GABA/Glutamate System and PAWS


If you are working to cut back or completely quit drinking alcohol, you may often experience neurological symptoms. We sometimes know this as Post Acute Withdrawal Syndrome (PAWS). To better understand these processes, we need to look at the core systems in the brain impacted by chronic alcohol use. As tolerance to alcohol develops, a gradual adaptation in your brain takes place. When a brain seeks to maintain homeostasis using Gaba and Glutamate, we call the process ‘neuroplasticity’.

At the end of this session, we will briefly introduce some of the medications used. These help the brain achieve balance in sobriety and improve sobriety outcomes.

GABA / Glutamate Pathway

Many neurologic systems in the brain exist to balance each other out. For instance, certain neurochemicals and receptors will essentially stimulate or activate the brain. Other chemicals will slow the brain down or inhibit certain functions. One such pathway involves the balance between GABA and Glutamate. GABA (Gamma-Aminobutyric Acid) is an inhibitor of the brain. It essentially functions as the ‘brakes’ for multiple brain functions. Anxiety processing, attention/coordination, and sleep involve GABA. The activating chemical in opposition to GABA is Glutamate. Associated with arousal, fight/flight responses, and focus, Glutamate will stimulate the brain.

One way these systems get disrupted is via the chronic introduction of an external substance to the brain’s system. Alcohol is such a substance and will functionally elevate GABA activity. A simple way of thinking about this is that alcohol adds to the ‘brake package’ of the brain. This is easy to understand when you acknowledge what happens when people become intoxicated with alcohol. Their coordination lessens, they feel often less anxious and sometimes disinhibited. They may pass out or black out from the intoxication.

Glutamate System

Neuroplasticity allows a person consuming alcohol in large quantities repeatedly to have an overgrowth of the brain’s Glutamate system. This is for maintaining balance. Continuing with our automotive analogy, this is kind of like a car constantly driving with heavy brakes on the floor and the owner installing more and more powerful engines to compensate.

Someone with a severe alcohol use disorder may be highly functional with a blood alcohol content even greater than that of a DWI threshold. We have had people enter residential treatment, walking and talking to nurses and staff, and showing a BAC as high as 0.505. Keep in mind that the threshold for a DWI in most states is 0.08!

Tolerance and Longer Healing Times

It takes a long time for someone to develop this kind of tolerance such that they can communicate and present relatively normal amidst heavy intoxication. It also will take a significant length of time for that person to heal once alcohol is taken away. Because of the compensatory Glutamate overgrowth, the brain now is actually more comfortable on steady alcohol than off and will often ‘fight back’ when the person sobers up. The brakes are lifted and the turbo-charged engine is too massive for the car to functionally stay on the track.

The most extreme of this occurring is with an alcohol withdrawal seizure. The chemical perpetuating the seizure in the brain is Glutamate which we’ve established is extremely high. Alcohol withdrawal seizures are dangerous enough that we acknowledge this as one of the potential causes of death for those going through withdrawal. Another complicated form of alcohol withdrawal is called withdrawal delirium or delirium tremens and has moderate rates of mortality associated with it. This condition also involves imbalance with the GABA/Glutamate system and starts to affect the cardiovascular system in addition to basic orientation and attention. Because these situations can be so dangerous, we often recommend medical oversight for a person working to detoxify from severe alcohol use.

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Medication Support for Withdrawal

To help stabilize the brain as it is re-balancing with the GABA/Glutamate system, there are numerous medications that have been studied and show good evidence in improving outcomes. The primary medications used in this situation to prevent severe complications from alcohol withdrawal are Benzodiazepines. These include such meds as lorazepam, diazepam, and chlorazepate. Benzodiazepines also activate the GABA neurotransmitter system and help us essentially ‘pump the brakes’ when alcohol is removed from the body. These medications prevent seizures and delirium and are the treatment of choice for medical alcohol detoxification in both inpatient centers and in an outpatient fashion.

Secondary medications use to help the brain with this imbalance are Glutamate modulator meds, often with anti-seizure properties. It makes intuitive sense that anti-seizure meds would interact with the Glutamate system as this chemical is primary culprit for seizure activity. Examples of these medications used in the stabilization and detox process include Gabapentin, Baclofen, Lamotrigine, and Topiramate. Of note, there is questionable data that these meds are strong enough to prevent withdrawal seizures alone and without the aid of benzodiazepines, so the use of the benzodiazepines still is the standard of medical care for treating alcohol withdrawal.

Negative State and PAWS

In the early 1980’s, a researcher out of San Diego named George Koob looked at chronic and semi-chronic changes connected to neuroanatomy and alcoholism. Prior to his research, the addiction field thought that an alcoholic would continue to drink to prevent alcohol withdrawal and that if we could get them through acute withdrawal, they would be at a baseline neural state. Koob found, through multiple animal models, that the neurologic healing was much slower than previously thought. He identified that although the alcoholic was not at further risk to have a seizure or delirium, that person would still experience a triad of symptoms including:

  • Anxiety
  • Agitation
  • Insomnia

Collectively, he coined this phenomenon of early recovery as a Negative State. He was able to demonstrate it with animal experiments and it was later confirmed through human observation. The addiction recovery community later adopted the term PAWS to describe the same symptoms of early alcohol sobriety:

  • Post
  • Acute
  • Withdrawal
  • Syndrome
Medication Support for PAWS

As alluded to above, the Glutamate medications seem to show the greatest promise for helping stabilize the excitatory components of early alcohol recovery in the brain. The med with the greatest medical literature supporting its use to alleviate symptoms of PAWS is Gabapentin. Multiple trials have demonstrated that Gabapentin was associated with increased number of sober days, reduced frequency of binge-drinking, and improved sleep patterns. One randomized controlled trial of 150 people showed significant improvement in these areas that was dose dependent on the Gabapentin [1]. Another trial of 150 people showed that combination Naltrexone medication and Gabapentin was superior to placebos of either or both[2].

[1] Mason BJ, Quello S, Goodell V, et al. Gabapentin treatment for alcohol dependence: a randomized clinical trial [published online November 4, 2013]. JAMA Intern Med. doi: 10.1001/jamainternmed.2013.11950.

[2] Anton RF, Myrick H, Wright TM, et al. Gabapentin combined with naltrexone for the treatment of alcohol dependence. Am J Psychiatry. 2011;168(7):709-717.

Read more CeDAR Education Articles about Alcohol and Its Effects including Medication Assisted Treatment.

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