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Colin MacKenzie M.D.
November 17, 2020

Introduction

  • Excessive ethanol (commonly called “alcohol”) use can cause many deleterious effects including harm to the cardiovascular, gastrointestinal, and nervous systems. However, when mixed with other central nervous system (CNS) depressants and stimulants, the effects can be even more detrimental.

Ethanol and Cocaine 1,2,3,7

Cocaine Powder
  • Cocaine is a stimulant drug with a high abuse potential that is still used today medically as a local anesthetic.  When both ethanol and cocaine are used simultaneously, the liver metabolizes them into a psychoactive substance called cocaethylene (cocaine + ethanol = cocaethylene + methanol). Cocaethylene inhibits the action of monamine (neurotransmitter) transporters located within neuron cell membranes at the pre-synaptic cleft of neurons (the connection point between two or more neurons).
  • These transporters are responsible for removing serotonin, norepinephrine, and dopamine from the extra-cellular space between the neurons (synaptic cleft); and thus, decreasing the activity of these neurotransmitters and their influence on the nervous system. Medications and drugs that prevent these transporters from removing the neurotransmitters from the extra-cellular space are called re-uptake inhibitors because they block the re-uptake of these neurotransmitters by the neuron from which the neurotransmitters originated.
  • Cocaethylene, acting as a potent re-uptake inhibitor, increases the extracellular (outside the neuron) concentratoins of serotonin, norepinephrine, and dopamine, allowing these neurotransmitters to prolong and enhance their activity in the brain.  This accounts for the physical and psychological effects of Cocaethylene which can produce increased blood pressure and heart rate (epinephrine), euphoria (dopamine), and pleasurable sensations (serotonin).  In addition, when the liver tries to eliminate cocaethylene, the alcohol slows down this process which results in more of the substance entering the bloodstream leading to greater effects on the body.  Heart disease, cerebrovascular events (strokes), and liver damage can occur.  Acute cardiovascular events leading to immediate death are 18 to 25 times more likely with cocaethylene than cocaine alone.

Ethanol and opioids 4,5,7

  • Opioids, such as, oxycodone and morphine, have analgesic, central nervous system depressant, and euphoric effects. Ethanol can enhance all these effects via the same or associated biochemical pathways.
  • Opioid drugs work by binding to the opioid receptors which are dispersed throughout the nervous system in various quantities and types.  Opioid medications compete with the brain’s endogenous opioids, such as the enkephalins, endorphins, and dynorphins, which typically stimulate three types of receptors (beta, kappa, and delta) located on neurons.  However, most opioid medications are far more potent than the body's natural opioids.
  • The opioid system controls pain regulation, stress and reward responses, and autonomic processes.  Opioids inhibit those neurons that perceive pain by activating a certain type of membrane channel called an inwardly rectifying potassium channel.  When this channel is activated, the neuron no longer fires, and thus pain impulses are no longer transmitted to downstream neurons.  Alcohol also activates these inwardly rectifying potassium channels. Together, opioids and alcohol produce an exaggerated effect that not only dampens pain fiber responses, but also suppresses other neurological structures such as the respiratory drive center causing a decrease in respiratory rate.  If taken in sufficient quantities, opioids and alcohol can cause enough respiratory depression to cause an individual to fall asleep and stop breathing.
  • Alcohol and opioids also share a common pathway in the “addiction circuit” of the brain.  When consumed, alcohol increases endogenous (natural) opioids which activate the opioid receptors in the addiction circuit.  This leads to an increase in dopamine in a group of neurons called the nucleus accumbens which leads to the feeling of euphoria, which then results in the positive reinforcement of further alcohol use. When opioid drugs are also used, they simultaneously activate the opioid receptors in the addiction circuit with alcohol causing a further increase in dopamine and a sense of euphoria greater than using either substance alone.

Ethanol and benzodiazepines 6

  • Ethanol and benzodiazepine, such as alprazolam and clonazepam, facilitate the inhibitory transmission of the gamma-aminobutyric acid (GABA) receptors. Normally, the neurotransmitter gamma-aminobutyric acid (GABA) attaches to the GABA receptors which causes an influx of negative chloride ions into the neuron, hyper-polarizing the cell and inhibiting neurotransmission.
  • Benzodiazepines also bind to the GABA receptor, and when GABA is also bound, the influx of chloride ions is increased, hyper-polarizing the cell even more and for longer durations of time. This causes the neurons to fire less frequently and leads to the sedative and anti-anxiety responses of these medications.
  • There are different subtypes of GABA receptors, some that bind benzodiazepines and some that do not.  Even those GABA receptors that bind benzodiazepines have various subtypes, with some subtypes causing stronger hypnotic effects when a benzodiazepine is attached, and other GABA receptor subtypes causing more anti-anxiety effects.
  • Alcohol also binds to the GABA receptor complex and activates these receptors causing neuronal hyper-polarization leading to similar effects of the benzodiazepines.  However, when combined with alcohol, the hyper-polarization of the neurons is exaggerated further, causing profound inhibition for longer durations of time.  This can lead to severe sedation as well as respiratory depression, coma, and even death.

References: 

  1. Laizure SC, Mandrell T, Gades NM, Parker RB. Cocaethylene metabolism and interaction with cocaine and ethanol: role of carboxylesterases. Drug Metab Dispos. 2003 Jan;31(1):16-20. doi: 10.1124/dmd.31.1.16. PMID: 12485948.
  2. Jones AW. Forensic Drug Profile: Cocaethylene. J Anal Toxicol. 2019 Apr 1;43(3):155-160. doi: 10.1093/jat/bkz007. PMID: 30796807.
  3. https://en.wikipedia.org/wiki/Cocaethylene 
  4. Cushman P Jr. Alcohol and opioids: possible interactions of clinical importance. Adv Alcohol Subst Abuse. 1987 Spring;6(3):33-46. doi: 10.1300/j251v06n03_04. PMID: 2821747.
  5. Gianoulakis C. (2001). Influence of the endogenous opioid system on high alcohol consumption and genetic predisposition to alcoholism. Journal of psychiatry & neuroscience : JPN, 26(4), 304–318. 
  6. Ticku MK, Burch TP, Davis WC. The interactions of ethanol with the benzodiazepine-GABA receptor-ionophore complex. Pharmacol Biochem Behav. 1983;18 Suppl 1:15-8. doi: 10.1016/0091-3057(83)90140-5. PMID: 6138771.
  7. Singh AK. Alcohol Interaction with Cocaine, Methamphetamine, Opioids, Nicotine, Cannabis, and γ-Hydroxybutyric Acid. Biomedicines. 2019;7(1):16. Published 2019 Mar 7. doi:10.3390/biomedicines7010016