly attenuate the toxicity and physiological effects of heroin" by binding to BChE molecules within the bloodstream, preventing them from degrading heroin into its active metabolites. This research is nascent, so whether these chemicals can be utilized as viable options to treat heroin addiction is yet to be determined. However, these findings are promising as some BChE inhibitors are already in use for treatment of Alzheimer's and other neurodegenerative diseases.

Lastly, passive immunization with a certain antibody has been shown to similarly blunt the effects of heroin in a dose-dependent manner. This treatment utilizes an abiogenic (i.e, synthesized in a laboratory) antibody called anti-6-AM that rapidly binds to 6-MAM molecules in the bloodstream, resulting in a molecular complex that is too large to cross the blood-brain barrier, effectively inhibiting the drug reward. Antibodies, although not enzymes themselves, are structurally and functionally related and can perform similar tasks.

Antibody treatment poses the advantage of specificity - because BChE aids in the metabolization of a number of substances beside heroin, inhibiting its function would make the use of certain unrelated drugs dangerous. Antibodies, however, bind only to one specific type of antigen, allowing the effect to be blocked without disrupting enzyme function.


European Molecular Biology Laboratory (n.d.) Butyrylcholinesterase Report Card ChEMBL https://www.ebi.ac.uk/chembl/target_report_card/CHEMBL1914/

Gottås, A., Boix, F., Øiestad, E. L., Vindenes, V., & Mørland, J. (2014). Role of 6-monoacetylmorphine in the acute release of striatal dopamine induced by intravenous heroin. International Journal of Neuropsychopharmacology, 17(9), 1357-1365. https://doi.org/10.1017/S1461145714000169

Hosztafi S. (2001). Heroin. II. Preparation, hydrolysis, stability, pharmacokinetics. Acta pharmaceutica Hungarica, 71(3), 373–383. https://pubmed.ncbi.nlm.nih.gov/11961908/

Nordberg, A., Ballard, C., Bullock, R., Darreh-Shori, T., & Somogyi, M. (2013). A review of butyrylcholinesterase as a therapeutic target in the treatment of Alzheimer's disease. The primary care companion for CNS disorders, 15(2), PCC.12r01412. https://doi.org/10.4088/PCC.12r01412

Oslo University Hospital (n.d.) The prodrug heroin: Studies of heroin´s active metabolites and immunotherapeutic approaches to block heroin effects. https://www.ous-research.no/home/neurobiology/Heroin%20-%20Injection%20to%20Treatment/21859

Perekopskiy, D., & Kiyatkin, E. A. (2019). 6-monoacetylmorphine (6-MAM), not morphine, is responsible for the rapid neural effects induced by intravenous heroin. ACS chemical neuroscience, 10(8), 3409-3414. https://doi.org/10.1021/acschemneuro.9b00305

Williams, A., Zhou, S., & Zhan, C. G. (2019). Discovery of potent and selective butyrylcholinesterase inhibitors through the use of pharmacophore-based screening. Bioorganic & medicinal chemistry letters, 29(24), 126754. https://doi.org/10.1016/j.bmcl.2019.126754


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