Ketamine vs Midazolam for Tobacco Use Disorder

(SED-TUD2 Trial)

Overseen By Merideth Addicott

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

52 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how different drugs affect smoking habits and cravings in people who are not trying to quit. Participants receive an injection of either ketamine, midazolam, dexmedetomidine, or a saltwater solution. The study aims to see if these drugs can help reduce cravings and withdrawal symptoms.

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.

How is ketamine unique as a drug for treating tobacco use disorder?

Ketamine is unique for treating tobacco use disorder because it acts rapidly on the brain's NMDA receptors, which are involved in mood and addiction pathways, potentially offering quick relief from cravings. This mechanism is different from traditional treatments like nicotine replacement therapies or behavioral interventions, which do not target these specific brain receptors. ^{1 2 3 4 5}

What evidence supports the effectiveness of the drug ketamine for treating tobacco use disorder?

Research suggests that ketamine has shown promise in treating addictions, such as alcohol and opiate dependence, and has been effective in psychiatric conditions like depression. This indicates potential for ketamine in treating tobacco use disorder, although specific studies on tobacco are not mentioned. ^{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

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]

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]

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 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]

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]

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 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]

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]

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]

Citations

1. Belgium pubmed.ncbi.nlm.nih.gov

[Ketamine: psychiatric indications and misuses]. [2015]

2. Ireland pubmed.ncbi.nlm.nih.gov

Other drug use does not impact cognitive impairments in chronic ketamine users. [2019]

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

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

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

Ketamine psychedelic therapy (KPT): a review of the results of ten years of research. [2022]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Longitudinal trajectories of ketamine use among young injection drug users. [2023]

6. India pubmed.ncbi.nlm.nih.gov

Low- versus high-dose combination of midazolam-ketamine for oral premedication in children for ophthalmologic surgeries. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Combined oral midazolam-ketamine better than midazolam alone for sedation of young children: a randomized controlled trial. [2022]

8. United States 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. [2022]

9. England pubmed.ncbi.nlm.nih.gov

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

10. England pubmed.ncbi.nlm.nih.gov

Impact of midazolam vs. saline on effect size estimates in controlled trials of ketamine as a rapid-acting antidepressant. [2021]