Papers

Research literature with structured metadata.

Trials

Registered studies by status, phase, and compound.

Topics

Indications and themes psychedelics are researched for.

Compounds

Evidence across molecules with rich data.

Countries

Regulation, access, and research activity by region.

Stakeholders

Organizations shaping the space across research, policy, and funding.

People

Investigators, clinicians, and authors with mapped output.

Courses

Training programs and certifications across modalities.

Events

Conferences, workshops, and convenings by date and focus.

Results

Compare outcome data across trials and publications.

Research Snapshot

One-page overview of trials, participants, papers, and research networks.

Clinical Guidelines

Trial-anchored manuals and protocol guidance with competency mapping.

Research recaps

Monthly evidence summaries with key takeaways.

Map of research

Landscape view of trials, compounds, and outcomes.

Newsletter

Weekly or daily updates on trials, publications, analysis, and more.

Research Groups

Worldwide map of psychedelic research centres by region.

Road to Access

Science, regulation, and economics on the path to patient access.

Research Network

Interactive co-authorship map of psychedelic researchers.

Top papers

Find needles in the haystack of psychedelic research per topic.

AskBeta
Pricing

The intelligence layer for psychedelic research.

Company

  • About
  • Contact
  • Newsletter

Product

  • Feedback
  • Roadmap
  • Changelog
  • API
  • Partners
  • Clinical Guidelines

Legal

  • Privacy
  • Terms

© 2026 Blossom. All rights reserved.

Home/Research/Nitrous Oxide/Major Depressive Disorder (MDD)

Nitrous Oxide for Major Depressive Disorder (MDD)

4 papers and 2 clinical trials exploring nitrous oxide as a treatment for major depressive disorder (mdd).

CompoundInorganic Gas

Nitrous Oxide

Nitrous oxide (N₂O) is a rapid-acting NMDA receptor antagonist with emerging evidence for antidepressant efficacy in treatment-resistant depression. Delivered as a 50% N₂O/50% O₂ inhalation mixture over one-hour sessions, it produces rapid mood improvements that can persist for days to weeks. Its established safety record in anesthesia, short session duration, minimal recovery time, and low cost position it as a potentially scalable alternative to IV ketamine and esketamine, though the psychiatric evidence base remains early-stage and no formal psychiatric indication exists. Key open questions include optimal dosing frequency, long-term durability, and the mechanism by which NMDA antagonism without intense psychedelic phenomenology produces antidepressant effects.

Full Nitrous Oxide profile
IndicationOver 264 million worldwide.

Major Depressive Disorder (MDD)

Major Depressive Disorder (MDD) represents a significant mental health challenge, with emerging research into the efficacy of psychedelics like psilocybin and ketamine offering new avenues for treatment. Recent studies have demonstrated the potential of these compounds to alleviate symptoms, particularly in treatment-resistant cases of MDD.

Full Major Depressive Disorder (MDD) profile

Academic Research

4 papers
Open Accessmeta

Nitrous Oxide: an emerging novel treatment for treatment-resistant depression

This review (2021) explores the possibilities of using Nitrous Oxide (NO2) for treating treatment-resistant depression (TRD). The use of NO2 as a psychiatric intervention is discussed along with its possible mechanism of action. Its antidepressant effects are believed to be mediated through the NMDA receptor.

Published
March 25, 2022
Journal
Journal of the Neurological Sciences
Authors
Quach, D. F., de Leon, V. C., Conway, C. R.
Open Accessindividual

Nitrous oxide as an adjunctive therapy in major depressive disorder: a randomized controlled double-blind pilot trial

This double-blind placebo-controlled between-subjects study (n=23) tested the antidepressant efficacy of inhaled nitrous oxide (50% N2O|50% O2 versus 100% O2) in patients diagnosed with major depression (MDD). Across multiple treatment sessions administered across a period of 4 weeks, there were significant reductions in depressive symptoms in the acute response to treatment and accumulatively across sessions.

Published
September 1, 2021
Journal
brazilian Journal of Psychiatry
Authors
Guimarães, M. C., Guimarães, T. M., Hallak, J. E., Abrão, J., Machado-de-Sousa, J. P.
Paywallindividual

A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression

In a phase 2 trial, inhaled nitrous oxide at 25% concentration improved symptoms of treatment‑resistant major depression and produced fewer adverse effects than the 50% concentration.

Published
June 9, 2021
Journal
Science Translational Medicine
Authors
Nagele, P., Palanca, B. J., Gott, B., Brown, F., Barnes, L., Nguyen, T., Xiong, W., Salloum, N. C., Espejo, G. D., Lessov-Schlaggar, C. N., Jain, N., Cheng, W. W. L., Komen, H., Yee, B., Bolzenius, J. D., Janski, A., Gibbons, R., Zorumski, C. F., Conway, C. R.
Open Accessindividual

Nitrous Oxide for Treatment-Resistant Major Depression: a Proof-of-Concept Trial

This double-blind, placebo-controlled, within-subjects proof-of-concept study (n=20) investigated the antidepressant efficacy of inhaled nitrous oxide (50/50 nitrous oxide/oxygen vs. 50/50 nitrogen/oxygen) in patients with treatment-resistant depression (TRD). Nitrous oxide resulted in treatment response in 20% of patients and symptom remission in 15%, an effect size comparable to that of ketamine.

Published
July 1, 2015
Journal
Biological Psychiatry
Authors
Nagele, P., Duma, A., Kopec, M., Gebara, M. A., Parsoei, A., Walker, M., Janski, A., Panagopoulos, V. N., Cristancho, P., Miller, J. P., Zorumski, C. F., Conway, C. R.

Clinical Trials

2 trials
CompletedPhase II

Nitrous Oxide for the Treatment of Major Depressive Disorder

Randomised, double-blind, parallel-group Phase 2 trial (n=81 actual) comparing weekly 1-hour inhaled nitrous oxide (25% or 50%) versus placebo (oxygen–air) for Major Depressive Disorder.

Started
January 22, 2019
Type
interventional
Blinding
double
Randomized
Yes
Registry ID
NCT03869736
CompletedPhase II

Nitrous Oxide as Treatment for Major Depression – a Pilot Study

Randomised, placebo-controlled, double-blind crossover pilot study (n=21) testing up to 50% nitrous oxide in oxygen versus placebo (50% nitrogen/50% oxygen) for one hour in patients with major depressive disorder.

Started
January 11, 2012
Type
interventional
Blinding
quadruple
Randomized
Yes
Registry ID
NCT02139540

Explore further

Search all Nitrous Oxide papers Search all Major Depressive Disorder (MDD) trials Full Nitrous Oxide profile Full Major Depressive Disorder (MDD) profile