A Drug That Cures Alcoholism May Be the Next Anti-anxiety Medication

Summary: Disulfiram, a drug commonly prescribed to treat chronic alcohol addiction, was shown to reduce anxiety levels in rodent models. The drug inhibits FROUNT protein and chemokine signaling pathways under its influence, suppressing overall glutamate transmission in the brain. This, in turn, helps reduce overall activity. The findings may signal a new way to treat anxiety in humans.

Source: Tokyo University of Science

Alcoholism, if left untreated, could have dangerous repercussions. Thus, it is no surprise that there are a range of drugs developed to treat this condition. Of these drugs, disulfiram (DSF) is approved by the Food and Drug Agency (FDA) for the treatment of alcoholism. DSF primarily inhibits the enzyme aldehyde dehydrogenase (ALDH), which is responsible for the metabolism of alcohol.

Could the inhibitory effects of DSF extend to signaling molecules as well?

According to recent studies, DSF in fact inhibits a cytoplasmic protein known as FROUNT, which controls the direction in which certain immune cells migrate. DSF blocks FROUNT from interacting with two chemokine receptors known as CCR2 and CCR5, which are involved in important cellular signaling pathways.

A few studies suggest that chemokine receptors may be involved in the regulation of emotional behaviors in rodents. However, there is a lack of data on the exact association between FROUNT-chemokine signaling and DSF.

To clarify this link, a team comprising Prof. Akiyoshi Saitoh from Tokyo University of Science and other researchers from institutes across Japan conducted a study examining the pharmacological properties of DSF.

The study, which was published online on March 7, 2022 in Frontiers in Pharmacology, describes how the research team used an elevated plus-maze (EPM) test—which is used to screen for anxiolytic drugs—to study the effects of DSF in mice.

The EPM apparatus consists of four arms set in a cross pattern, connected to a central square. Two arms are protected by vertical boundaries, whereas two have unprotected edges. Usually, mice with anxiety prefer to spend time in the closed arms.

In this case, some mice were administered diazepam (a drug commonly used to treat anxiety) and others, DSF. These mice were then placed in the EPM apparatus, and their activity was monitored. 

To their surprise, the team found that mice treated with DSF spent significantly more time in the open arms of the apparatus, which indicates that they were less anxious. The team also tested the anxiolytic effects of a more potent FROUNT inhibitor, known as DSF-41, and observed similar results.

What’s interesting is that these behavioral changes were similar to those observed in mice treated with diazepam. How exactly did DSF achieve this?

The team had previously discovered that increased extracellular glutamate (which is an important amino acid and neurotransmitter) levels are associated with increased anxiety in mice.

This cartoon shows a brain with a lock around it and a man holding a key
The team had previously discovered that increased extracellular glutamate (which is an important amino acid and neurotransmitter) levels are associated with increased anxiety in mice. Image is in the public domain

“We propose that DSF inhibits FROUNT protein and the chemokine signaling pathways under its influence, which may suppress presynaptic glutamatergic transmission in the brain,” says Prof. Saitoh. “This, in turn, attenuates the levels of glutamate in the brain, reducing overall anxiety.”

The team was also pleasantly surprised to find that in contrast with diazepam, DSF treatment did not lead to adverse effects such as amnesia, coordination disorders, or sedation.

According to Prof. Saitoh, “These results indicate that DSF can be used safely by elderly patients suffering from anxiety and insomnia and has the potential to become a breakthrough psychotropic drug.”

What are the long-term implications of these results? Dr. Saitoh explains, “We plan to further clarify how DSF exerts its pharmaceutical actions. Hopefully, we will also be able to elucidate the exact role of the FROUNT molecule in the central nervous system.”

This is one of the first studies to reveal that DSF exhibits anti-anxiety properties comparable to those of existing benzodiazepines without exhibiting any side effects observed with benzodiazepines. Hopefully, DSF’s inhibitory activity against FROUNT functioning could be explored for successful anxiolytic drug development.

