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NITROUS OXIDE | +20 articles

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Can Nitrous Oxide help people with Treatment-Resistant Depression?

by Robert Glatter, MD | 9 Jun 2021

In up to a third of patients with major depression, standard medications that block receptors for the key neurotransmitters, serotonin and norepinephrine, are not effective. Beyond this, it may take several weeks to months before the beneficial effects of the medication are realized.

While unique brain network disruptions may provide a potential explanation for the treatment failure, looking at alternative pathways and receptors that may have more immediate effects represent more recent advances for so-called treatment-resistant depression, or depression that does not improve with standard medications and therapy.

This recent approach has included ketamine, a drug which blocks the NMDA receptor, now shown to be a possible factor in those with treatment-resistant depression. The treatments, which may be delivered by intravenous infusions or as a nasal spray (Esketamine) are done in an office-based setting the under the supervision of a psychiatrist, as well as other medical professionals based on risk factors and underlying medical history. Patients must be observed for about 2 hours until the sedative effects of the medication wears off. Ketamine has been quite effective for many patients—leading to relief within a few hours after the infusion or treatment itself—but its beneficial effects subside after several weeks resulting in the need for repeat infusions/treatments.

Now, researchers from Washington University School of Medicine in St. Louis and the University of Chicago are using a unique approach that also takes advantage of blocking the NMDA receptor. It involves a one-hour treatment inhaling a mixture of nitrous oxide, aka “laughing gas,” along with oxygen, offering potential advantages over ketamine. (Nitrous oxide is commonly used as an anesthetic in dental surgery, since it is able to provide short term pain relief and sedation lasting only minutes.)

What the researchers found in a Phase 2 clinical trial is that symptoms of depression improved within a few hours—and lasted for several weeks—after treatment with inhaled nitrous oxide and oxygen.

The findings were published today in the journal Science Translational Medicine.

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“A large percentage of patients don’t respond to standard antidepressant therapies — the patients in this study had failed an average of 4.5 antidepressant trials — and it’s very important to find therapies to help these patients,” said Charles R. Conway, MD, Professor of Psychiatry at Washington University and one of the study’s senior investigators said in a press release. “That we saw rapid improvements in many such patients in the study suggests nitrous oxide may help people with really severe, resistant depression.”

Conway, and his co-senior investigator, Peter Nagele, MD, Professor and Chair of the Department of Anesthesia & Critical Care at the University of Chicago, have been investigating the utility of nitrous oxide as an antidepressant over the past decade. In 2015, they published a proof-of-concept study demonstrating that inhaled nitric oxide (50% nitric oxide/50% oxygen administered over 1 hour) had rapid and significant antidepressant effects in patients with treatment-resistant depression, compared to a placebo. Beneficial effects were seen at 2 hours and even up to 24 hours post treatment. Three patients had full remission, with nausea and paradoxical anxiety as the main adverse effects.

Compared with ketamine, nitrous oxide also has a relatively rapid onset of antidepressant action (within about 2 hours) but does not result in so-called “psychotomimetic” side effects seen with ketamine (delusions, hallucinations, illusions), which may be the result of nitric oxide’s effects lasting only a matter of minutes.

“Our primary goals in this study were twofold: to determine whether a lower dose of nitrous oxide might be just as effective as doses we’d tested previously—and it was for most patients—and we also wanted to see how long the relief lasted,” said Nagele. “In a proof-of-concept study several years ago, we assessed patients for 24 hours. In this study, we continued to assess them for two weeks, and most continued to feel better.”

The researchers recruited 24 patients for this small study. Each participant received 3 treatments, about one month apart. For the first treatment, participants were treated with a mixture of 50% nitrous oxide and 50% oxygen for 1 hour. For the second treatment, each participant was treated with a mixture of 25% nitrous oxide and 75% oxygen. Finally, during the third treatment, as a placebo, participants breathed only oxygen, with no nitrous oxide. During the study, many of those who were taking antidepressants were allowed to continue taking these medications during the study period.

“You can’t really get a better comparison group than when you compare a person to himself or herself,” said Nagele. “Serving as your own control is ideal. The alternative is studying the effects of a drug in two similar groups of people in which you either get one treatment or another. But the problem with that is that you need much larger numbers of patients before you really can draw conclusions.”

The study found that nitrous oxide—both at 25% and in a 50% mixture with oxygen — improved symptoms of depression in 17 of the study participants. While there was a slightly greater antidepressant effect noted in participants after the 50% mixture—with positive effects lasting up to 2 weeks after the treatment, the 25% mixture had much fewer adverse events, the main one being nausea. That said, the researchers concluded that the 25% mixture was nearly as effective as the 50% mixture in relieving symptoms of depression, but with significantly fewer side effects such as nausea, haziness, and headache. In a small number of patients, treatment effects lasted up to 4 weeks.

“Some patients experience side effects—it’s a small subset, but it’s very real — and the main one is that some people get nauseated,” said Conway. “But in our study, only when people got the 50% dose did they experience nausea. When they received 25% nitrous oxide, no one developed nausea. And that lower dose was just about as effective as the higher dose at relieving depression.”

