Addiction Medicine Made Easy | Fighting back against addiction

Could N-Acetylcysteine Be the Key to Beating Cannabis Use Disorder?

• Casey Grover, MD, FACEP, FASAM

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This episode delves into the role of N-acetylcysteine (NAC) in treating cannabis use disorder, exploring scientific studies and their findings. Listeners will gain insights on the efficacy of NAC, its potential in addiction treatment, and practical considerations for use.

• Overview of cannabis use disorder statistics and the need for treatment options 
• Explanation of N-acetylcysteine and its mechanism of action in addiction 
• Review of clinical trials evaluating NAC's effectiveness in reducing cannabis use 

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To contact Dr. Grover: ammadeeasy@fastmail.com

Speaker 1:

Welcome to the Addiction Medicine Made Easy podcast. Hey there, I'm Dr Casey Grover, an addiction medicine doctor based on California's Central Coast. For 14 years, I worked in the emergency department, seeing countless patients struggling with addiction. Now I'm on the other side of the fight, helping people rebuild their lives when drugs and alcohol take control. Thanks for tuning in. Let's get started.

Speaker 1:

Today, we will be talking about using N-acetylcysteine to treat cannabis use disorder. Now this episode comes from one of my patients who has cannabis use disorder. She, at her first appointment with me, asked about using N-acetylcysteine often referred to as NAC or NAC for cannabis use, and I hadn't heard of this. So I told her I needed to research it and I finally had time to dig into this topic. Now I went to the scientific literature to research this topic and on the National Library of Medicine, I found a great paper on the topic of N-acetylcysteine for cannabis use disorder. The author of the paper is Rishi Sharma and the article is entitled N-Acetylcysteine in the Treatment of Cannabis Use Disorder a Systematic Review of Clinical Trials. It was published in Addictive Behaviors in 2022. I wanted to give you all a heads up. This episode is a review of a scientific article, so it will be a little more science-y than some of my recent episodes. All right, let's dig in. I always love the introduction section, as it gives us a great background of the topic. The authors begin by reminding us that cannabis is a commonly used substance with high rates of cannabis use disorder and cannabis dependence. It's estimated that 22 million people globally have cannabis use disorder, also known as cannabis addiction, and as many as 30% of regular cannabis users develop cannabis dependence, meaning that they will experience withdrawal symptoms when they stop. Now, interestingly, the authors point out there are no FDA-approved medications for cannabis use disorder. And that brings us back to N-acetylcysteine, which I will refer to as NAC for the rest of the episode.

Speaker 1:

Nac is an antioxidant molecule derived from the amino acid cysteine that is involved with the synthesis and metabolism of glutathione. A quick pause here. The authors didn't discuss what glutathione is, so I wanted to jump in. Glutathione is a key molecule in multiple metabolic processes. It is an antioxidant and is involved with the synthesis and storage of multiple key compounds in the body. Back to the article. The authors go on to share that researchers have tried to use NAC for the treatment of multiple addictions, including nicotine, alcohol, cocaine, methamphetamine and cannabis. They move on to discuss why NAC might be useful in treating addiction, which is that it affects glutamatergic transmission. And if you're wondering what that means, it refers to signaling in the brain involving the neurotransmitter glutamate.

Speaker 1:

Another quick break-in from me. Glutamate is an excitatory neurotransmitter, meaning that it is a brain chemical that acts as a natural upper in the brain. You may remember from some of our episodes on alcohol and alcohol withdrawal that alcohol reduces how well glutamate works, which is one of the ways alcohol functions. As a downer, it reduces how much excitation there is in the brain by reducing the function of glutamate. Back to the article. The authors note that repeated use of an addictive substance results in excessive amounts of glutamate in the reward center of the brain, and that reward center of the brain is also known as the nucleus accumbens. Too much stimulation by glutamate can cause damage to the neurons in the brain, and so one target for treating addiction is glutamate, and we know that some medications for addiction work through this pathway, like acamprosate and topiramate, also known as topamax. Nac, by being a potent antioxidant, is thought to have the potential to reverse some of the damage caused by too much glutamate with addiction in the reward center of the brain, and NAC also upregulates the glutamate transporter in the reward center of the brain as well, allowing the excess glutamate in the state of addiction to be removed, which reverses some of the changes from addiction in the brain and prevents further damage to the reward center of the brain.

Speaker 1:

Now that was pretty complicated. Let me simplify and summarize. Addiction involves damage to the reward center of the brain by there being too much stimulation from the brain, chemical glutamate. Nac helps to heal this damage and reduces the amount of glutamate stimulating the reward center of the brain. Hopefully that makes sense. It's actually pretty cool if you ask me, but then again, I'm a giant geek, particularly when it comes to addiction medicine.

