Ketamine vs Midazolam for Tobacco Use Disorder

(SED-TUD2 Trial)

Overseen By Merideth A Addicott, MD

Age: 18 - 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Wake Forest University Health Sciences

Must not be taking: Psychoactive drugs

Disqualifiers: Chronic pulmonary disease, coronary artery disease, hypertension, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 2 weeks per infusion cycle

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how different treatments, including ketamine (an anesthetic), midazolam, and dexmedetomidine, affect cigarette smoking habits and cravings. Participants will receive two injections in random order: one of the experimental drugs and one placebo (a harmless solution with no active ingredients). The goal is to identify which treatment might help reduce smoking and understand its impact on the brain. The trial seeks individuals who have smoked daily for at least two years and can pass a drug and alcohol screening. As an Early Phase 1 trial, this research focuses on understanding how these treatments work in people, offering participants a chance to contribute to groundbreaking research.

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

The trial does not specify if you need to stop taking your current medications, but it excludes those using drugs that would interact with the study drug or increase the risk of adverse events. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that both ketamine and midazolam have been safely used in people, though each has specific considerations. Ketamine acts quickly as an anesthetic. It is generally safe in medical settings but can cause drowsiness and affect coordination. Patients should fully recover from its effects before leaving the medical facility.

Midazolam is often used to make patients sleepy and calm before medical procedures. Studies indicate it is safe under medical supervision. However, it can cause drowsiness and slow breathing, so monitoring is important.

Healthcare professionals must administer both drugs carefully to ensure safety. This trial is in an early phase, and researchers are still collecting safety data to better understand how these treatments affect people. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using ketamine for tobacco use disorder because it offers a novel approach compared to traditional smoking cessation aids like nicotine replacement therapies, varenicline, and bupropion. Unlike these options, which often target nicotine receptors or mood regulation, ketamine acts on the brain's glutamate system, potentially altering addiction pathways in a new way. Additionally, ketamine can provide rapid effects, possibly reducing cravings and withdrawal symptoms quicker than conventional treatments. This innovative mechanism and the potential for fast-acting results make ketamine a promising candidate for those struggling to quit smoking.

What evidence suggests that this trial's treatments could be effective for tobacco use disorder?

This trial will compare the effects of ketamine and midazolam on tobacco use disorder. Research suggests that ketamine might help with substance use disorders by reducing cravings. However, one small study found that ketamine did not significantly change smoking habits or cravings for tobacco, although participants tolerated it well. Midazolam is often used to help people relax, but little evidence exists about its effect on tobacco addiction. The most effective treatments for quitting smoking usually combine counseling with proven methods like nicotine patches or gum. In summary, while ketamine and midazolam show some promise, strong evidence does not yet support their effectiveness in treating tobacco addiction specifically. Participants in this trial will receive different combinations of these treatments to evaluate their effectiveness. ^{6 7 8 9 10}

Who Is on the Research Team?

Merideth A Addicott, MD

Principal Investigator

Wake Forest University Health Sciences

Are You a Good Fit for This Trial?

This trial is for daily cigarette smokers of at least 2 years, with specific levels of carbon monoxide or cotinine in their breath/urine and no recent use of psychoactive drugs. It excludes those with serious head trauma, certain mental health conditions, unstable medical issues, pregnant or breastfeeding women, extreme obesity, poor vision not correctable to 20/40, severe hypertension or liver/kidney dysfunction.

Inclusion Criteria

Afternoon expired breath carbon monoxide at least 5 ppm or morning urinary cotinine at least 100 ng/ml

Negative urine drug screen for psychoactive drugs and negative breath alcohol

Smokes cigarettes daily for at least 2 years

Exclusion Criteria

I do not have any health conditions that could affect the study treatment.

I have had a serious head injury or a neurological condition like seizures.

I am not pregnant or breastfeeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intravenous infusions of either ketamine, midazolam, dexmedetomidine, or placebo, with a 7-day ecological momentary assessment of craving, withdrawal, and smoking behavior before and after each infusion.