Of the 20 study participants, 55% (11 of 20) described a significant improvement in at least half of their depressive symptoms, and 40% (8 of 20) were noted to be in remission (no longer were clinically depressed) after completing the 3 treatments in the study, each one month apart. The study also found that 85% (17 of 20) of the study participants experienced a major improvement in their symptoms and were able to be reclassified from having severe to moderate depression. That said, the researchers still noted that nitrous oxide did not have a beneficial effect in some of the study participants, and the reasons behind this lack of treatment effect were not clear. Needless to say, every patient is unique, Conway emphasized, and the lack of efficacy is still not unexpected.

While as many as one-third of those who take antidepressants don’t experience clinical improvement in their depressive symptoms, it’s important to note that ketamine (and nitrous oxide) have both shown promise in those with treatment-resistant depression. Conway and Nagele feel that these approaches may offer hope and be breakthroughs for people with treatment-resistant depression, but they believe nitrous oxide may have some practical advantages.

“One potential advantage to nitrous oxide, compared with ketamine, is that because it’s a volatile gas, its anesthetic effects subside very quickly,” Conway said. “It’s similar to what happens in a dentist’s office when people drive themselves home after getting a tooth pulled. After treatment with ketamine, patients need to be observed for two hours following treatment to make sure they are ok, and then they have to get someone else to drive them.”

Since the elimination half-life of nitrous oxide is about 5 minutes, one might envision potential advantages to large scale adoption of this drug in the outpatient setting compared to ketamine (with an elimination half-life of up to 2.5 hours), if large scale trials continue to demonstrate efficacy.

To better understand the effects seen in the present study, it will be important to conduct a large, multicenter study involving hundreds of patients, comparing the effects of ketamine as well as nitrous oxide to placebo. On a deeper level, understanding the genetic profiles of people with treatment-resistant depression, including their unique brain network disruptions may help medical professionals select an optimal approach to therapy in the near future.

“There is hope for those who suffer from treatment-resistant depression,” said Conway. “While the results of this study are relatively preliminary, they demonstrate clinical benefit and require further study on a larger scale.”

One limitation of the research involved the study design itself, with each study participant the recipient of all three treatments: 25% mixture, 50% mixture and a placebo over a 3-month period. This is in contrast to a randomized placebo controlled clinical trial, in which one group receives the treatment or drug and the other group is given a placebo. By allowing the researchers to use patients as their self-control instead of comparing them to other patients, it may have biased or even confounded the results due to a lingering effect of one treatment that could have influenced the outcome of the next treatment.

Finally, one possible safety-related concern raised by Conway and Nagele in their 2015 study involves vitamin B12 inactivation by nitrous oxide. While a single treatment will not likely lead to hematologic or neurological complications, the authors wrote that “the risk for such complications is substantially higher when nitrous oxide administrations are repeated within short periods of time.” Megaloblastic anemia and myelopathy have also been reported among persons who chronically abuse nitrous oxide as well as in patients with chronic disturbances of folate metabolism. They do caution that “it is likely that for its sustained antidepressant effect, nitrous oxide must be administered several times, which would increase the risk for such complications.” That said, Conway explained that the effects of recurrent dosing of nitrous oxide will need to be investigated in ongoing trials. (He has not observed B12 deficiencies thus far, emphasizing that the trials his research group has conducted to date were not repetitive dosing trials.)

What we do know is that nitrous oxide is a drug of abuse (whippets). As a result, it’s important to consider that its abuse potential might reduce or limit its clinical utility in major depressive disorder. That said, the authors explain that their research was not designed to address this possible concern related to the drug’s abuse potential.

“Treatment refractory depression can be quite a disabling condition,” explained Dr. Scott Krakower, a child and adolescent psychiatrist at Zucker Hillside Hospital in Glen Oaks, New York. While there are treatments that may help, including pharmacology and ECT, treatment has turned toward looking at certain agents which inhibit NMDA receptors.”

“Ketamine has shown promising data and is readily available in clinical treatment centers. More recently, nitrous oxide has been reviewed as a potential agent which would could also help with this condition. There has been less data proving efficacy with this agent, although more research is to be done,”
offered Krackower.

“If data continues to show improvement with this compound, it may present as an efficient and widely available viable agent which practitioners could access and use. Like other substances in it's class, there is an abuse potential, so benefits would also have to outweigh the harm.” he added.

Robert Glatter is an emergency physician on staff at Lenox Hill Hospital in New York City, where I have practiced for the past 15 years. I also serve as an adviser and editor to Medscape Emergency Medicine, an educational portal for physicians, and an affiliate of WebMD.
 
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Low doses of Nitrous Oxide are fast, effective treatment for Severe Depression

University of Chicago | Neuroscience News | 9 Jun 2021

Nitrous oxide, a common anesthesia most often associated with dental procedures, may have a new purpose. Researchers found a single inhalation of 25% nitrous oxide gas was effective at alleviating symptoms of depression in those with a treatment-resistant form of the mental health disorder.

A new study at the University of Chicago Medicine and Washington University found that a single inhalation session with 25% nitrous oxide gas was nearly as effective as 50% nitrous oxide at rapidly relieving symptoms of treatment-resistant depression, with fewer adverse side effects.

The study, published June 9 in Science Translational Medicine, also found that the effects lasted much longer than previously suspected, with some participants experiencing improvements for upwards of two weeks.

