N-Acetylcysteine for Substance Use Disorder

(NAC_CUD-TUD Trial)

Overseen By Madeline Martinez Rivas, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Ellen Herbst

Must not be taking: NAC, NRT, Bupropion, Varenicline

Disqualifiers: Psychotic disorders, Bipolar, Pregnancy, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 10

Duration: 8 weeks

59 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests NAC, a medication and supplement, to help adults who use both tobacco and cannabis reduce their cravings. NAC works by calming overactive brain signals and reducing stress, making it easier to control cravings. N-acetylcysteine (NAC) has been tested in previous trials for cannabis use disorder, showing mixed results in efficacy.

Do I have to stop taking my current medications to join the trial?

Yes, you must stop using medications for tobacco use disorder (like NRT, bupropion, or varenicline) and non-study NAC during the trial. If you're taking bupropion for depression, you can still participate.

Will I have to stop taking my current medications?

You will need to stop using any medications for tobacco use disorder (like nicotine replacement therapy, bupropion, or varenicline) during the study. If you're taking bupropion for depression, not for smoking cessation, you can still participate.

What safety data is available for N-Acetylcysteine in treating substance use disorders?

N-Acetylcysteine (NAC) is considered a safe and well-tolerated treatment option for substance use disorders. Clinical studies, including a double-blind placebo-controlled crossover Phase I trial, have shown that NAC is well tolerated in cocaine-dependent individuals, with only mild side effects reported. Preliminary results suggest NAC may reduce withdrawal symptoms and craving. Animal studies also support its potential therapeutic use in addiction treatment, indicating that NAC can attenuate drug reward-associated behaviors and inhibit reinstatement of drug-seeking behavior. ^{1 2 3 4 5}

Is N-Acetylcysteine (NAC) safe for humans?

N-Acetylcysteine (NAC) is generally considered safe and well-tolerated in humans, with only mild side effects reported in studies involving individuals with substance use disorders. It has been tested in various conditions and shows promise in reducing withdrawal symptoms and cravings, particularly in cocaine-dependent individuals. ^{1 2 3 4 5}

Is N-Acetylcysteine a promising drug for substance use disorder?

Yes, N-Acetylcysteine (NAC) shows promise as a drug for treating substance use disorders. It may help reduce cravings and withdrawal symptoms in people with addictions, including cocaine and possibly alcohol. ^{2 3 5 6 7}

How is the drug N-Acetylcysteine (NAC) unique in treating substance use disorder?

N-Acetylcysteine (NAC) is unique because it helps restore balance in brain chemicals affected by drug use, potentially reducing cravings and withdrawal symptoms. Unlike some treatments, NAC is an over-the-counter supplement that has shown promise in treating various substance use disorders, including cocaine and alcohol dependence. ^{2 3 5 6 7}

What data supports the idea that N-Acetylcysteine for Substance Use Disorder is an effective treatment?

The available research shows that N-Acetylcysteine (NAC) may be effective in treating substance use disorders. For example, a pilot study on cocaine dependence found that most participants who completed the study either stopped using cocaine or significantly reduced their use. Another study on cannabis-dependent adolescents suggested that NAC could help them quit cannabis, a group for whom other treatments have not been very effective. While results from different studies have been mixed, NAC is considered safe and well-tolerated, and it shows promise in helping people reduce or stop using substances like cocaine, nicotine, and cannabis. ^{1 3 6 8 9}

What data supports the effectiveness of the drug N-Acetylcysteine for treating substance use disorder?

Research suggests that N-Acetylcysteine (NAC) may help reduce substance use and promote abstinence in people with addictions, including cocaine and cannabis. Studies show that NAC is generally safe and well-tolerated, and it may work by affecting brain chemicals involved in addiction. ^{1 3 6 8 9}

Who Is on the Research Team?

Ellen Herbst, MD

Principal Investigator

San Francisco Veterans Affairs Medical Center

Madeline Martinez Rivas, PhD

Principal Investigator

San Francisco Veterans Affairs Medical Center

Are You a Good Fit for This Trial?

This trial is for adult smokers in California who smoke cigarettes daily and have used cannabis in the last 30 days. They must want to quit smoking, not be using other cessation drugs or participating in another cessation study, and can't have certain psychiatric conditions or be pregnant.