Funding: This study was partially supported by the Tsukuba Clinical Research and Development Organization (T-CReDO) from the Japan Agency for Medical Research and Development (AMED).

About this anxiety and psychopharmacology research news

Author: Tsutomu Shimizu
Source: Tokyo University of Science
Contact: Tsutomu Shimizu – Tokyo University of Science
Image: The image is in the public domain

Original Research: Open access.
Disulfiram Produces Potent Anxiolytic-Like Effects Without Benzodiazepine Anxiolytics-Related Adverse Effects in Mice” by Saitoh et al. Frontiers in Pharmacology


Abstract

Disulfiram Produces Potent Anxiolytic-Like Effects Without Benzodiazepine Anxiolytics-Related Adverse Effects in Mice

Disulfiram is an FDA approved drug for the treatment of alcoholism. The drug acts by inhibiting aldehyde dehydrogenase, an enzyme essential to alcohol metabolism. However, a recent study has demonstrated that disulfiram also potently inhibits the cytoplasmic protein FROUNT, a common regulator of chemokine receptor CCR2 and CCR5 signaling.

Several studies have reported that chemokine receptors are associated with the regulation of emotional behaviors in rodents, such as anxiety.

Therefore, this study was performed to clarify the effect of disulfiram on emotional behavior in rodents.

The anxiolytic-like effects of disulfiram were investigated using an elevated plus-maze (EPM) test, a typical screening model for anxiolytics.

Disulfiram (40 or 80 mg/kg) significantly increased the amount of time spent in the open arms of the maze and the number of open arm entries without affecting the total open arms entries. Similar results were obtained in mice treated with a selective FROUNT inhibitor, disulfiram-41 (10 mg/kg).

These disulfiram-associated behavioral changes were similar to those observed following treatment with the benzodiazepine anxiolytic diazepam (1.5 mg/kg). Moreover, disulfiram (40 mg/kg) significantly and completely attenuated increased extracellular glutamate levels in the prelimbic-prefrontal cortex (PL-PFC) during stress exposure on the elevated open-platform.

However, no effect in the EPM test was seen following administration of the selective aldehyde dehydrogenase inhibitor cyanamide (40 mg/kg). In contrast to diazepam, disulfiram caused no sedation effects in the open-field, coordination disorder on a rotarod, or amnesia in a Y-maze.

This is the first report suggesting that disulfiram produces anxiolytic-like effects in rodents.

We found that the presynaptic inhibitory effects on glutaminergic neurons in the PL-PFC may be involved in its underlying mechanism. Disulfiram could therefore be an effective and novel anxiolytic drug that does not produce benzodiazepine-related adverse effects, such as amnesia, coordination disorder, or sedation, as found with diazepam.

We propose that the inhibitory activity of disulfiram against FROUNT function provides an effective therapeutic option in anxiety.

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  1. Actually, disulfiram has never been routinely used for anxiety. If the research is replicated, then the question will be rapidity of action. Disulfiram has been around long enough to know that it’s addiction risk is very low.

  2. I’m an alcoholic and have relapsed many times over the years. I had 14 years once but that doesn’t matter. What matters is that somebody is working to help those in need with this disease. I was given Neurontin to help with obsessive aspects of alcoholism 20 years ago and weather it actually helped or I was convincing myself that it did. I’m sober today and that’s a great thing. Believe it or not one of the best remedies for substance abuse individuals is Love. Drunks can tell most of the time if someone is disingenuous. The real thing does wonders. Our whole crazy world needs a dose of it. If somebody takes this drug and it helps them cope then more power to them. The brain is a vast and undiscovered place and I’m glad there are some smart folks out there trying.

  3. I want this… My doc has messed me up on so many meds. I’ve been asking if there was a med that affects your brain without being drunk. I was so sociable and happy. I will never go back to drinking, I learned my lesson. I want to know more about this and I will be part of a clinical trial

  4. If Antabuse actually cured alcoholism I’m pretty sure somebody would’ve already noticed that it would almost certainly have to do so by redirecting or “curing” the underlying anxiety (obsession) alcoholism (compulsion) doesn’t…so common sense rather doubts the threat of emesis would have so-long been it’s therapeutic mechanism (though it might be useful to quantify how much added anxiety presumably doesn’t need to be offset when the very therapy hasn’t been said anxiety’s vector of introduction).