These results bolster the evidence that non-traditional treatments may be a viable option for patients whose depression is not responsive to typical antidepressant medications. It may also provide a rapidly effective treatment option for patients in crisis.

Often called “laughing gas,” nitrous oxide is frequently used as an anesthetic that provides short-term pain relief in dentistry and surgery.

In a prior study, the investigators tested the effects of a one-hour inhalation session with 50% nitrous oxide gas in 20 patients, finding that it led to rapid improvements in patient’s depressive symptoms that lasted for at least 24 hours when compared to placebo. However, several patients experienced negative side effects, including nausea, vomiting and headaches.

“This investigation was motivated by observations from research on ketamine and depression,” said Peter Nagele, MD, Chair of Anesthesia and Critical Care at UChicago Medicine. “Like nitrous oxide, ketamine is an anesthetic, and there has been promising work using ketamine at a sub-anesthetic dose for treating depression. We wondered if our past concentration of 50% had been too high. Maybe by lowering the dose, we could find the ‘Goldilocks spot’ that would maximize clinical benefit and minimize negative side effects.”

In the new study, the investigators repeated a similar protocol with 20 patients, this time adding an additional inhalation session with 25% nitrous oxide. They found that even with only half the concentration of nitrous oxide, the treatment was nearly as effective as 50% nitrous oxide, but this time with just one quarter of the negative side effects.

Furthermore, the investigators looked at patients’ clinical depression scores after treatment over a longer time course; while the last study only evaluated depression symptoms up to 24 hours after treatment, this new study conducted additional evaluations over two weeks. To their surprise, after just a single administration, some patients’ improvements in their depression symptoms lasted for the entire evaluation period.

“The reduction in side effects was unexpected and quite drastic, but even more excitingly, the effects after a single administration lasted for a whole two weeks,” said Nagele. “This has never been shown before. It’s a very cool finding.”

These results indicate promise for nitrous oxide as a rapid and effective treatment for those suffering from severe depression that fails to respond to other treatments, such as SSRIs, a common type of antidepressant medication.

“A significant percentage — we think around 15% — of people who suffer from depression don’t respond to standard antidepressant treatment,” said Charles Conway, MD, Professor of Psychiatry and Director of the Treatment Resistant Depression and Neurostimulation Clinic at Washington University School of Medicine. “These ‘treatment-resistant depression’ patients often suffer for years, even decades, with life-debilitating depression. We don’t really know why standard treatments don’t work for them, though we suspect that they may have different brain network disruptions than non-resistant depressed patients. Identifying novel treatments, such as nitrous oxide, that target alternative pathways is critical to treating these individuals.”

Despite its reputation as "langhing gas," patients who receive such a low dosage actually fall asleep.

“They’re not getting high or euphoric, they get sedated,” Nagele said.

While it remains challenging to get non-traditional treatments for depression accepted in the mainstream, researchers hope that these results, and other similar studies, will open the minds of reluctant physicians toward the unique properties of these drugs.

“These have just been pilot studies,” said Nagele. “But we need acceptance by the larger medical community for this to become a treatment that’s actually available to patients in the real world. Most psychiatrists are not familiar with nitrous oxide or how to administer it, so we’ll have to show the community how to deliver this treatment safely and effectively. I think there will be a lot of interest in getting this into clinical practice.”

With broader public acceptance, Nagele hopes that these results can open doors for those patients who are struggling to find adequate therapies for their depression.

“There is a huge unmet need,” he said. “There are millions of depressed patients who don’t have good treatment options, especially those who are dealing with suicidality. If we develop effective, rapid treatments that can really help someone navigate their suicidal thinking and come out on the other side — that’s a very gratifying line of research.”

*From the article here :
 
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Neuropathy following recreational use of Nitrous Oxide*

by Kate Kneisel | MedPage Today | 23 Aug 2021

Clinicians should be aware of adverse effects of this increasingly popular drug.

A 19-year-old man presented to the emergency department (ED) after falling down a flight of stairs. He denied any health problems or medication use. However, he told clinicians that for the past month or more, he had been experiencing an increasing problem with numbness in his hands and feet. This worsened and he found that his sense of balance was affected. He also noted weakness in his lower legs.

Clinicians initially suspected that the patient's symptoms might be due to Guillain-Barre syndrome, neurological infection, or another neuropathic condition. They performed an extensive workup that included a lumbar puncture, electroneuronography, and an MRI of the medulla totalis. Results of these tests were normal, and there was no evidence of pathology changes on the MRI.

Most lab test results were within reference range, except for his homocysteine and methylmalonic acid levels:​
  • Homocysteine: 92 μmol/L (reference range <10 μmol/L)​
  • Methylmalonic acid: >10 μmol/L (range 0.08-0.28 μmol/L)​
  • Folate: 21 nmol/L (range >9 nmol/L)​
  • Vitamin B12: 234 pmol/L (range 200-600 pmol/L)​
  • Creatinine: 61 μmol/L (range 60-105 μmol/L)​
Results of the lab tests and diagnostic workup led to a diagnosis of severe sensorimotor neuropathy. After considering the patient's history and all exam results, ED physicians concluded that his sensorimotor neuropathy was due to functional vitamin B12 deficiency.

His self-reported history of recreational use of nitrous oxide up to 10 times within recent months, mainly on weekends, likely triggered his neuropathy, they determined. The patient had told several members of the ED staff that he had used nitrous oxide about twice per week within recent months (maximum of 50-75 cartridges per time). He said he did not use any other recreational drugs.