2 weeks per infusion cycle

Multiple visits for infusions and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment, including measures of craving, withdrawal, MRI scan, and smoking latency.

24 hours post-infusion

1 visit (in-person) for follow-up assessments

Long-term follow-up

Participants may be monitored for any long-term effects or adverse events after the completion of the main trial phases.

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ketamine
• Midazolam

Trial Overview The study tests the effects of sedatives (ketamine, midazolam, dexmedetomidine) versus a placebo (saline) on smoking behavior and cravings. Participants are randomly assigned to receive one treatment intravenously without knowing which one they get—a method known as double-blind.

How Is the Trial Designed?

Group I: Saline first injection; midazolam second injection Experimental Treatment 2 Interventions

Subjects in this arm will receive a single intravenous infusion of placebo at the first injection visit and a single intravenous infusion midazolam at the second injection visit

Group II: Saline first injection; ketamine second injection Experimental Treatment 2 Interventions

Subjects in this arm will receive a single intravenous infusion of placebo at the first injection visit and a single intravenous infusion ketamine at the second injection visit.

Group III: Saline first injection; dexmedetomidine second injection Experimental Treatment 2 Interventions

Subjects in this arm will receive a single intravenous infusion of placebo at the first injection visit and a single intravenous infusion dexmedetomidine at the second injection visit.

Group IV: Midazolam first injection; ketamine second injection Experimental Treatment 2 Interventions

Subjects in this arm will receive a single intravenous infusion of midazolam at the first injection visit and a single intravenous infusion ketamine at the second injection visit.

Group V: Midazolam first injection; dexmedetomidine second injection Experimental Treatment 2 Interventions

Subjects in this arm will receive a single intravenous infusion of midazolam at the first injection visit and a single intravenous infusion dexmedetomidine at the second injection visit.

Group VI: Midazolam first injection; Saline second injection Experimental Treatment 2 Interventions

Subjects in this arm will receive a single intravenous infusion of midazolam at the first injection visit and a single intravenous infusion placebo at the second injection visit.

Group VII: Ketamine first injection; midazolam second injection Experimental Treatment 2 Interventions

Subjects in this arm will receive a single intravenous infusion of ketamine at the first injection visit and a single intravenous infusion midazolam at the second injection visit.

Group VIII: Ketamine first injection; dexmedetomidine second injection Experimental Treatment 2 Interventions

Subjects in this arm will receive a single intravenous infusion of ketamine at the first injection visit and a single intravenous infusion dexmedetomidine at the second injection visit.

Group IX: Ketamine first injection; Saline second injection Experimental Treatment 2 Interventions

Subjects in this arm will receive a single intravenous infusion of ketamine at the first injection visit and a single intravenous infusion placebo at the second injection visit.

Group X: Dexmedetomidine first injection; midazolam second injection Experimental Treatment 2 Interventions

Subjects in this arm will receive a single intravenous infusion of dexmedetomidine at the first injection visit and a single intravenous infusion midazolam at the second injection visit.

Group XI: Dexmedetomidine first injection; ketamine second injection Experimental Treatment 2 Interventions

Subjects in this arm will receive a single intravenous infusion of dexmedetomidine at the first injection visit and a single intravenous infusion ketamine at the second injection visit.

Group XII: Dexmedetomidine first injection; Saline second injection Experimental Treatment 2 Interventions

Subjects in this arm will receive a single intravenous infusion of dexmedetomidine at the first injection visit and a single intravenous infusion placebo at the second injection visit.

Ketamine is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in European Union as Ketalar for:

• Anesthesia
• Treatment-resistant depression

Approved in United States as Spravato for:

• Treatment-resistant depression

Approved in European Union as Spravato for:

• Treatment-resistant depression

Approved in Canada as Spravato for:

• Treatment-resistant depression

Who Is Running the Clinical Trial?

