Wait, Can Nitrous Oxide Alleviate Depression?

Good morning and welcome to the first Drop In of 2026! We're kicking things off with a story about a newly published review looking at the antidepressant effects of nitrous oxide. (Ice cold fatty anyone? 🎈)

A new meta-analysis suggests that nitrous may deliver rapid (even if it's short-lived) relief from depressive symptoms with effects showing up within hours. But can the fleeting lift of gas be sustained beyond that initial burst? We talk about that and more in today’s story. You can find that immediately below!

If you keep scrolling, you’ll find guides on liquid culture, Albino A+ , and a piece on how AI is showing up in psychedelic medicine.

Stay weird this year 🖖,

Mary Carreón
Editor-in-Chief

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Can Nitrous Oxide Relieve Depression?

The scientific revolution of psychedelics has done one thing: given all of the popular party drugs 15 minutes of clinical legitimacy, in which each substance is platformed and taken out of the context of addiction and abuse, and presented to us as an antidote to the mental health crisis. Now, nitrous oxide, colloquially known as “whippits,” “nos,” “gas,” or “ice cold fatties,” is getting a moment to shine beyond the balloon-studded parking lots outside of Phish or Dead & Co. shows.

According to a new systematic review and meta-analysis published in eBioMedicine, researchers examined seven clinical trials (with a total of 247 participants) looking at the effects of nitrous on major depressive disorder, treatment-resistant depression, and bipolar depression. The analysis found that a single inhaled session of 50% nitrous oxide was associated with a measurable reduction in depressive symptoms within hours. The researchers note that the effects were brief and mild, but the question remains whether relief can be sustained.

“N2O demonstrates rapid, reproducible antidepressant effects in early-phase trials,” says Kiranpreet Gill, a leading author of the review. “Its future clinical value depends on whether these effects can be sustained over time through optimised dosing and extended/repeated use. Improved trial design, outcome standardisation, and population diversity are required to clarify its full potential for the treatment of depression.”

To better understand, the authors gathered and analyzed existing research rather than running a new trial. They reviewed clinical trials, exploratory studies, and published study protocols to understand what the current data says. Their search covered major scientific databases and included studies published through June 2025.

They found that nitrous oxide was administered by inhalation at concentrations of either 25% or 50%. Some studies tested a single session, while others examined repeated sessions over several weeks. Control conditions varied and included air, oxygen, or midazolam (a short-acting benzodiazepine), depending on the study design.

When the researchers combined data from three trials that tested a single session of 50% nitrous oxide, they found one consistent pattern: Depressive symptoms were significantly reduced two hours after inhalation and again at 24 hours. However, when symptoms were assessed one week later, the pooled results no longer showed a statistically significant difference compared to placebo.

“Evidence mapping showed that most trials are early-phase and focused on short-term outcomes in adults with MDD and TRD,” the study’s authors write.

Safety-wise, the paper describes adverse events as generally manageable — often things like nausea, dizziness, headache, and transient dissociation — showing up during or soon after inhalation and resolving on their own. Across trials, 25% nitrous oxide tended to be better tolerated than 50%, even as researchers continue to debate which dose (and schedule) offers the best balance between impact and comfort.

“Adverse events decreased with lower doses,” the review says. “Direct comparisons of the risk of AEs between doses suggested improved tolerability with 25% N2O compared to 50%.”

The authors’ bottom line is cautious: nitrous oxide looks promising as a fast-acting intervention, but its real-world value will hinge on whether researchers can stretch that early relief into something sturdier, through optimized dosing, longer follow-up, and more standardized trial design across more diverse patient groups.

So, will nitrous make it out of Shakedown parking lots and into clinical settings where people can access it formally? It’s impossible to know for sure, but stay tuned for our coverage, in which we discuss the possibility of whippits entering the alternative therapy machine.

What Science Actually Says About the Stoned Ape Theory

When Terence McKenna first floated the Stoned Ape Theory in the early '90s, it landed somewhere between philosophical provocation and a drugged-out, fringe hypothesis, embraced by psychedelic thinkers and dismissed by evolutionary scientists.

Now, his younger brother, ethnobotanist Dennis McKenna, argues that the ground beneath the theory has shifted. Advances in neuroscience, epigenetics, and evolutionary biology — fields that scarcely existed in their current form when Food of the Gods was published — have complicated long-held assumptions about how brains change, and how quickly. In this week’s feature, we examine why McKenna believes these developments move the Stoned Ape Theory out of the realm of psychedelic fantasy and into a more uncomfortable, unresolved space at the edges of mainstream science, where evidence is suggestive but incomplete, and where the origins of human consciousness remain, stubbornly, an open question.

Upgrade your subscription here to read the full story by Mattha Busby on Friday.

DoubleBlind Digs

• READ: DoubleBlind just published its first book—and DoubleBlind+ members get a free copy of The DoubleBlind Guide to Psychedelics, a beautifully designed, safety-forward handbook covering substances, dosage, contraindications, and what to expect. Learn more here.

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• DONATE: The Indigenous Medicine Conservation Fund (IMC Fund) has appointed a 100% Indigenous Board of Directors, marking a historic step toward ensuring that the protection of sacred medicines, lands, and knowledge is led by the Peoples who have safeguarded them for millennia. This new governance model redefines global philanthropy by centering Indigenous leadership, sovereignty, and spirituality in conservation. Donate here.

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