The patient was treated with oral vitamins, including 1 mg once daily of vitamin B12, 5 mg once daily of folate (vitamin B9), and 300 mg once daily of thiamine (vitamin B1); he also started physiotherapy treatment.

His symptoms improved over the course of the following 14 days, and he was prepared for discharge to a rehabilitation center. Just before his release from hospital, he began experiencing acute non-radiating chest pain, which worsened when he breathed deeply.

Vital signs included blood pressure of 112/64 mm Hg, pulse of 86 beats per minute, and oxygen saturation of 98%. Clinicians suspected aortic dissection and performed an acute CT angiography of the aorta. Imaging showed no evidence of dissection; however, it revealed bilateral central pulmonary embolism with signs of pulmonary infarction in both lower lobes with consolidated changes. An MRI scan of the cervical column did not reveal any definite pathological findings.

Given the patient's hemodynamic stability and normal findings on echocardiography, clinicians treated the pulmonary embolism with an oral anticoagulant (20-mg once-daily rivaroxaban). He was discharged from hospital a few days later.

Clinical follow-up assessment 6 months later showed only mild sensory-motor residual symptoms. The patient had no symptoms associated with the pulmonary embolism or anticoagulant treatment he received. He was screened for thrombophilia, but all test results were normal, with no antiphospholipid antibodies or lupus anticoagulant, no genetic polymorphisms, and no lack of natural anticoagulants. In addition, his homocysteine level had returned to normal (9.5 μmol/L). Thus, anticoagulant treatment was discontinued.

Discussion

Clinicians reporting this case of a 19-year-old who presented with peripheral neuropathy after several months of occasional recreational use of nitrous oxide, followed by a bilateral central pulmonary embolism during hospitalization, suggested that these were related to functional vitamin B12 deficiency and an increased level of homocysteine associated with nitrous oxide use.

Nitrous oxide, or so-called "laughing gas," has been in use as an anesthetic for more than a century, the case authors noted. However, recent years have seen the recreational use of nitrous oxide growing among young people, perhaps due to its "presumed innocent effect combined with an easy and legal availability," they wrote. For example, nitrous oxide can be easily obtained from whipped cream charging bottles.

Daily heavy use (i.e., >200 cartridges) and long-term recreational use of nitrous oxide can lead to functional vitamin B12 deficiency -- resulting in nerve damage and other complications such as macrocytic anemia, thromboembolic phenomena, myocardial infarction, spontaneous pneumomediastinum, and even death, presumably due to hypoxia.

The case authors noted that peripheral neuropathy has been associated with recreational use of nitrous oxide in the past, mainly after long-term use. Chronic use of nitrous oxide causes irreversible inactivation of vitamin B12, thus resulting in functional vitamin B12 deficiency, they said.

Active vitamin B12 is required for the conversion of methylmalonic acid and the degeneration of homocysteine to methionine; therefore, persistent inactivation of vitamin B12 by use of nitrous oxide results in elevated levels of methylmalonic acid and homocysteine, the authors explained (Figure).


image

Schematic overview of the effect of vitamin B12 on the metabolism of methylmalonic acid and homocysteine. Nitrous oxide oxygenates the core of vitamin B12, leading to inactivation and functional vitamin B12 deficiency. This results in elevated levels of methylmalonic acid and homocysteine.

Because methionine is necessary for all methylations, inactivation of vitamin B12 resulting from nitrous oxide inhalation can cause nerve damage due to lack of myelination of the nerve cell axons, the group explained.

They suggested that this mechanism likely resulted in their patient's peripheral neuropathy, given the elevated levels of methylmalonic acid and homocysteine shown in lab tests at admission, and concurrent normal plasma levels of vitamin B12, folate, and creatinine.

Regarding the fact that the patient's vitamin B12 level was normal, the authors explained that since cobalamin must bind to transcobalamin to be available for circulation, the levels available for the cells can still be suboptimal; this could explain the symptoms observed in their patient, whose transcobalamin was not measured. In addition, the MRI showed no conclusive evidence of pathology, they added.

When the patient stopped using nitrous oxide, vitamin B12 inactivation no longer persisted, the authors noted; thus, blood levels returned to normal and nerve cell myelination was restored. The rapid fall/normalization in homocysteine level supports their theory that use of nitrous oxide caused the significant increase in homocysteine level, they said.

Furthermore, they suggested that the patient's pulmonary embolism may have been related to his remaining in his room (despite being able to walk) for the 2 weeks after admission, since immobilization is known to increase the risk for thromboembolic complications. The patient's nitrous oxide use may also have been a contributing factor in the development of the pulmonary embolism, they said.

The authors cited a previous report of pulmonary embolism following recreational use of nitrous oxide, although this patient had long-term use.

They noted several factors that may increase risk of thromboembolic complications: the greatly increased level of homocysteine, which has been reported to affect hemostasis by causing endothelium dysfunction; platelet activation; and impaired fibrinolysis, which can also increase the risk of myocardial infarction.

In addition to the effects of increased homocysteine on hemostasis, they pointed to a case report of a recreational user of nitrous oxide who developed a blood clot in the aortic arch. Given its location in the artery of a patient with no other risk factors for thrombosis, this supported the possibility that nitrous oxide contributed to a hypercoagulable state.

