Laughing Gas as a Treatment for Depression?

Clinical depression leads to substantial disability, and it can be a fatal disease. Although many people with this disorder respond well to standard treatments, a significant number of patients do not improve. Their illness is considered “treatment-resistant.” It is likely that there are multiple causes/types of depression; some types may respond to one type of treatment and not to others.

The pain this illness causes can be so severe that a person may consider suicide. When suicidally depressed patients come to psychiatric attention, they may remain an extreme risk to themselves even weeks after various treatment trials have been initiated. This risk of suicide may continue even when a person is hospitalized.

Ketamine is a drug that is used during certain emergency room procedures particularly in children. One example of such a procedure is resetting a dislocated shoulder. Ketamine diminishes the sensation of pain and also leads to a brief period during which the patient is conscious but indifferent to the procedure. (This is called dissociative anesthesia.) The drug provides this type of anesthesia without compromising the ability to breathe.

Ketamine can also diminish pain and produce conscious sedation and analgesia in adults. Unlike children, however, adults often experience significant psychiatric side effects and may develop hallucinations, perceptual disturbances, and delusions with ketamine. Thus, ketamine, like its cousin phencyclidine (PCP, aka angel dust), is considered a psychotomimetic, that is, a drug that can cause psychotic symptoms. It is thought that children don’t experience the psychotic effects of ketamine because the wiring of certain brain regions is still immature. Major functional brain pathways continue to form throughout adolescence.

Studies over the past decade have found that a single 40-minute intravenous infusion of ketamine at sub-anesthetic doses can lead to rapid improvement in mood and alleviation of suicidal ideation in a significant percentage of severely depressed persons. This effect begins within several hours after ketamine administration and lasts for several days. The most noticeable downside of ketamine is that it can cause psychotic and cognitive side effects. Such effects typically don’t last long, but they can be disturbing. Optimal dosing, frequency of administration, and even route of administration are all active areas of investigation.

Ketamine is thought to work by blocking the effect of a neurotransmitter called glutamate on a specific type of glutamate receptor known as the NMDA receptor. Blocking NMDA receptors can rapidly alter how certain brain pathways function and connect with one another. These changes in brain pathways may be involved in alleviating depressive symptoms.

Considering ketamine as a potential treatment for depression is complicated by its psychiatric side effects and by the fact that it is sometimes abused as a recreational drug. A recent study published by Dr. Peter Nagele and colleagues in the journal Biological Psychiatry reports that nitrous oxide (“laughing gas”), an inhaled anesthetic commonly administered by dentists during dental procedures, may help patients with treatment-resistant depression. (Disclosure: One of us (CZ) is a co-author on this paper.)

Why would someone even consider the possibility that nitrous oxide would help persons with severe depression? It turns out that nitrous oxide, like ketamine, blocks the action of glutamate at NMDA receptors, but by a mechanism that differs from ketamine. (Disclosure: CZ was involved in the initial discovery of nitrous oxide as an NMDA receptor inhibitor.) Unlike ketamine, nitrous oxide does not have psychosis-inducing properties, although, like ketamine, it can sometimes be abused.

In a proof of concept study, Nagele and colleagues compared the antidepressant effect of a single administration of nitrous oxide to a placebo gas (nitrogen) in 20 patients with treatment-resistant depression. Each patient was tested with both treatments (nitrous oxide and placebo) in separate, crossover trials one week apart. Nitrous oxide was administered for approximately 50 minutes at a dose similar to that used in a dentist’s office.

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The results of this study are intriguing. When compared to the placebo gas, nitrous oxide led to substantial improvement: 35 percent of patients demonstrated a very good to excellent response with nitrous oxide versus 5 percent with placebo. The benefits lasted for several days and at least a week in some patients. This response rate is remarkable considering that the patients selected for this study had previously failed an average of 8 (range 4-12) antidepressant treatments.

Psychotic side effects were not observed. A few patients experienced gastrointestinal (GI) side effects or anxiety at the dose of nitrous oxide used in the study. It is possible that a lower dose of nitrous oxide still might be effective and may have even fewer side effects. Because nitrous oxide is a commonly used agent, it is likely that studies following up these initial findings will occur soon.

Future studies will determine the lowest effective dose and length of treatment as well as the effectiveness of repeated administrations. Until these findings are replicated and until much more information is known about dosing and safety, this treatment should be administered only in a research setting.

It would be remarkable if a drug known as “laughing gas” turned out to be beneficial in alleviating severe depressive symptoms including thoughts of suicide. If so, this might become an emergency intervention for those with severe depressive symptoms accompanied by suicidal intent. Also, certain symptoms of depression such as suicidal thoughts can occur in other disorders such as personality disorders. Do suicidal thoughts improve with this treatment in people with personality disorders? There is no answer to this question at present.

This research involving nitrous oxide as a potential treatment for depressive symptoms is very preliminary. A lot more work is needed before a reasonable understanding of the potential benefit versus the risks can be determined. Hopefully, this small study will lead to further well designed clinical studies.

This column was written by Eugene Rubin MD, PhD and Charles Zorumski MD