Speaker 1:

Okay, the authors move on to point out that research on NAC has shown efficacy in treating multiple addictions, including, as I mentioned before, cocaine, methamphetamine, alcohol, nicotine and cannabis. Right now I am asking myself why haven't I heard about this sooner? It sounds like I could be adding this in to the treatment regimen for all of my patients. My apologies for getting excited. Okay, back to the article. The authors decided to look at the research on using NAC for cannabis addiction, which brings us to the methodology of this paper NAC for cannabis addiction. Which brings us to the methodology of this paper.

Speaker 1:

This is a systematic review of randomized controlled trials looking at NAC for the treatment of cannabis use. The authors used excellent methodology when conducting their review, which I will skip over to avoid us getting too lost in the details, but if you want to check out the methods, it is a well-done analysis. A quick point from me. There are many different types of study design, and randomized controlled trials are the best design, which gives us the most accurate information. So let's unpack this a bit.

Speaker 1:

Randomized controlled trials, also called RCTs, are the strongest form of medical evidence because they are designed to eliminate bias and ensure that any differences in outcomes are due to the treatment itself, not other factors. In a randomized controlled trial, participants are randomly assigned to either the treatment group or a placebo or control group, which helps balance out differences between individuals such as age, lifestyle or health conditions. This makes the results more reliable and allows doctors to determine whether a treatment truly works. Compared to other types of studies, randomized controlled trials provide the highest level of confidence that a medication or intervention is effective and safe. So this review article looks at randomized controlled trials looking at NAC for cannabis use disorder. So this article is an analysis of all of the best research studies on this topic. So, with that in mind, what did they find? Well, the authors identified eight randomized controlled trials looking at NAC for cannabis use disorder randomized controlled trials looking at NAC for cannabis use disorder, and in the article results section they actually summarized the results of each of the studies.

Speaker 1:

The first study was a randomized controlled trial of 116 adolescents and young adults with cannabis dependence, which showed a significant decrease in cannabis use in the NAC group as compared to placebo. They found that patients treated with NAC were more likely to have a urine drug test that was negative for cannabis as compared to placebo, and it was statistically significant with an odds ratio of 2.4. The second study was a double-blind placebo-controlled trial of 302 adults with cannabis use disorder and it didn't show any difference in terms of cannabis use between the NAC treatment group and the placebo group. So that was a negative study. The third study they reviewed was a study of 89 adolescents. They found that adolescents treated with NAC self-reported less cannabis cravings, but when they did the statistical analysis comparing those adolescents treated with NAC to those treated with placebo, the difference was not statistically significant. So this was another negative trial Next up.

Speaker 1:

The authors looked at a small study of 54 adolescents. When they compared those adolescents treated with NAC to those who received placebo, the NAC group had reduced impulsivity, improved medication adherence and a higher likelihood of having a negative urine drug test. And they were actually looking at urine drug tests specifically to detect cannabis use. And in this study the difference between the groups was statistically significant. Okay, on to the fifth study, which was a study of 300 adults. In this study, the adults who received NAC were more likely to be abstinent from cannabis compared to those treated with placebo, and these results were statistically significant.

Speaker 1:

Okay, study number six. This study involved 302 adults. In the adults who received NAC, there was reduced cannabis craving, reduced cannabis withdrawal and reduced frequency of cannabis use compared to the adults who received placebo, and the results were statistically significant. The authors noted that the effect of NAC was greater in women than men. All right. Study number seven. This was a study of 74 adolescents with depressive symptoms who used cannabis. In the group that received NAC, there was a higher rate of cannabis cessation as compared to the group that received placebo, and the results were statistically significant. And finally, study number eight. Very interestingly, study number eight was done by the same author as study number seven. This was a study of 302 adults with cannabis dependence and depressive symptoms, and yet in this study there was no difference in the rate of cannabis cessation in the NAC group as compared to the group that received placebo.

Speaker 1:

Let's sum up the results of these eight studies Now. I can certainly sum it up, but let's see what ChatGPT says when I ask it for a summary of these eight studies. Here we go. This is what ChatGPT had to say.

Speaker 1:

Quote the effect of N-acetylcysteine, also known as NAC, on cannabis use appears mixed, with some studies showing significant benefits, while others do not. Nac appears to have more consistent benefits in adolescents, with multiple studies showing reduced cannabis use cravings or increased cessation. In adults, the results are more variable, some trials showing significant reductions in use and withdrawal symptoms, while others do not. Notably, nac may be more effective in adults with cannabis use disorder who do not have comorbid depressive symptoms. So ChadGBT was pretty good. Now it's my turn. Here we go. The results from these studies are inconsistent. Here we go. The results from these studies are inconsistent. Nac appears to have some benefit in reducing cannabis use, but we haven't found a consistent trend yet. So I think we can all agree that ChadGBT sounds way smarter than me, but our conclusions are the same.

