Post-Traumatic Stress Disorder

When It Comes to PTSD, Laughing Gas Is No Laughing Matter

Nitrous oxide may help military veterans with post-traumatic stress disorder.

Posted Jul 04, 2020

John Gomez/Shutterstock
Source: John Gomez/Shutterstock

A one-hour dose of 50 percent nitrous oxide (N2O) and 50 percent pure oxygen (delivered via face mask) may help military veterans with post-traumatic stress disorder (PTSD), according to preliminary results from a new pilot study. Nitrous oxide is commonly referred to as "laughing gas." These findings (Varias et al., 2020) were published on June 30 in the Journal of Clinical Psychiatry.

Within a couple of hours of this 60-minute laughing gas treatment, two of the three veterans in this very small (N =3) pilot study self-reported a reduction of PTSD symptoms; these benefits lasted up to one week.

"Effective treatments for PTSD are limited," co-author Peter Nagele said in a July 2 news release. "While small in scale, this study shows the early promise of using nitrous oxide to quickly relieve symptoms of PTSD."

Nagele is an anesthesiologist and chair of the Department of Anesthesia and Critical Care at the University of Chicago (UChicago Medicine). Two other principal investigators for this study are Stanford University School of Medicine's Carolyn Rodriguez and David Clark, along with a team from the VA Palo Alto Health Care System.

This pilot study has several limitations: In addition to the study's cohort only involving three veterans with PTSD, the researchers couldn't rule out the "placebo effect" and other nonspecific effects of nitrous oxide. That said, the initial results do show promise. As the authors explain:

"This case series suggests that adjunctive nitrous oxide can reduce self-reported PTSD symptoms within one day, lasting up to one week without causing new onset psychiatric symptoms. Future research is warranted to determine whether nitrous oxide effects are replicated in a larger sample under randomized, controlled conditions and whether the effects benefit specific PTSD domains."

To be clear: This nitrous oxide treatment is currently not FDA approved. Assuming that the researchers are able to replicate these initial findings in a larger independent sample, it's possible that nitrous oxide could get FDA approval for treating PTSD at some point in the distant future. 

Most likely, any therapeutic use of laughing gas to treat PTSD in the long-term would be integrated into a personalized combination of existing PTSD treatments such as exposure therapy, cognitive-behavioral therapy (CBT), mindfulness meditation, other psychopharmacological drugs, and traditional psychotherapy.

Nitrous Oxide May Help Patients With Treatment-Resistant Depression

A few years ago, Nagele published a landmark laughing gas study (Nagele et al., 2015), which found that two-thirds of patients with treatment-resistant depression (TRD) showed fewer depressive symptoms after receiving nitrous oxide. In this placebo-controlled crossover trial, 20 patients with treatment-resistant depression were randomly assigned to receive a one-hour inhalation of 50% nitrous oxide/50% oxygen or a placebo control.

For patients with treatment-resistant depression who responded to this laughing gas treatment, depressive symptoms improved significantly within two hours after receiving nitrous oxide in comparison to the placebo; these improvements lasted for at least 24 hours. According to the authors, this type of laughing gas treatment wasn't associated with any severe adverse reactions and "demonstrated that nitrous oxide has rapid and marked antidepressant effects in patients with treatment-resistant depression."

Regarding the use of laughing gas to treat PTSD, the next step for Nagele et al. is to conduct a Phase 2 clinical trial using a larger sample under randomized, controlled conditions. This clinical trial, "Nitrous Oxide for PTSD," was registered in May 2020 (Identifier: NCT04378426) but is not yet recruiting; the estimated start date is September 1, 2020. Here's a summary of this study from the ClinicalTrials.gov website:

"Post-traumatic stress disorder (PTSD) seriously disrupts the lives of many Veterans. Current first-line treatments, serotonin reuptake inhibitors, or prolonged exposure therapy take weeks to months to bring meaningful improvement, leaving Veterans experiencing prolonged suffering. A promising new treatment approach for rapidly reducing PTSD symptoms is nitrous oxide, an inhalation anesthetic and putative glutamate modulator that diminishes depression symptoms within one day and has limited side effects. If shown to be similarly effective in PTSD, nitrous oxide may add dramatically to the treatment armamentarium by bringing rapid symptom decrease before longer-term therapies take hold. The proposed projects test the efficacy of nitrous oxide in relieving Veteran's PTSD symptoms and, in parallel, explore how nitrous oxide may modify cognitive and pain outcomes." 

In 2019, a new depression drug (esketamine), which is derived from ketamine, was approved by the FDA as a breakthrough therapy for patients with treatment-resistant depression or those with major depressive disorder (MDD) who fail to respond to one or more traditional antidepressant medications.

Whereas antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are designed to target serotonin receptors, nitrous oxide is more akin to ketamine, which works by blocking N-methyl-D-aspartate (NMDA) receptors. It's important to note that some patients do not benefit from SSRIs, and it appears that some patients don't experience a reduction of depressive symptoms or PTSD symptoms after receiving nitrous oxide.

Exactly how and why inhaling nitrous oxide relieves symptoms of TRD and PTSD in some (but not all) patients remains a mystery. "Like many other treatments, nitrous oxide appears to be effective for some patients but not for others," Nagele said in the press release. "Often, drugs work only on a subset of patients, while others do not respond. It's our role to determine who may benefit from this treatment, and who won't."

In future research, Nagele will focus on pinpointing the optimal dose of nitrous oxide that most effectively helps the broadest range of patients. The cohort for this upcoming nitrous oxide study, which is being funded by Brain and Behavior Research Foundation, will receive different doses of nitrous oxide so that Nagele and his team can compare the effectiveness and possible side effects of inhaling different doses of laughing gas.

Although these preliminary findings show promise and suggest that laughing gas may be a possible treatment for TRD and PTSD, much more research is needed to determine the long-term safety and efficacy of nitrous oxide therapies and to pinpoint the optimal therapeutic dosage.

References

Andrea Varias, Peter van Roessel, Maryam Parsiani, Maria Filippou-Frye, Thomas C. Neylan, Peter Nagele, Jerome Yesavage, J. David Clark, and Carolyn I. Rodriguez. "Does Nitrous Oxide Help Veterans With Posttraumatic Stress Disorder? A Case Series" The Journal of Clinical Psychiatry (First published online: June 30, 2020) DOI: 10.4088/JCP.20l13393

Peter Nagele, Andreas Duma, Michael Kopec, Marie Anne Gebara, Alireza Parsoei, Marie Walker, Alvin Janski, Vassilis N. Panagopoulos, Pilar Cristancho, J. Philip Miller, Charles F. Zorumski, Charles R. Conway. "Nitrous Oxide for Treatment-Resistant Major Depression: A Proof-of-Concept Trial." Biological Psychiatry (First published: July 01, 2015) DOI: 10.1016/j.biopsych.2014.11.016