Ketamine for Methamphetamine Use Disorder

(KMD Trial)

Recruiting at 2 trial locations

Overseen By Alain Litwin, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Texas Southwestern Medical Center

Disqualifiers: Pregnancy, Breastfeeding, Incarceration, others

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

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

Compensation: Varies

Number of Visits: 20

Duration: 6 weeks

120 Participants Needed

Trial Summary

What is the purpose of this trial?

This study aims to determine whether treatment response with IV ketamine is superior to treatment response with IV midazolam in adults with moderate to severe MUD. The study design is a 12-week randomized, double-blind, controlled trial comparing intravenous (IV) ketamine against IV midazolam, delivered over six weeks in 120 adults with moderate to severe methamphetamine use disorder (MUD).

Do I need to stop my current medications to join the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team during the screening visit.

What data supports the effectiveness of the drug Ketamine Hydrochloride for Methamphetamine Use Disorder?

Research shows that ketamine can have rapid antidepressant effects in people with mood disorders, and it is effective for sedation and pain relief in medical procedures. This suggests it might help with methamphetamine use disorder by addressing mood issues and providing sedation. ^{1 2 3 4 5}

Is ketamine safe for use in humans?

Research shows that ketamine, often used with midazolam, is generally safe for sedation in both children and adults, with some side effects like nausea and vomiting. It has been used safely in emergency and pain management settings, especially in children, with no major complications reported. ^{6 7 8 9 10}

How is the drug combination of ketamine and midazolam unique for treating methamphetamine use disorder?

The combination of ketamine and midazolam is unique because ketamine can provide deep sedation and has been used effectively for procedural sedation, while midazolam helps reduce anxiety and unpleasant side effects associated with ketamine. This combination may offer a novel approach for methamphetamine use disorder, as there are no standard treatments specifically for this condition. ^{2 4 10 11 12}

Research Team

Manish Jha, MBBS

Principal Investigator

Associate Professor

Eligibility Criteria

Adults with moderate to severe methamphetamine use disorder (MUD) can join this study. The trial is designed for those who are seeking treatment and have not found success with other options.

Inclusion Criteria

I am between 18 and 65 years old.

Use acceptable methods of contraception during participation in the study

Be interested in reducing or stopping methamphetamine use

Exclusion Criteria

Have been in a research study of pharmacological or behavioral treatment for addiction within 6 months prior to written informed consent

Be currently in jail, prison, or inpatient overnight facility as required by court of law

I have surgery scheduled soon.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either IV ketamine or IV midazolam over six weeks, with eight infusions and weekly medical management sessions

6 weeks

8 visits (in-person) for infusions, 6 visits (in-person) for medical management

Cognitive Behavioral Therapy

Participants engage in weekly cognitive behavioral therapy sessions on non-infusion days

12 weeks

12 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ketamine Hydrochloride
• Midazolam Hydrochloride

Trial Overview The trial is testing if IV ketamine works better than IV midazolam in treating MUD. Participants will be randomly assigned to receive one of the two drugs over a six-week period, as part of a 12-week study.

Participant Groups

Group I: Ketamine Experimental Treatment 1 Intervention

Participants will receive IV ketamine (0.50mg/kg) dissolved in 0.9% sodium chloride in a total volume of 100mL and administered with an infusion pump at a constant rate over 40 minutes. IV ketamine will be administered 8 times over 6 weeks.

Group II: Midazolam Active Control 1 Intervention

Participants will receive IV midazolam (0.02mg/kg) dissolved in 0.9% sodium chloride in a total volume of 100mL and administered with an infusion pump at a constant rate over 40 minutes. IV midazolam will be administered 8 times over 6 weeks.

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

Approved in United States as Ketalar for:

• Anesthesia
• Pain management
• Depression
• Suicidal ideation

Approved in European Union as Ketamine Hydrochloride for:

• Anesthesia
• Pain management
• Treatment-resistant depression

Approved in Canada as Ketamine Hydrochloride for:

• Anesthesia
• Pain management
• Depression

Who Is Running the Clinical Trial?

