Page 96 - ITPS-7-3

INNOSC Theranostics and
Pharmacological Sciences Alpha-2A receptor agonist and addiction

9 Department of Psychiatry, University of Vermont, Burlington, Vermont, United States of America
10 Department of Psychiatry, Wright University, Boonshoft School of Medicine, Dayton, Ohio, United States of America
11 Division of Personalized Medicine, Ketamine Infusion Clinic of South Florida, Pompano, Florida, United States of America
12 Department of Nutrigenomic Research, Victory Nutrition International, Inc., Bonita Springs, Florida, United States of America
13 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, United
States of America
14 Department of Family Medicine, Jefferson Health Northeast, Philadelphia, Pennsylvania, United States of America
15 Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of
Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, New York,
United States of America
16 Department of Psychology, State University of New York at Buffalo, Buffalo, New York, United States of America
17 Division of Personalized Pain Therapy Research, Center for Advanced Spine Care of Southern Arizona, Tucson, Arizona, United States of
America
18 Department of Orthopaedics, Fundación Universitaria Sanitas, Bogotá, Colombia
19 Department of Orthopedics, Hospital Universitário Gaffree Guinle Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, Brazil
20 Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Gilan, Iran
21 Department of Psychiatry, School of Medicine, Harvard University, Cambridge, Massachusetts, United States of America
22 Department of Psychiatry, Mt. Sinai School of Medicine, New York City, New York, United States of America
23 Department of Psychiatry, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States of America

(This article belongs to Special Issue: Behavioral Addictions: From Bench to Bedside)

1. Introduction (PFC). Alpha-2A adrenergic receptors inhabit the
presynaptic cleft of the neuron and, when activated by
Clonidine is a well-researched molecule patented in 1961 an agonist, inhibit downstream neurons. The stimulation
but was not used medically until 1966. Catapres is a brand of alpha-2 receptors arrests the secretion of the
1
name for clonidine, which is used to treat high blood neurotransmitter norepinephrine (NE).
pressure, as well as, off-label, attention deficit hyperactivity
disorder (ADHD), withdrawal from substances such as While usually not severe, common side effects of
2,3
opioids, alcohol and nicotine, menopausal flushing, and clonidine include dry mouth, dizziness, headaches,
selected painful conditions. Administration of clonidine and sleepiness. However, in rare cases, severe adverse
2,3
can be oral, transdermal, or by injection with an onset of effects include heart arrhythmias, confusion, and even
action within 1 h. Most side-effects are reversible when hallucinations. Clonidine should be avoided during
withdrawn. 4 pregnancy or breastfeeding because it crosses the placental
barrier and is present in breast milk. Moreover, if abruptly
To design a comprehensive review, our team searched
PubMed, MEDLINE, Cochrane Library, and references stopped, withdrawal reactions could occur. Clonidine, first
patented in 1961, was the 79 most commonly prescribed
th
from relevant articles for publications dating from June 1,
2014, to August 1, 2020. We searched for the Medical Subject pharmacologic agent in the United States and by 2017,
8
Headings terms “Opioid-Related Disorders,” or “Analgesics, with over 10 million prescriptions.
Opioid” and “Substance Withdrawal Syndrome.” This Following oral ingestion, the drug is absorbed into the
work is worthy of a thorough review as current reviews bloodstream very promptly and almost completely, with
of clonidine often overlook much of the laboratory and peak concentrations in human plasma within 60 – 90 min.
9
clinical discovery work focusing on 2014 – 2020. 5 It is important to emphasize that clonidine is lipid-soluble
to some extent. The partition coefficient logarithm (log P)
2. Pharmacokinetics and is equal to 1.6. It is well-known that the optimal log P
10
pharmacodynamics of clonidine for a drug to enter the central nervous system through the
blood-brain barrier is 2.0. 11
Importantly, clonidine crosses the blood-brain barrier.
6
Gold et al. demonstrated that clonidine’s molecular Approximately one-fifth of an oral dose will not be
7
mechanism of action occurs due to its agonism at the absorbed and is excreted in the feces, while under half of
alpha-2A receptor, a subtype of the alpha-2 adrenergic the absorbed dose will be metabolized by the hepatic tissue
receptor, found primarily within the prefrontal cortex into inactive metabolites, with the rest excreted unchanged

Volume 7 Issue 3 (2024) 2 doi: 10.36922/itps.1918