Nitrous Oxide for Depression

Recruiting at 1 trial location

Overseen By Peter Nagele, MD, MSc

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Chicago

Must not be taking: NMDA-antagonists

Disqualifiers: Bipolar, Schizophrenia, Substance use, others

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

Compensation: Varies

Number of Visits: 4

Duration: 4 weeks

172 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the effectiveness of nitrous oxide, commonly known as laughing gas, in treating major depression. Researchers are testing different doses to determine which works best and for how long. Individuals diagnosed with major depressive disorder (MDD) who find it affecting their daily life might be suitable candidates for this trial. Participants will receive either nitrous oxide or a placebo (a treatment with no active effect) during the study sessions. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you've used NMDA-antagonists like ketamine in the past 3 months or are undergoing ECT treatment.

Is there any evidence suggesting that nitrous oxide is likely to be safe for humans?

Research shows that nitrous oxide, commonly known as "laughing gas," is under study for its potential to help with depression. Studies suggest it might reduce symptoms of major depression, even in individuals who haven't found relief with other treatments.

Nitrous oxide is generally safe when used in medical settings, such as at the dentist, and has been for many years. However, researchers are still gathering safety information specifically for its use in treating depression. Current research hasn't identified major safety issues.

Nitrous oxide is currently being tested in a phase 2 trial. This phase evaluates how well participants tolerate the treatment and examines side effects. While more information is needed to fully understand its safety for depression, reaching this stage indicates it has been safe enough so far. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for depression?

Unlike the standard treatments for depression, which often involve medications like SSRIs or SNRIs, nitrous oxide uses a unique delivery method: inhalation. This method allows it to potentially provide rapid relief of depressive symptoms, which is a significant advantage over traditional oral medications that can take weeks to become effective. Researchers are particularly excited about nitrous oxide because it may work through a different mechanism, possibly involving modulation of neurotransmitter systems in the brain, offering a new avenue for those who don't respond to existing treatments.

What evidence suggests that nitrous oxide might be an effective treatment for depression?

Research has shown that nitrous oxide, often called "laughing gas," can alleviate symptoms in people with major depressive disorder. Specifically, using nitrous oxide at a 50% concentration has improved symptoms of depression, even for those unresponsive to other treatments. In this trial, participants will receive either nitrous oxide at 25% or 50% concentration or a placebo consisting of an oxygen-air mixture. This gas works similarly to ketamine by blocking certain brain signals that may lead to depression. Early studies suggest that the positive effects can occur quickly and be quite strong, although they might not last long. Overall, promising evidence indicates that nitrous oxide could be a helpful option for managing depression. ^{1 2 4 6 7}

Who Is on the Research Team?

Peter Nagele, MD, MSc

Principal Investigator

University of Chicago, Department of Anesthesia and Critical Care

Paul Myles, MD

Principal Investigator

The Alfred Hospital, Department of Anesthesiology and Perioperative Medicine

Are You a Good Fit for This Trial?

This trial is for adults with major depressive disorder (MDD), confirmed by specific criteria and a score >16 on the HDRS-21 scale. Participants must not have psychosis, recent substance abuse (except nicotine), ongoing ECT treatment, significant medical issues, or be pregnant/breastfeeding. Those with suicidal intentions, bipolar disorder, schizophrenia, panic disorder or certain other mental health conditions are excluded.

Inclusion Criteria

I have been diagnosed with major depression without psychosis.

Exclusion Criteria

Active suicidal intention, as determined by clinical interview assessment tool (Sheehan-STS) and clinical examination

A current or past history of bipolar disorder, schizophrenia, or schizoaffective disorder

Pregnancy or breastfeeding

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive weekly 1-hour inhalational sessions of either nitrous oxide or placebo for 4 weeks

4 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Nitrous Oxide
• Placebo

Trial Overview The study tests the antidepressant effects of nitrous oxide gas compared to a placebo in people with MDD. It aims to find the best dose and usage pattern for nitrous oxide to improve depression symptoms quickly and sustainably as preparation for a larger future trial.

How Is the Trial Designed?

Group I: Treatment; Nitrous Oxide 50% or 25%, group Active Control 1 Intervention

Four-weekly, 60-minute inhalation sessions of 25% or 50% nitrous oxide, randomly assigned.

Group II: Control; Oxygen-air mixture, group Placebo Group 1 Intervention

Four-weekly, 60-minute inhalation sessions of an oxygen and air mixture.

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

Approved in European Union as Nitrous oxide for:

• Anesthesia
• Pain relief
• Hypoxic respiratory failure in neonates

Approved in United States as Nitrous oxide for:

• Anesthesia
• Pain relief
• Hypoxic respiratory failure in neonates

Approved in Canada as Nitrous oxide for:

• Anesthesia
• Pain relief
• Hypoxic respiratory failure in neonates

Who Is Running the Clinical Trial?

University of Chicago

Lead Sponsor

Trials

1,086

Recruited

844,000+

The Alfred

Collaborator

Trials

110

Recruited

10,030,000+

Published Research Related to This Trial

Nitrous oxide (N2O) demonstrated a significant reduction in depression severity scores in patients with major depressive disorder (MDD) at 2 hours, 24 hours, and after 2 weeks, indicating both rapid and sustained antidepressant effects based on a meta-analysis of 4 studies involving 133 patients.