The authors of the present case also referenced another report of a patient with isolated cortical vein thrombosis after long-term recreational use of nitrous oxide, whose homocysteine level was normal upon admission. However, regarding their patient, the authors cautioned that the 2-week gap between his cessation of nitrous oxide use and development of the pulmonary embolism leaves the direct contributing effect of nitrous oxide uncertain.

"This report shows that even moderate recreational use of nitrous oxide can lead to severe peripheral neuropathy due to functional vitamin B12 deficiency and can be associated with pulmonary embolism, even in young and previously healthy individuals," the group concluded. As in their patient's case, completely stopping nitrous oxide use and receiving treatment with relevant vitamins can lead to a rapid recovery.

According to the Global Drug Survey (GDS) from 2014, the largest survey of recreational drug use in the world, findings from 74,864 respondents showed that use of nitrous oxide is very common, particularly in the U.K. and U.S. (39 percent) and 30 percent lifetime prevalence, respectively).

"Nitrous oxide was generally consumed via gas-filled balloons, at festivals and clubs where use of other substances was common," the survey study authors wrote. Most use is infrequent and not associated with significant harm, they added, although a subgroup of heavy users may be using in a dependent pattern. Analysis of last-year users (n=4,883) showed that use was associated with hallucinations (28 percent), confusion (24 percent), persistent numbness (4 percent), and accidental injury (1 percent), with the latter linked with the highest number of "hits" per session, suggesting a dose-response relationship.

Due to the GDS's noted increasing popularity of recreational nitrous oxide consumption among young people, the case authors urged awareness among healthcare professionals when treating patients who develop unexplained neuropathy or thromboembolic events. Furthermore, they urged clinicians to inform young people about the risks of adverse effects from the recreational use of nitrous oxide.

*From the article here :
 
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Nitrous Oxide may bring relief to PTSD sufferers*

Neuroscience News

Summary: Nitrous oxide may provide temporary relief to veterans suffering from PTSD, a new study reports.

Source: University of Chicago


For military veterans suffering from post-traumatic stress disorder (PTSD), symptoms such as anxiety, anger and depression can have a devastating impact on their health, daily routine, relationships and overall quality of life.

A new pilot study by the University of Chicago Medicine and the Stanford University School of Medicine team from the VA Palo Alto Health Care System (principal investigators Carolyn Rodriguez, MD, and David Clark, MD, PhD) provides an early glimpse of how some of these veterans may benefit from one simple, inexpensive treatment involving nitrous oxide, commonly known as laughing gas.

“Effective treatments for PTSD are limited,” said anesthesiologist Peter Nagele, MD, chair of the Department of Anesthesia & Critical Care at UChicago Medicine and co-author of the paper. “While small in scale, this study shows the early promise of using nitrous oxide to quickly relieve symptoms of PTSD.”

The findings, based on a study of three military veterans suffering from PTSD and published June 30 in the Journal of Clinical Psychiatry, could lead to improved treatments for a psychiatric disorder that has affected thousands of current and former members of the U.S. military.

For this new study, three veterans with PTSD were asked to inhale a single one-hour dose of 50% nitrous oxide and 50% oxygen through a face mask. Within hours after breathing nitrous oxide, two of the patients reported a marked improvement in their PTSD symptoms. This improvement lasted one week for one of the patients, while the other patient’s symptoms gradually returned over the week. The third patient reported an improvement two hours after his treatment but went back to experiencing symptoms the next day.

“Like many other treatments, nitrous oxide appears to be effective for some patients but not for others,” explained Nagele, who is himself a veteran of the Austrian Army and grateful to have identified an opportunity to help other veterans. “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.”

Nagele is a pioneer in the field of using nitrous oxide to treat depression. Most commonly known for its use by dentists, nitrous oxide is a low-cost, easy-to-use medication. Although some patients may experience side effects like nausea or vomiting while receiving nitrous oxide, the reactions are temporary.

Exactly how and why nitrous oxide relieves symptoms of depression in some people has yet to be fully understood. Most traditional antidepressants work through a brain chemical called serotonin. Nitrous oxide, like ketamine, an anesthetic that recently received FDA-approval in a nasal spray form to treat major depression, works through a different mechanism, by blocking N-methyl-D-aspartate (NMDA) receptors.

A 2015 landmark study by Nagele found that two-thirds of patients with treatment-resistant depression experienced an improvement in symptoms after receiving nitrous oxide.

For his next study, Nagele is researching the ideal dose of nitrous oxide to treat intractable depression. Study participants with treatment-resistant depression received different doses of nitrous oxide so that Nagele and his team could compare each dose’s effectiveness and side effects. The study is being funded by the Brain & Behavior Research Foundation.

“Does nitrous oxide help veterans with Post Traumatic Stress Disorder?” was funded by the VA Office of Research and Development Clinical Science Research & Development Service.

Source:
University of Chicago

Original Research: Open access
“Does Nitrous Oxide Help Veterans With Posttraumatic Stress Disorder? A Case Series” by Peter Nagele et al. Journal of Clinical Psychiatry

*From the article here :
 
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Cambridge

Is Nitrous Oxide a Psychedelic Drug?

by Alaina M. Jaster, BS | Psychedelic Science Review | 20 Jul 2021

Despite its similar effects, nitrous oxide is not considered psychedelic.