Wake Forest University Health Sciences

Lead Sponsor

Trials

1,432

Recruited

2,506,000+

Nida Addiction Research Center

Collaborator

Trials

1

Recruited

50+

Published Research Related to This Trial

In a study involving 41 healthy children under 36 months, the combination of oral midazolam and ketamine (MK) significantly improved cooperative behavior during dental treatment compared to midazolam alone (MS) or no sedation (PS).

No immediate or post-discharge side effects were observed in the groups receiving midazolam and ketamine, indicating that this sedation method is safe for young children undergoing dental procedures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined oral midazolam-ketamine better than midazolam alone for sedation of young children: a randomized controlled trial. Moreira, TA., Costa, PS., Costa, LR., et al.[2022]

In a study of 87 children undergoing ophthalmologic surgeries, a combination of low-dose midazolam and ketamine provided effective sedation and reduced anxiety, similar to high-dose midazolam and ketamine.

The low-dose combination resulted in faster recovery times and a lower incidence of excessive salivation compared to the high-dose group, making it a safer option for premedication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low- versus high-dose combination of midazolam-ketamine for oral premedication in children for ophthalmologic surgeries. Darlong, V., Shende, D., Singh, M., et al.[2022]

Intramuscular ketamine (2.5 mg/kg) resulted in less crying and a lower need for restraint during suturing procedures in children compared to intranasal midazolam (0.5 mg/kg), indicating it may provide a more effective sedation experience.

Both sedation methods had similar recovery behaviors and discharge times, but ketamine was preferred by medical staff and parents, suggesting it may be a more favorable option for procedural sedation in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An alternative to "brutacaine": a comparison of low dose intramuscular ketamine with intranasal midazolam in children before suturing. McGlone, RG., Ranasinghe, S., Durham, S.[2022]

Chronic ketamine users exhibit significant impairments in verbal and visual memory, while their working memory and executive functions remain intact, based on a study involving 286 non-heavy and 279 heavy other drug users compared to 261 healthy controls.

The study found that the frequency and dosage of ketamine use correlate with worse memory performance, particularly in visual memory for non-heavy users and short-term verbal memory for heavy users, indicating that increased ketamine use negatively affects specific cognitive functions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Other drug use does not impact cognitive impairments in chronic ketamine users. Zhang, C., Tang, WK., Liang, HJ., et al.[2019]

Ketamine has shown potential benefits in treating psychiatric conditions like major depression and in supporting abstinence from alcohol and opiates, based on a literature review of studies from 2003 to 2013.

Despite its promising therapeutic effects, ketamine poses a risk of abuse and dependence, leading to various somatic, psychiatric, and cognitive complications, highlighting the need for careful consideration in its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Ketamine: psychiatric indications and misuses]. Delimbeuf, N., Petit, A., Karila, L., et al.[2015]

In a study involving 367 patients with mood disorders, ketamine demonstrated significant efficacy in improving clinical outcomes compared to both midazolam and saline, with effect sizes of 0.7 and 1.8 respectively, indicating strong therapeutic potential.

Using midazolam as a control in ketamine studies resulted in smaller observed effects of ketamine compared to using saline, suggesting that midazolam may enhance the perceived effectiveness of ketamine due to its own impact on mood.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of midazolam vs. saline on effect size estimates in controlled trials of ketamine as a rapid-acting antidepressant. Wilkinson, ST., Farmer, C., Ballard, ED., et al.[2021]

Oral ketamine has shown effectiveness in treating severe depression, including treatment-resistant cases and those with suicidal ideation, based on various studies including randomized controlled trials with doses ranging from 0.25 to 7 mg/kg.

Despite its lower bioavailability (20%-25% reaching the bloodstream), oral ketamine is well tolerated and can be adjusted for individual needs, making it a practical option for depression treatment alongside conventional antidepressants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Ketamine for Depression, 1: Pharmacologic Considerations and Clinical Evidence. Andrade, C.[2019]

In a study involving 38 ponies undergoing field castration, the combination of ketamine and midazolam for anaesthetic induction resulted in significantly better scores for induction quality, ease of intubation, and surgical relaxation compared to ketamine alone.