  5. If Antabuse actually cured alcoholism I’m pretty sure somebody would’ve already noticed that it would almost certainly have to do so by redirecting or “curing” the underlying anxiety (obsession) alcoholism (compulsion) doesn’t…so common sense rather doubts the threat of emesis would have so-long been it’s therapeutic mechanism (though it might be useful to quantify how much added anxiety presumably doesn’t need to be offset when the very therapy hasn’t been said anxiety’s vector of introduction).

    Surely the reckless title of this article isn’t condoned even by the already irresponsibly-optimistic quackery that releases it’s own study in such a context. That there’s even room for nonsense like this is because displacing unidentified and/or unresolved causative trauma by fabricating a disease that blames “genetics“ and demonizes the substance of choice ensures addiction treatment remains in the dark ages.

    The 12 step model is just a functional workaround for the most vexing behaviors associated with posttraumatic antisocial adaptation (remorselessness, no unprompted self examination, refusal to take accountability) severely limited by the necessity of self-direction being the only direction to which narcissistic personality pathology willingly submits. In a dozen years’ experience in AA over a span of 30 I finally figured out that yes indeed “there are such unfortunates” whose compulsions don’t result from the anxiety of insatiable egos…so will not be relieved by simple satisfaction of that particular compensatory maladaptation by feeding it a steady diet of group approval (fake hugs tons of applause and rewards for effing everything) and superiority to the never-ending stream of failing “newcomers“.

    The genome’s been sequenced for a decade and still no alcoholism genes (though surely plenty of behavioral heritability selecting for adaptive epigenetic expression), so the expectation of medicine solving what’s now irrefutably a secondary (behaviorally-habituated) pathology with a medically untreatable primary cause is magical thinking too regressed even for the arrogant folk wisdom-based fellowship so pettily competitive and devoid of integrity it has to pretend not to define its own leadership and cites anonymity to avoid going on record with it’s miraculous works LMFAO. If psychiatry wants to help these patients more than itself maybe taking note of what a con the best thing going is wouldn’t be the worst position from which to revisit the possibility.

    Substance abuse is an attempt to cope with trauma, and addiction is caused by substance abuse—so it’s neither a naturally occurring disease nor likely to be “cured”without processing the underlying causative trauma

  6. This is the most ridiculous article and irresponsible to boot. First of all Valium does not cure alcoholism, it is used in a detox center to help with withdrawal and stopped after the withdrawal stops in a week or so. It is a highly addictive benzo.
    Secondly, there is no cure for alcoholism at this point. Thirdly, Valium has been used to treat anxiety for many years but most responsible doctors do not prescribe because of the high addictive rates..Doctors have replaced Disulfuram or valium for anxiety with SSRI, which are not addictive, usually Celexa or Lexapro

    1. Actually, disulfiram has never been routinely used for anxiety. If the research is replicated, then the question will be rapidity of action. Disulfiram has been around long enough to know that it’s addiction risk is very low.

  7. A drug that cures alcoholism… hmm. A fairly ludicrous statement from a publication listed as neuroscience news. Disulfuram does create negative feedback for persons who consume etoh, but is far from a ‘cure’. This drug has been available for years, with no discernible change in frequency nor course of this challenging disease. https://apnews.com/article/public-health-health-statistics-health-us-news-ap-top-news-f1f81ade0748410aaeb6eeab7a772bf7
    Current abstinence rates for disulfuram are 50%, but that is when combined with other drugs and 12 step recovery, and in monitored programs only.
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3919718/
    I appreciate the research regarding anxiety, but caution is warranted when using the ‘cure’ word.
    Cameron Gardner, MD
    Sober 9 years.

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