While N2O showed promising efficacy in improving depression symptoms, it was associated with a higher risk of nausea and vomiting, suggesting that safety considerations are important when using this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and tolerability of inhaled nitrous oxide in major depressive disorder: a systematic review and meta-analysis. Qiu, Y., Li, L., Duan, A., et al.[2023]

In a pilot study involving 23 participants with major depressive disorder, augmenting standard antidepressant treatment with nitrous oxide (N2O) significantly improved depressive symptoms, with a reduction in Hamilton Depression Rating Scale scores from 22.58 to 5.92 compared to a placebo group.

The study found that 91.7% of participants receiving N2O experienced a significant response (≥ 50% reduction in symptoms), and 75% achieved remission, although common side effects included nausea, vomiting, and headache.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrous oxide as an adjunctive therapy in major depressive disorder: a randomized controlled double-blind pilot trial. Guimarães, MC., Guimarães, TM., Hallak, JE., et al.[2021]

An 18-year-old female developed severe cognitive dysfunction and encephalatrophy after 5 months of recreational N2O use, suggesting that long-term exposure can lead to significant neurological issues.

Treatment with hyperbaric oxygen therapy (HBOT) over approximately 20 days resulted in a complete recovery of cognitive function, indicating that HBOT may be an effective intervention for N2O-related toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperbaric oxygen therapy to improve cognitive dysfunction and encephalatrophy induced by N2O for recreational use: a case report. Luo, D., Xu, J., Hu, L., et al.[2020]

A 22-year-old woman developed severe health issues, including polyneuropathy and pancytopenia, due to recreational nitrous oxide use, which caused a functional vitamin B12 deficiency and increased homocysteine levels.

After receiving vitamin B12 supplementation and rehabilitation, the patient showed significant recovery, highlighting the importance of recognizing and treating the serious complications associated with nitrous oxide abuse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrous oxide-induced polyneuropathy, pancytopenia and pulmonary embolism: a case report. Parein, G., Bollens, B.[2023]

This study aims to investigate whether a single inhaled dose of nitrous oxide (N2O) can provide rapid antidepressant effects in adolescents with major depressive disorder, with assessments at 2 and 24 hours post-administration.

The research will also explore if combining N2O with the SSRI fluoxetine leads to greater mood improvements over 12 weeks compared to fluoxetine alone, addressing the common delay in symptom relief associated with SSRIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrous oxide (N2O) and subsequent open-label SSRI treatment of adolescents with depression (NOTAD): study protocol for a randomised controlled trial. Stewart, RM., Wong, JWY., Runions, KC., et al.[2022]

Chronic abuse of nitrous oxide (N2O) in pediatric patients can lead to serious neurological issues, including symptoms like limb numbness and weakness, as seen in a study of 9 patients diagnosed with N2O-induced spinal cord degeneration.

Vitamin B12 deficiency was common among these patients, and while all received B12 supplementation and recovered muscle power within 2 months, some experienced lasting sensory deficits, highlighting the importance of prompt treatment to prevent permanent damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recreational nitrous oxide abuse related subacute combined degeneration of the spinal cord in adolescents - A case series and literature review. Lan, SY., Kuo, CY., Chou, CC., et al.[2022]

A systematic review identified 59 cases of nitrous oxide (N2O) use disorder and 17 cases of EMONO use disorder, highlighting the potential for addiction, especially when used in larger quantities and for longer durations than intended.

The study suggests that N2O use disorder can develop not only from recreational use but also from medical exposure, indicating a need for careful monitoring of its use in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nitrous oxide: What do we know about its use disorder potential? Results of the French Monitoring Centre for Addiction network survey and literature review. Fidalgo, M., Prud'homme, T., Allio, A., et al.[2020]

Two patients developed serious neurological issues, including limb weakness and numbness, after long-term recreational use of nitrous oxide (N2O), leading to a diagnosis of subacute combined degeneration (SCD).

Treatment involved stopping N2O use and administering vitamin B supplements, which significantly improved their symptoms, highlighting the need for awareness of N2O's neurotoxic effects and the importance of early diagnosis to prevent irreversible damage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subacute combined degeneration induced by nitrous oxide inhalation: Two case reports. Zhao, B., Zhao, L., Li, Z., et al.[2022]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S2667174325000588

Antidepressant Effects of Nitrous Oxide in Major ... In this study, we confirm that nitrous oxide has likely beneficial antidepressant effects in people with MDD.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03932825

NCT03932825 | Nitrous Oxide for Major Depressive Disorder This study aims at investigating the persistence of antidepressant effect of Nitrous Oxide (N2O) for Treatment-Resistant Depression(TRD).

3. psychiatryonline.org psychiatryonline.org/doi/10.1176/appi.ajp-rj.2024.200207

Nitrous Oxide in the Treatment of Depression: A Brief Review N2O is an N-methyl-d-aspartate receptor antagonist similar to ketamine and can produce rapid, robust, and short-acting reductions in depressive ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/34108247/

A phase 2 trial of inhaled nitrous oxide for treatment- ... Nitrous oxide at 50% inhaled concentration has been shown to improve depressive symptoms in patients with treatment-resistant major depression (TRMD).

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40503328/

Antidepressant Effects of Nitrous Oxide in Major ... We found some evidence that nitrous oxide had beneficial and persistent antidepressant effects in people with severe depression.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5825282/

Exploring Nitrous Oxide as Treatment for Mood Disorders Nitrous oxide (laughing gas) has shown early promise as a rapidly acting antidepressant in patients with treatment-resistant major depression.

7. journals.plos.org journals.plos.org/plosone/article?id=10.1371/journal.pone.0297330

Study protocol for a randomized placebo-controlled pilot trial ... Indeed, reductions in symptoms of depression have been observed as early as 2 hours post-treatment and sustained for 24 hours [14–16], with a ...