The ketamine-midazolam group also required fewer additional doses of sedatives and had longer times before the ponies began to move or stand, indicating a smoother and more controlled anaesthetic experience without affecting the quality of recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of the use of midazolam as a co-induction agent with ketamine for anaesthesia in sedated ponies undergoing field castration. Allison, A., Robinson, R., Jolliffe, C., et al.[2022]

In a clinical trial, ketamine-assisted psychotherapy (KPT) significantly improved treatment outcomes for alcoholism, with 65.8% of patients achieving total abstinence for over a year, compared to only 24% in the conventional treatment group.

KPT appears to induce beneficial psychological changes, such as improved self-concept and life values, while also affecting neurotransmitter systems related to alcohol dependence, suggesting a multifaceted mechanism of action for its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine psychedelic therapy (KPT): a review of the results of ten years of research. Krupitsky, EM., Grinenko, AY.[2022]

A longitudinal study of 101 young injection drug users (IDUs) in Los Angeles revealed that ketamine is injected infrequently compared to other drugs, with most users either stopping or reducing their use over time due to negative experiences or declining availability.

The study identified three patterns of ketamine injection among participants: 'Moderates,' 'Occasionals,' and 'Abstainers,' suggesting that targeted interventions for specific groups, like homeless youth, may be effective in reducing ketamine injection rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Longitudinal trajectories of ketamine use among young injection drug users. Lankenau, SE., Bloom, JJ., Shin, C.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6094990/

Efficacy of Ketamine in the Treatment of Substance Use ... Their results showed that ketamine could suppress physiologic response to opiate withdrawal. Mean arterial pressure, heart rate, and serum cortisol were ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05796791

Study Details | NCT05796791 | Ketamine and Motivational ... The purpose of the study is to examine whether an investigational medication called ketamine is able to improve treatment outcomes for tobacco use disorder when ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39834135/

tolerability and initial impact on tobacco use outcomes Results: Intravenous ketamine was well tolerated with transient side effects. No significant effects were noted on cigarette smoking, craving, ...

4. researchgate.net researchgate.net/publication/388234568_A_pilot_study_of_ketamine_among_individuals_with_tobacco_use_disorder_tolerability_and_initial_impact_on_tobacco_use_outcomes

A pilot study of ketamine among individuals with tobacco ... Based on the AUD, OUD, and CUD literature, subanesthetic ketamine administration may reduce key symptoms of SUDs, manifesting subjectively as decreased cravings ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2949875925000840

Role of ketamine in the treatment of substance use disorders This review evaluates ketamine's potential for treating alcohol, cocaine, opioid, and cannabis use disorders.

6. northamerica.covetrus.com northamerica.covetrus.com/Content/pdfs/P010177.pdf

SAFETY DATA SHEET May be harmful if absorbed through the skin. (based on components) . Known Clinical Effects: Ketamine is an anesthetic agent which is known to cause double ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2017/016812s043lbl.pdf

KETALAR (ketamine hydrochloride) injection WHEN KETALAR IS USED ON AN OUTPATIENT BASIS, THE PATIENT SHOULD NOT BE RELEASED. UNTIL RECOVERY FROM ANESTHESIA IS COMPLETE AND THEN SHOULD BE ACCOMPANIED BY. A ...

8. drugs.com drugs.com/illicit/ketamine.html

Ketamine Abuse, Hazards & Overdose It is often "snorted" up the nose, injected, mixed into drinks, or smoked with marijuana or tobacco. Examples of other dissociative drugs include ...

9. dailymed.nlm.nih.gov dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=14e8f864-8b8a-4e7e-8439-e510d3107063

Label: KETALAR- ketamine hydrochloride injection - DailyMed Withdrawal symptoms have been reported after the discontinuation of frequently used (more than weekly), large doses of ketamine for long periods of time.

10. go.drugbank.com go.drugbank.com/drugs/DB01221

Ketamine: Uses, Interactions, Mechanism of Action Ketamine is a rapid-acting general anesthetic producing an anesthetic state characterized by profound analgesia, normal pharyngeal-laryngeal reflexes.