<p>Heroin (also called <em>diacetyl morphine</em>) is synthesized from crude morphine via a process called acetylation. This process adds two acetyl groups to the morphine molecule.</p>
<p>Due to this addition of acetyl groups, <a href="https://pubmed.ncbi.nlm.nih.gov/11961908/" rel="nofollow noreferrer">heroin is relatively non-polar</a> 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.</p>
<p>Once ingested, heroin <a href="https://pubs.acs.org/doi/10.1021/acschemneuro.9b00305" rel="nofollow noreferrer">is metabolized sequentially</a>: An enzyme called <a href="https://www.ebi.ac.uk/chembl/target_report_card/CHEMBL1914/" rel="nofollow noreferrer"><em>butyrylcholinesterase</em></a> (BChE)  breaks down heroin into its primary metabolite - the chemical <em>6-monoacetylmorphine</em> (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.</p>
<p>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 <a href="https://academic.oup.com/ijnp/article/17/9/1357/2356845" rel="nofollow noreferrer">increase in dopamine in the striatum</a>, where the brain's &quot;reward system&quot; is located. This increase in dopamine is a development and maintenance factor for heroin addiction.</p>
<p>Recent research has identified a number of chemicals that selectively inhibit the function of BChE and <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953623/" rel="nofollow noreferrer">&quot;significantly attenuate the toxicity and physiological effects of heroin&quot;</a> 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 <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733526/" rel="nofollow noreferrer">some BChE inhibitors are already in use for treatment of Alzheimer's and other neurodegenerative diseases</a>.</p>
<p>Lastly, <a href="https://www.ous-research.no/home/neurobiology/Heroin%20-%20Injection%20to%20Treatment/21859" rel="nofollow noreferrer">passive immunization with a certain antibody has been shown to similarly blunt the effects of heroin</a> in a dose-dependent manner. This treatment utilizes an abiogenic (i.e, synthesized in a laboratory) antibody called <em>anti-6-AM</em> 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.</p>
<p>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.</p>
<h2>References</h2>
<p>European Molecular Biology Laboratory (n.d.) Butyrylcholinesterase Report Card <em>ChEMBL</em> <a href="https://www.ebi.ac.uk/chembl/target_report_card/CHEMBL1914/" rel="nofollow noreferrer">https://www.ebi.ac.uk/chembl/target_report_card/CHEMBL1914/</a></p>
<p>Gottås, A., Boix, F., Øiestad, E. L., Vindenes, V., &amp; Mørland, J. (2014). Role of 6-monoacetylmorphine in the acute release of striatal dopamine induced by intravenous heroin. <em>International Journal of Neuropsychopharmacology, 17</em>(9), 1357-1365. <a href="https://doi.org/10.1017/S1461145714000169" rel="nofollow noreferrer">https://doi.org/10.1017/S1461145714000169</a></p>
<p>Hosztafi S. (2001). Heroin. II. Preparation, hydrolysis, stability, pharmacokinetics. <em>Acta pharmaceutica Hungarica, 71</em>(3), 373–383. <a href="https://pubmed.ncbi.nlm.nih.gov/11961908/" rel="nofollow noreferrer">https://pubmed.ncbi.nlm.nih.gov/11961908/</a></p>
<p>Nordberg, A., Ballard, C., Bullock, R., Darreh-Shori, T., &amp; Somogyi, M. (2013). A review of butyrylcholinesterase as a therapeutic target in the treatment of Alzheimer's disease. <em>The primary care companion for CNS disorders, 15</em>(2), PCC.12r01412. <a href="https://doi.org/10.4088/PCC.12r01412" rel="nofollow noreferrer">https://doi.org/10.4088/PCC.12r01412</a></p>
<p>Oslo University Hospital (n.d.) <em>The prodrug heroin: Studies of heroin´s active metabolites and immunotherapeutic approaches to block heroin effects</em>. <a href="https://www.ous-research.no/home/neurobiology/Heroin%20-%20Injection%20to%20Treatment/21859" rel="nofollow noreferrer">https://www.ous-research.no/home/neurobiology/Heroin%20-%20Injection%20to%20Treatment/21859</a></p>
<p>Perekopskiy, D., &amp; Kiyatkin, E. A. (2019). 6-monoacetylmorphine (6-MAM), not morphine, is responsible for the rapid neural effects induced by intravenous heroin. <em>ACS chemical neuroscience, 10</em>(8), 3409-3414. <a href="https://doi.org/10.1021/acschemneuro.9b00305" rel="nofollow noreferrer">https://doi.org/10.1021/acschemneuro.9b00305</a></p>
<p>Williams, A., Zhou, S., &amp; Zhan, C. G. (2019). Discovery of potent and selective butyrylcholinesterase inhibitors through the use of pharmacophore-based screening. <em>Bioorganic &amp; medicinal chemistry letters, 29</em>(24), 126754. <a href="https://doi.org/10.1016/j.bmcl.2019.126754" rel="nofollow noreferrer">https://doi.org/10.1016/j.bmcl.2019.126754</a></p>

CC BY-SA 4.0
2023-01-18T01:03:16.150Z
2023-01-18T11:13:43.927Z
2023-01-18T11:13:43.927Z
Rider
<p>Since heroin is a <a href="https://sph.rutgers.edu/centers/chibps/heroin.html" rel="nofollow noreferrer">prodrug</a> (i.e <em>inactive</em>) 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.</p>

CC BY-SA 4.0
2023-01-17T10:45:39.017Z
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*](https://www.collinsdictionary.com/dictionary/english/oid) synthetics created in a lab.
Chris Rogers
CC BY-SA 4.0
2023-01-17T17:41:57.143Z
@ChrisRogers thanks for clarifying!
Rider
CC BY-SA 4.0
2023-01-17T21:18:21.867Z
"Esterase" is a huge category of enzymes, not a particular enzyme; this question seems to treat it as one.
Bryan Krause
CC BY-SA 4.0
2023-01-18T01:15:01.657Z
@BryanKrause noted, thank you. Question has been updated to reflect this.
Rider
<psychopharmacology><addiction>
Could opiate addictions be treated with esterase inhibitors?
Rider
# Could opiate addictions be treated with esterase inhibitors?

(Asked by: username_0 on 2023-01-17)

Since heroin is a [prodrug](https://sph.rutgers.edu/centers/chibps/heroin.html) (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.

**Tags:** psychopharmacology, addiction

> **Comments:**
> **username_1**: 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*](https://www.collinsdictionary.com/dictionary/english/oid) synthetics created in a lab.  
> **username_0**: @ChrisRogers thanks for clarifying!  
> **username_2**: "Esterase" is a huge category of enzymes, not a particular enzyme; this question seems to treat it as one.  
> **username_0**: @BryanKrause noted, thank you. Question has been updated to reflect this.  

---

## 1 answers

### Answer by username_0 on 2023-01-18. Score: 2 | Accepted answer

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](https://pubmed.ncbi.nlm.nih.gov/11961908/) 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](https://pubs.acs.org/doi/10.1021/acschemneuro.9b00305): An enzyme called [*butyrylcholinesterase*](https://www.ebi.ac.uk/chembl/target_report_card/CHEMBL1914/) (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](https://academic.oup.com/ijnp/article/17/9/1357/2356845), 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"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953623/) 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](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733526/).

Lastly, [passive immunization with a certain antibody has been shown to similarly blunt the effects of heroin](https://www.ous-research.no/home/neurobiology/Heroin%20-%20Injection%20to%20Treatment/21859) 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.

## References

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>


---