Inclusion Criteria

You must smoke regular cigarettes every day, without adding cannabis.

All participants must be California residents (Veterans enrolled in VA healthcare in another state are eligible)

I am taking bupropion for depression, not to quit smoking.

Exclusion Criteria

Individuals who are pregnant or lactating

I am not using non-study chemotherapy now or during the study.

Participants with psychotic disorders, bipolar disorder, neurocognitive disorder, or other psychiatric or medical conditions judged by the PI to be unstable in the past 30 days, based on MINI

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive N-acetylcysteine (NAC) 3600 mg per day or placebo, along with weekly cognitive behavioral therapy sessions for 8 weeks

8 weeks

8 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments at Weeks 0, 4, 8, and 12

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• N-Acetyl cysteine

Trial Overview The trial tests N-Acetylcysteine (NAC) against a placebo while participants also receive Cognitive Behavioral Therapy (CBT). It aims to see if NAC helps reduce cravings and use of both tobacco and cannabis compared to just CBT alone.

How Is the Trial Designed?

Group I: N-acetyl cysteine (NAC) & cognitive behavioral therapy Experimental Treatment 2 Interventions

N-acetyl cysteine (NAC) \& cognitive behavioral therapy experimental arm consists of 30 regular cigarette smokers and cannabis users with current TUD, who will be randomized to receive N-acetyl cysteine 3600 mg per day over 8 weeks to experimental arm. Participants will also receive weekly cognitive behavioral therapy for substance use disorders targeting TUD and cannabis use.

Group II: Placebo Comparator: Placebo & cognitive behavioral therapy Placebo Group 2 Interventions

Placebo comparator \& cognitive behavioral therapy arm consists of 30 regular cigarette smokers and cannabis users with current TUD, who will be randomized to receive placebo over 8 weeks. Participants will also receive weekly cognitive behavioral therapy for substance use disorders targeting TUD and cannabis use.

N-Acetyl cysteine is already approved in United States, European Union for the following indications:

Approved in United States as NAC for:

• Antidote for acetaminophen overdose
• Mucolytic agent

Approved in European Union as NAC for:

• Antidote for paracetamol overdose
• Mucolytic agent

Who Is Running the Clinical Trial?

Ellen Herbst

Lead Sponsor

Trials

1

Recruited

60+

Tobacco Related Disease Research Program

Collaborator

Trials

27

Recruited

26,300+

Published Research Related to This Trial

In a double-blind, placebo-controlled trial involving 116 cannabis-dependent adolescents over 8 weeks, N-acetylcysteine (NAC) significantly increased the odds of achieving negative urine cannabinoid tests, suggesting it is an effective treatment for cannabis cessation.

NAC was well tolerated with minimal adverse events, indicating it is a safe option to use alongside psychosocial treatments for cannabis dependence in adolescents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. Gray, KM., Carpenter, MJ., Baker, NL., et al.[2022]

N-acetylcysteine (NAC) is highlighted as a safe and well-tolerated glutamatergic agent that shows promise as a pharmacotherapy for substance use disorders (SUDs), particularly in promoting abstinence from cocaine, nicotine, and cannabis.

While preliminary studies suggest NAC may be effective, results from randomized clinical trials have been mixed, indicating the need for further research to refine its use and better understand its mechanisms in treating SUDs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potential role of N-acetylcysteine in the management of substance use disorders. McClure, EA., Gipson, CD., Malcolm, RJ., et al.[2022]

N-acetylcysteine (NAC) significantly reduces craving symptoms in individuals with substance abuse, showing a standardized mean difference of -0.67 in a meta-analysis of 16 randomized controlled trials.

NAC also demonstrates a notable improvement in withdrawal and depressive symptoms combined, with a standardized mean difference of -0.35, indicating its potential effectiveness in treating these issues without increasing adverse effects compared to control groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of N-acetylcysteine in Treating Clinical Symptoms of Substance Abuse and Dependence: A Meta-analysis of Randomized Controlled Trials. Chang, CT., Hsieh, PJ., Lee, HC., et al.[2022]

N-acetylcysteine (NAC) shows promise as a treatment for substance abuse disorders, particularly for cocaine and cannabis dependence, based on a systematic review of nine clinical trials involving 165 patients.