Nitrous oxide (N2O) is both commonly used in medicine and recreationally. There are some similarities between the intoxicating effects of N2O and psychedelics, but ultimately they are very different in their mechanism of action and drug classification. These differences make nitrous oxide non-psychedelic.

What is Nitrous Oxide?

N2O is a naturally occurring gas used for sedation and pain relief for minor medical procedures. It is commonly used in dentistry as general anesthesia, as well as in some emergency rooms.1,2 Besides its medical usages, the gas also has narcotic effects when inhaled, leading to its recreational use. N2O is also referred to as “laughing gas” due to side effects from inhalation. When used recreationally, the method of use is typically inhalation via filling balloons.

Similarities and differences with the effects of psychedelics

Classic psychedelics such as LSD and psilocybin are known for their ability to produce alterations in cognition, sensory perception, and more. Nitrous oxide also produces some feelings of euphoria and alterations in sensory perception. Inhalation effects usually manifest as laughter or general feelings of happiness and a tingling face. Other body and sensory sensations such as numbness, muffled noise or ringing in the ears, and blurred vision or sometimes hallucinations may occur. Unlike most psychedelics, these effects are very short-lived and typically dissipate within a few minutes of acute nitrous inhalation.

Psychedelics produce their behavioral and cognitive effects mainly through the serotonergic neurotransmitter system. The direct mechanism of action of N2O is still being investigated, but the giggles and good feelings that come with inhalation are thought to be due to the gas displacing oxygen in the lungs and bloodstream.3 Other systems have been implicated in the pain-mediating and calming effects of N2O, including opioid receptors, glutamate receptors, and GABA neurotransmission.

Another large difference between psychedelics and N2O is their safety profile. While psychedelics produce longer-lasting and stronger sensory effects, N2O is considered more dangerous. There have been several case reports in which prolonged use of the gas causes vitamin B12 deficiency, which can cause neurological and muscular dysfunction. Chronic recreational use of N2O has also been reported to cause death through lack of oxygen to the brain. In the case of psychedelics, no deaths from LSD overdoses have been reported, even in cases where over 500 times the normal recreational dose of LSD was taken. Studies on the pharmacokinetics and safety profile of psilocybin have reported no serious physical or psychological adverse effects of different ingested doses of psilocybin.

Conclusion

Although there is some overlap with the effects of nitrous oxide and classic psychedelics, nitrous oxide is not considered a psychedelic. Psychedelics represent a unique class of compounds that are characterized by serotonin receptor activation, as well as their long-lasting and strong effects on perception and cognition. Interestingly, recent clinical studies have assessed N2O as a treatment for depression,9 similar to psychedelics, but the potential therapeutic effects may be through different pathways. Despite some similarities in effects, nitrous oxide’s basic pharmacology keeps it from being classified as a psychedelic.

 
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Researchers at Washington University School of Medicine have found that a one-hour treatment of breathing in a mixture
of oxygen and nitrous oxide can significantly improve symptoms in people with treatment-resistant depression.

Nitrous Oxide relieves symptoms in people with Treatment-Resistant Depression

Single treatment provides patients with rapid, lasting antidepressant effects.

by Jim Dryden | Washington University School of Medicine | 9 Jun 2021

A single, one-hour treatment that involves breathing in a mixture of oxygen and nitrous oxide — otherwise known as laughing gas — significantly improved symptoms in people with treatment-resistant depression, according to new data from researchers at Washington University School of Medicine in St. Louis and the University of Chicago.

In a phase 2 clinical trial, the researchers demonstrated that symptoms of depression improve rapidly following treatment with inhaled nitrous oxide. Further, they reported the benefits can last for several weeks.

The findings are published June 9 in the journal Science Translational Medicine.

“A large percentage of patients don’t respond to standard antidepressant therapies — the patients in this study had failed an average of 4.5 antidepressant trials — and it’s very important to find therapies to help these patients,” said Charles R. Conway, MD, a professor of psychiatry at Washington University and one of the study’s senior investigators. “That we saw rapid improvements in many such patients in the study suggests nitrous oxide may help people with really severe, resistant depression.”

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Conway, and the study’s other co-senior investigator, Peter Nagele, MD, professor and chair of the Department of Anesthesia & Critical Care at the University of Chicago, and who previously had an appointment in the Department of Anesthesiology at Washington University School of Medicine, have been studying the potential of nitrous oxide as an antidepressant for the past decade.

Standard antidepressant drugs affect norepinephrine and serotonin receptors in the brain, yet they often take weeks to improve a person’s symptoms. Nitrous oxide, however, interacts with different receptors on brain cells — NMDA glutamate receptors — and tends to improve symptoms within hours when effective.

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“Our primary goals in this study were twofold: to determine whether a lower dose of nitrous oxide might be just as effective as doses we’d tested previously — and it was for most patients — and we also wanted to see how long the relief lasted,” Nagele said. “In a proof-of-concept study several years ago, we assessed patients for 24 hours. In this study, we continued to assess them for two weeks, and most continued to feel better.”