Speaker 1:

Now, the next thing that the authors looked at were side effects from the NAC, to quote the authors. Quote NAC was found to be safe with a minimum incidence of adverse effects in most studies. End quote. Some of the side effects that were reported included irritability, heartburn, insomnia, abdominal discomfort, hot flashes, headaches and vivid dreams. In one study, adverse effects were more common in the placebo group. There were six cases of serious side effects in the placebo group, with only one in the NAC group. So overall, nac is safe and well-tolerated and I have to say side effects from placebo always make me smile.

Speaker 1:

In terms of the dosing of NAC, it was the same in every study it was 2400 milligrams per day. However, the review article didn't give much explanation of how this was done, so I had to dig in a little bit. Unfortunately, addiction in general and cannabis use disorder are not FDA-approved indications for NAC. So I looked up NAC on UpToDate, but I couldn't find anything about how to prescribe NAC for addiction or cannabis use. So I logged into my electronic health record and opened up the chart of our test patient. It turns out, I can prescribe NAC in the form of 600 milligram oral capsules, nac in the form of 600 milligram oral capsules, and there's also a 600 milligram extended release capsule too. I then went back and looked at the studies that this article reviewed, and 1,200 milligrams of NAC orally twice daily was the way that it was dosed. Now I tried to figure out the difference between regular and extended release N-acetylcysteine, and I really couldn't find any information on when one is used versus the other. But the studies that I reviewed all just said NAC and not extended-release NAC. So my assumption is that it was 1,200 mg of regular NAC used twice daily orally. Okay, back to the article.

Speaker 1:

Here we go, getting to the discussion section. The authors looked at what they found in their review of the eight randomized controlled trials looking at NAC for cannabis use, and they tried to provide us with some good summary data, and their conclusion was the same as mine and ChatGPT's, which is that there seems to be some signal that NAC works for cannabis use disorder, but we haven't figured out exactly who it works for and in what clinical circumstance. The authors then, in the discussion section, went on to discuss some of their thoughts on why there were mixed results. The studies had different durations and study outcomes, which certainly could explain why some studies showed a difference while others did not. The authors then looked at study limitations. Most of the studies had very similar limitations. Some patients dropped out or did not follow up, and not everyone took their medication NAC or placebo reliably. So that's probably not a major reason why some studies showed a benefit while others did not, as medication noncompliance and dropping out of the study were likely pretty similar across all of the studies, and with that the authors moved on to their conclusions. With that, the authors moved on to their conclusions.

Speaker 1:

Quote in summary, it is premature to conclude that there is a strong level of evidence for NAC use in cannabis use disorder. In this review we found the strength of the evidence available on which to make a recommendation as strong, but the results of the studies are equivocal as to whether NAC is helpful for treating cannabis use disorder. The studies collectively offer mixed results for diverse clinical endpoints such as abstinence, frequency of use, cannabis cessation, craving withdrawal and medication adherence. Collectively, these problems prevent us from fully understanding the efficacy of NAC for cannabis use disorder and indicate the need for future well-designed, rigorous and high-quality randomized controlled trials with homogenous endpoints to develop an evidence base that can more decisively provide an estimate of NAC effectiveness, which, to me, is spot on.

Speaker 1:

There seems to be some signal that NAC helps for cannabis use, but we haven't worked out all the details yet. What do we do with this information? Or, better yet, what are some take-home points from this article? First, there is some limited evidence that N-acetylcysteine, also known as NAC or NAC, dosed at 1,200 milligrams twice daily orally can reduce cannabis use. Second, more research is needed on the optimal clinical scenario in which NAC will help patients using cannabis. And third, in the meantime, nac is overall a benign medication that is generally well tolerated In patients who want to reduce or stop their cannabis use who have not responded to other interventions. It would be reasonable to try, so long as the patient knows that the data on NAC for cannabis use is preliminary and the patient is on board with trying it.

Speaker 1:

Before we wrap up, a huge thank you to the Montage Health Foundation for backing my mission to create fun, engaging education on addiction, and a shout out to the nonprofit Central Coast Overdose Prevention for teaming up with me on this podcast. Our partnership helps me get the word out about how to treat addiction and prevent overdoses To those healthcare providers out there treating patients with addiction. You're doing life-saving work and thank you for what you do For everyone else tuning in. Thank you for taking the time to learn about addiction. It's a fight we cannot win without awareness and action. There's still so much we can do to improve how addiction is treated. Together we can make it happen. Thanks for listening and remember treating addiction saves lives. You.