The findings support the idea that NAC may work by influencing glutamatergic pathways, which are believed to play a role in the development of addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic review of N-acetylcysteine in the treatment of addictions. Asevedo, E., Mendes, AC., Berk, M., et al.[2019]

In a pilot study involving 23 cocaine-dependent patients over 4 weeks, N-acetylcysteine (NAC) was found to be well tolerated at doses of 1200 mg, 2400 mg, and 3600 mg per day.

Higher doses of NAC (2400 mg and 3600 mg) were associated with better retention rates, and most participants who completed the study either stopped using cocaine completely or significantly reduced their use, indicating NAC's potential as a treatment for cocaine dependence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study. Mardikian, PN., LaRowe, SD., Hedden, S., et al.[2022]

In a Phase I trial involving 13 healthy, cocaine-dependent participants, N-Acetylcysteine (NAC) was found to be well tolerated with only mild side effects reported, indicating its safety for use in this population.

Preliminary results suggest that NAC may help reduce withdrawal symptoms and cravings associated with cocaine dependence, showing potential efficacy as a treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of N-acetylcysteine in cocaine-dependent individuals. LaRowe, SD., Mardikian, P., Malcolm, R., et al.[2018]

Chronic administration of high doses of N-acetylcysteine (NAC) during the extinction phase significantly reduced morphine reward-associated behaviors in rats, suggesting its potential as a treatment for addiction.

Acute administration of NAC also decreased the reinstatement of morphine-induced conditioned place preference, indicating that NAC may help combat morphine dependence by affecting the glutamatergic system involved in addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic administration of N-acetylcysteine during the extinction period and on the reinstatement day decreased the maintenance of morphine rewarding properties in the rats. Katebi, SN., Torkaman-Boutorabi, A., Vousooghi, N., et al.[2022]

AD4, a form of N-acetylcysteine, effectively reduced cocaine-seeking behavior in rats, particularly in those with depression-like symptoms, suggesting its potential as a treatment for cocaine use disorder.

Repeated administration of AD4 or NAC during extinction training sessions significantly decreased the likelihood of relapse in drug-seeking behavior, indicating their efficacy in preventing relapse in addiction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N-acetylcysteine amide (AD4) reduces cocaine-induced reinstatement. Jastrzębska, J., Frankowska, M., Filip, M., et al.[2019]

In a study involving 302 participants with cannabis use disorder, those taking N-acetylcysteine (NAC) showed a 30% reduction in alcohol consumption compared to a placebo, indicating its potential efficacy in treating alcohol use disorder.

Participants receiving NAC had significantly higher odds of achieving alcohol abstinence and reported fewer drinks and drinking days per week, suggesting NAC could be a promising treatment option for individuals with alcohol use disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of N-acetylcysteine on alcohol use during a cannabis cessation trial. Squeglia, LM., Tomko, RL., Baker, NL., et al.[2019]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Potential role of N-acetylcysteine in the management of substance use disorders. [2022]

3. Korea (South) pubmed.ncbi.nlm.nih.gov

Effectiveness of N-acetylcysteine in Treating Clinical Symptoms of Substance Abuse and Dependence: A Meta-analysis of Randomized Controlled Trials. [2022]

4. Brazil pubmed.ncbi.nlm.nih.gov

Systematic review of N-acetylcysteine in the treatment of addictions. [2019]

5. England pubmed.ncbi.nlm.nih.gov

An open-label trial of N-acetylcysteine for the treatment of cocaine dependence: a pilot study. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Safety and tolerability of N-acetylcysteine in cocaine-dependent individuals. [2018]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Systemic administration of N-acetylcysteine during the extinction period and on the reinstatement day decreased the maintenance of morphine rewarding properties in the rats. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

N-acetylcysteine amide (AD4) reduces cocaine-induced reinstatement. [2019]

9. Ireland pubmed.ncbi.nlm.nih.gov

The effect of N-acetylcysteine on alcohol use during a cannabis cessation trial. [2019]