The study involved 24 patients. Each one received three treatments about one month apart. In one session, patients breathed gas for an hour that was half nitrous oxide, half oxygen. In a second treatment, the same patients breathed a solution that was 25% nitrous oxide. A third treatment, the placebo, involved breathing only oxygen, with no nitrous oxide.

“You can’t really get a better comparison group than when you compare a person to himself or herself,” Nagele said. “Serving as your own control is ideal. The alternative is studying the effects of a drug in two similar groups of people in which you either get one treatment or another. But the problem with that is that you need much larger numbers of patients before you really can draw conclusions.”

The primary conclusions in this study were that nitrous oxide — both at 25% and in a 50-50 mixture with oxygen — improved depression in 17 of those study participants. The differences between a 25% mix and a 50% mix mainly involved how long the antidepressant effects lasted. Whereas the 50% dosage had greater antidepressant effects two weeks after treatment, the 25% dose was associated with fewer adverse events, the most common of which was feeling nauseated.

“Some patients experience side effects — it’s a small subset, but it’s very real — and the main one is that some people get nauseated,” Conway said. “But in our study, only when people got the 50% dose did they experience nausea. When they received 25% nitrous oxide, no one developed nausea. And that lower dose was just about as effective as the higher dose at relieving depression.”

Of the 20 people who completed all of the study’s treatments and follow-up exams, 55% (11 of 20) experienced a significant improvement in at least half of their depressive symptoms, and 40% (eight of 20) were considered to be in remission — meaning they no longer were clinically depressed — after breathing a nitrous oxide solution for one hour.

Over the course of the entire study, having received both dose levels of nitrous oxide and the placebo treatment, some 85% (17 of 20) of the study participants experienced a significant enough improvement that their clinical classification moved at least one category — for example, from severe to moderate depression.

Many of those in the study also took antidepressant drugs — medications that, for the most part, had failed to relieve their depression — but they were allowed to continue using those drugs while they participated in the study.

As many as one-third of those who take antidepressants don’t improve. Nitrous oxide and ketamine, another anesthetic drug that interacts with NMDA glutamate receptors, recently have shown promise in those with treatment-resistant depression. Conway and Nagele believe both drugs may represent breakthroughs for people with treatment-resistant depression, but they believe nitrous oxide may have some practical advantages.

“One potential advantage to nitrous oxide, compared with ketamine, is that because it’s a volatile gas, its anesthetic effects subside very quickly,” Conway said. “It’s similar to what happens in a dentist’s office when people drive themselves home after getting a tooth pulled. After treatment with ketamine, patients need to be observed for two hours following treatment to make sure they are OK, and then they have to get someone else to drive them.”

Nagele and Conway said it is important for scientists soon to conduct a large, multicenter study comparing the effects of ketamine and nitrous oxide to placebo.

 
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Nitrous Oxide for Treatment-Resistant Depression*

Washington University School of Medicine

Peter Nageleac, Andreas Dumaa, Michael Kopec, Marie Anne Gebarab, Alireza Parsoei, Marie Walker, Alvin Janski, Vassilis Panagopoulos, Pilar Cristancho, J. Philip Millerd, Charles Zorumski, Charles R. Conway

Treatment-resistant depression (TRD) is a severe form of major depressive disorder. Patients with TRD often fail multiple treatments with standard antidepressants and have an unfavorable long-term prognosis; one in three patients with major depression (estimated prevalence in the United States is 10 million adults) is affected. Therapeutic options for TRD are very limited.

There is a strong biological rationale supporting the potential therapeutic use of nitrous oxide in TRD. Although nitrous oxide is known to modulate several central nervous system targets, like ketamine, the primary target of nitrous oxide appears to be the N-methyl-D-aspartate (NMDA) receptor, where nitrous oxide acts as a noncompetitive inhibitor. NMDA receptor signaling has been implicated in the neurobiology of depression and is a key component of central nervous system information processing. Consistent with the relevance of NMDA receptor signaling in the pathophysiology of major depression, NMDA receptor antagonists, such as ketamine (a general, dissociative anesthetic), have been shown to provide rapid and sustained antidepressant effects at subanesthetic doses in TRD. Given the similar mechanisms of action, we hypothesized that nitrous oxide may also have rapid antidepressant effects in TRD. This proof-of-concept trial assessed the immediate (2 hours) and sustained (24 hours) antidepressant effects of nitrous oxide in a population of well-characterized patients with TRD.​

Discussion

This proof-of-concept trial demonstrated that nitrous oxide has rapid antidepressant effects in patients with TRD. These antidepressant effects were sustained for at least 24 hours and in some patients for 1 week. Nitrous oxide resulted in a treatment response in 20% of patients with TRD and remission in 15%. Although a subset of patients experienced adverse events requiring a short interruption or discontinuation of treatment, the mild to moderate nature and immediate reversibility of these events (nausea, anxiety, vomiting) suggest an acceptable risk/benefit ratio for nitrous oxide use in the setting of TRD.

The internal validity of our crossover trial was affected by the observed carryover effect (i.e., patients having a different baseline at different treatment sessions). In our study, several patients who returned for their second treatment session had markedly lower depression scores. Typically, carryover effects bias results toward the null hypothesis (i.e., reduce the observable effect size). This was the case in our study: the 10 patients who received nitrous oxide treatment first had a mean reduction in depressive symptoms of 8.6 points on the HDRS-21 compared with 5.5 points for the full cohort. This observation supports the notion that nitrous oxide has true antidepressant efficacy. A second effect that influenced the internal validity of our trial was the presence of a placebo effect. Placebo effects are common in trials of antidepressants and may introduce bias by masking or exaggerating treatment effects.

