Many Drugs of Abuse May Be Acutely Transformed to Dopamine, Norepinephrine and Epinephrine In Vivo.

Paul J Fitzgerald

doi:10.3390/ijms221910706

Paul J Fitzgerald

Open Access

https://doi.org/10.3390/ijms221910706

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Abstract

It is well established that a wide range of drugs of abuse acutely boost the signaling of the sympathetic nervous system and the hypothalamic–pituitary–adrenal (HPA) axis, where norepinephrine and epinephrine are major output molecules. This stimulatory effect is accompanied by such symptoms as elevated heart rate and blood pressure, more rapid breathing, increased body temperature and sweating, and pupillary dilation, as well as the intoxicating or euphoric subjective properties of the drug. While many drugs of abuse are thought to achieve their intoxicating effects by modulating the monoaminergic neurotransmitter systems (i.e., serotonin, norepinephrine, dopamine) by binding to these receptors or otherwise affecting their synaptic signaling, this paper puts forth the hypothesis that many of these drugs are actually acutely converted to catecholamines (dopamine, norepinephrine, epinephrine) in vivo, in addition to transformation to their known metabolites. In this manner, a range of stimulants, opioids, and psychedelics (as well as alcohol) may partially achieve their intoxicating properties, as well as side effects, due to this putative transformation to catecholamines. If this hypothesis is correct, it would alter our understanding of the basic biosynthetic pathways for generating these important signaling molecules, while also modifying our view of the neural substrates underlying substance abuse and dependence, including psychological stress-induced relapse. Importantly, there is a direct way to test the overarching hypothesis: administer (either centrally or peripherally) stable isotope versions of these drugs to model organisms such as rodents (or even to humans) and then use liquid chromatography-mass spectrometry to determine if the labeled drug is converted to labeled catecholamines in brain, blood plasma, or urine samples.

Highlights

Many drugs of abuse, such as cocaine or opium, either occur naturally in plants or can be readily derived from plant-based chemicals [1,2]
Whereas many drugs are transformed into metabolites with active psychotropic properties, most drugs are not typically thought to be converted to molecules that occur naturally in the body and participate in normal, endogenous signaling pathways. Aside from their widely varying intoxicating or euphoriant subjective properties, different classes of drugs of abuse share the property of acutely boosting the body’s stress signaling pathways, namely the sympathetic nervous system and HPA axis which use norepinephrine and epinephrine as major output molecules [4,5,6,7]. This results in what can be perceived as unpleasant side effects such as boosting the heart rate, elevating blood pressure, increasing the rate of breathing, elevating body temperature and accompanied sweating, as well as pupillary dilation
This paper puts forth the hypothesis that a broad range of drugs of abuse—stimulants, opioids, psychedelics—are acutely converted to catecholamines in the body. This biochemical conversion, which may occur in a wide range of animals as well as in humans, may underlie the boosting of sympathetic nervous system and HPA axis signaling described above, and contribute to the intoxicating or rewarding properties of these drugs

Summary

Introduction

Many drugs of abuse, such as cocaine or opium, either occur naturally in plants or can be readily derived from plant-based chemicals [1,2]. This paper puts forth the hypothesis that a broad range of drugs of abuse—stimulants, opioids, psychedelics—are acutely converted to catecholamines in the body This biochemical conversion, which may occur in a wide range of animals as well as in humans (and possibly other organisms), may underlie the boosting of sympathetic nervous system and HPA axis signaling described above, and contribute to the intoxicating or rewarding properties of these drugs (along with their known interaction with monoaminergic or opioid signaling molecules or receptors). Ring) that may allow them to be enzymatically converted to dopamine, norepinephrine, or epinephrine

Opioids

Psychedelics

Evaluation of the Hypothesis

Consequences of the Hypothesis