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

Findings from Research

In a study involving 140 out-patients undergoing maxillo-facial surgery, low-dose ketamine combined with midazolam was found to effectively reduce intraoperative anxiety and provide amnesia for the procedure, with patients reporting positive sensations compared to the control group.

The higher dosage of ketamine (0.5 mg/kg) not only maintained effective sedation during surgery but also improved postoperative vigilance, making it a suitable option for conscious sedation, while lower doses resulted in less favorable operating conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Analgesia-sedation for maxillo-facial surgery with midazolam-pentazocine and miazolam-ketamine. Clinical double-blind study of anxiety, analgesia, sedation and amnesia]. Lipp, M., Daubländer, M., Sebastian, M., et al.[2019]

The combination of midazolam and ketamine is explored for its effectiveness in emergency medicine, particularly for sedation and pain management.

This combination may benefit specific patient populations, although the abstract does not provide detailed data on the number of subjects or specific outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midazolam with ketamine: Who benefits? Kennedy, RM., McAllister, JD.[2017]

Ketamine hydrochloride has shown rapid and significant antidepressant effects in patients with treatment-resistant mood and anxiety disorders, although the studies supporting this have small sample sizes and limited long-term data.

While ketamine may offer benefits for some patients, there are important safety concerns and limitations in the existing research that must be considered when using it as an off-label treatment for psychiatric disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. Sanacora, G., Frye, MA., McDonald, W., et al.[2022]

In a study of 41 adult patients, intravenous ketamine provided deeper sedation compared to midazolam/fentanyl for procedural sedation during fracture and joint dislocation reductions.

While ketamine was found to be as effective as midazolam/fentanyl, it was associated with more adverse effects, and three patients in the midazolam/fentanyl group experienced oxygen desaturation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous ketamine is as effective as midazolam/fentanyl for procedural sedation and analgesia in the emergency department. Jamal, SM., Fathil, SM., Nidzwani, MM., et al.[2022]

A systematic review of five randomized controlled trials involving 346 uncooperative children found that the combination of midazolam and ketamine was significantly more effective for sedation, achieving an 84% success rate compared to midazolam alone.

Children receiving the midazolam and ketamine combination exhibited calmer behavior (50%) compared to those receiving midazolam alone (37%), with only modest adverse effects that did not require special treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Evaluation of Ease of Dental Treatment and Clinical Efficiency of Midazolam vs Midazolam and Ketamine Combination for Sedation in Young Uncooperative Pediatric Patients: A Systematic Review. Rathi, GV., Padawe, D., Takate, V., et al.[2023]

A review of four studies involving children in emergency departments found that both ketamine and midazolam provide similar efficacy and safety for conscious sedation.

Despite their comparable profiles, ketamine is favored by both parents and physicians, suggesting a preference for its use in pediatric sedation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midazolam or ketamine for procedural sedation of children in the emergency department. Munro, A., Machonochie, I.[2018]

In a study involving 92 pediatric oncology patients undergoing 226 procedures, the combination of midazolam and ketamine was found to be safe and effective for managing pain, with no complications reported.

The treatment provided satisfactory analgesia in 89 out of 92 patients and induced brief unconscious sedation lasting an average of ten minutes, demonstrating its efficacy in a clinical setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of intravenous ketamine-midazolam association for pain procedures in children with cancer. A prospective study. Pellier, I., Monrigal, JP., Le Moine, P., et al.[2022]

In a study of 58 pediatric oncology patients undergoing procedural sedation, midazolam-ketamine (M-K) resulted in a shorter induction time but longer overall sedation and emergence times compared to midazolam-fentanyl (M-F).

Patients receiving M-K experienced a higher rate of vomiting but reported less pain during the procedure compared to those receiving M-F, with overall satisfaction and adverse effects being similar for both sedation regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of midazolam with fentanyl versus midazolam with ketamine for bedside invasive procedural sedation in pediatric oncology patients: A randomized, double-blinded, crossover trial. Monsereenusorn, C., Malaithong, W., Lertvivatpong, N., et al.[2022]

In a study of 182 adult emergency department patients, coadministering midazolam with ketamine significantly reduced recovery agitation from 25% to 8%, indicating its efficacy in improving patient comfort during recovery (number needed to treat = 6).

The study found no significant difference in the incidence of adverse events, such as recovery agitation, respiratory issues, or nausea/vomiting, between intravenous and intramuscular routes of ketamine administration, suggesting both methods are equally safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ketamine with and without midazolam for emergency department sedation in adults: a randomized controlled trial. Sener, S., Eken, C., Schultz, CH., et al.[2013]

A nurse-led conscious sedation protocol using oral ketamine and midazolam for pediatric burn patients was found to be safe, with only 2.3% of cases requiring conversion to general anesthesia and 6.9% needing an anesthetist for reasons other than sedation top-ups.

The study involved 45 children undergoing 131 procedures, demonstrating that this method effectively managed pain and anxiety during burn dressing changes without the need for direct anesthetic supervision.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A 2 year experience of nurse led conscious sedation in paediatric burns. O'Hara, D., Ganeshalingam, K., Gerrish, H., et al.[2022]

Ketamine and midazolam are both effective as intravenous induction anesthetics, but they are typically used in combination with other agents like propofol or etomidate due to their side effects and specific clinical indications.

The review evaluates the use of these induction hypnotics in various clinical situations, highlighting that while ketamine and midazolam can be used alone, their combination with other drugs often enhances safety and efficacy in anesthesia induction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Drugs for intravenous induction of anesthesia: ketamine, midazolam and synopsis of current hypnotics]. Halbeck, E., Dumps, C., Bolkenius, D.[2019]

In a study involving 80 patients undergoing emergency surgery, both midazolam and a midazolam-ketamine combination were found to be safe and effective for rapid induction of anesthesia, offering better hemodynamic stability compared to thiopental.

Midazolam not only provided effective anxiolysis and reduced unpleasant emergence reactions associated with ketamine but also helped mitigate the cardiostimulatory effects seen with ketamine, making it a preferable choice in hemodynamically sensitive situations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative evaluation of intravenous agents for rapid sequence induction--thiopental, ketamine, and midazolam. White, PF.[2019]

References

1. Germany pubmed.ncbi.nlm.nih.gov

[Analgesia-sedation for maxillo-facial surgery with midazolam-pentazocine and miazolam-ketamine. Clinical double-blind study of anxiety, analgesia, sedation and amnesia]. [2019]

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

Midazolam with ketamine: Who benefits? [2017]

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

A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. [2022]

4. Malaysia pubmed.ncbi.nlm.nih.gov

Intravenous ketamine is as effective as midazolam/fentanyl for procedural sedation and analgesia in the emergency department. [2022]

5. India pubmed.ncbi.nlm.nih.gov

Comparative Evaluation of Ease of Dental Treatment and Clinical Efficiency of Midazolam vs Midazolam and Ketamine Combination for Sedation in Young Uncooperative Pediatric Patients: A Systematic Review. [2023]

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

Midazolam or ketamine for procedural sedation of children in the emergency department. [2018]

7. France pubmed.ncbi.nlm.nih.gov

Use of intravenous ketamine-midazolam association for pain procedures in children with cancer. A prospective study. [2022]

8. England pubmed.ncbi.nlm.nih.gov

The efficacy and safety of midazolam with fentanyl versus midazolam with ketamine for bedside invasive procedural sedation in pediatric oncology patients: A randomized, double-blinded, crossover trial. [2022]

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

Ketamine with and without midazolam for emergency department sedation in adults: a randomized controlled trial. [2013]

10. Netherlands pubmed.ncbi.nlm.nih.gov

A 2 year experience of nurse led conscious sedation in paediatric burns. [2022]

11. Germany pubmed.ncbi.nlm.nih.gov

[Drugs for intravenous induction of anesthesia: ketamine, midazolam and synopsis of current hypnotics]. [2019]

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

Comparative evaluation of intravenous agents for rapid sequence induction--thiopental, ketamine, and midazolam. [2019]