Pilot studies, such as this early phase II clinical trial, are designed to detect an efficacy signal in a small group of patients and cannot provide robust and definitive measures of effectiveness. Pilot trials should be interpreted with caution because results must be replicated in larger cohorts. Although the antidepressant efficacy results in this trial are promising, several potential limitations should be taken into consideration. First, although our study team went to great lengths to maintain blinding, the euphoric effects of nitrous oxide inhalation are difficult to mask. Nitrous oxide induces sedation and has a slightly sweet smell and taste. It is possible that some patients were able to determine whether they were receiving nitrous oxide or placebo inhalation. We did not test patients to determine if they were aware of their group assignment, and this limits our conclusions. We intentionally selected the 24-hour postinhalation mark as the primary measure to minimize acute euphoric effects. However, there remains the possibility that nitrous oxide inhalation may have produced a “masking” of depressive symptoms (i.e., the depressive symptoms were not really altered, but rather “covered up” by other effects). Symptom “masking” has been observed with rapidly acting psychostimulants (methylphenidate and cocaine), which promote a transient alteration in mood but not a true antidepressant effect.

Second, although we clinically assessed the presence of euphoria and psychosis at each time point, we did not do standardized testing of either. In general, at 2 hours and 24 hours, the patients did not report euphoric feelings. Third, the use of the HDRS-21 and QIDS-SR scales to measure rapid antidepressant action was a limitation because both scales assess symptom changes occurring over the course of days and weeks rather than hours, including questions related to sleep and weight, and are not ideal for assessing changes in antidepressant action that occur rapidly. Different scales, such as the International Positive and Negative Affect Schedule Short Form or a visual analog scale, might have been superior. Fourth, we had no prior knowledge about dosing in this patient population and opted to use a 50% inspiratory concentration of nitrous oxide, a dose commonly used in dentistry and obstetric analgesia. Subsequent studies may determine that different dosing regimens improve efficacy and tolerance.

Compared with ketamine, the most commonly investigated NMDA receptor antagonist drug in major depressive disorder, nitrous oxide had a similarly rapid onset of antidepressant action (within 2 hours) but appeared to be devoid of psychotomimetic side effects seen with ketamine (delusions, illusions, hallucinations), which may result from the more favorable pharmacokinetics of nitrous oxide because its offset occurs on the order of minutes. The fact that both ketamine and nitrous oxide have antidepressant effects in patients with TRD supports the notion that NMDA receptor signaling plays a crucial role in the neurobiology of major depressive disorder. However, recent data indicate that other neurotransmitter receptor systems, including nicotinic acetylcholine receptors, may be important contributors to rapid antidepressant actions.

We can only speculate why certain NMDA receptor antagonists (ketamine, nitrous oxide) appear to have rapid antidepressant properties, whereas others, such as memantine, do not. Differences in NMDA receptor channel blocking seem unlikely to contribute because differences between ketamine and memantine are often observable only under extreme depolarization or pathologic receptor activation (simulated ischemia). The presence of extracellular magnesium may distinguish the effects of ketamine and memantine on NMDA receptors, with memantine being relatively ineffective against NMDA receptor–mediated synaptic currents in magnesium. This latter effect also appears to contribute to differences in the ability of the two drugs to promote brain-derived neurotrophic factor production. Differences in mode of administration and pharmacokinetics may also contribute to observed clinical differences between ketamine and memantine. Although nitrous oxide, similar to ketamine, is a noncompetitive NMDA receptor antagonist, it differs from ketamine in lacking use dependence and is not a trapping open channel blocker. Nitrous oxide represents an alternative way to modulate NMDA receptor function clinically.

Although a single administration of 50% nitrous oxide/oxygen has been found to be generally safe (4% nonserious adverse event rate among 25,828 patients receiving sedation), two potential safety concerns exist. First, nitrous oxide administration had to be interrupted or discontinued in a subset of our patients (typically near the end of the 1-hour treatment session), and the adverse event profile indicates that some patients may experience emotional discomfort, paradoxically increased anxiety levels, and nausea during nitrous oxide administration. Although nearly all side effects were limited to the immediate treatment period and disappeared shortly after discontinuation, their nature suggests that perhaps a shorter treatment duration or lower nitrous oxide concentration may be advantageous.

A second potential safety concern relates to inactivation of vitamin B12 by nitrous oxide. Although a single exposure is unlikely to result in clinically relevant hematologic or neurologic complications, the risk for such complications is substantially higher when nitrous oxide administrations are repeated within short periods of time. Hematologic and neurologic complications, such as megaloblastic anemia and myelopathy, have been reported among persons who chronically abuse nitrous oxide and patients with chronic disturbances of folate metabolism. It is likely that for sustained antidepressant effect, nitrous oxide must be administered several times, which would increase the risk for such complications. Nitrous oxide is a drug of abuse, and its abuse potential represents a potential limitation for its clinical utility in major depressive disorder. Our pilot study was not designed to address this safety concern.

In conclusion, this preliminary, proof-of-concept clinical trial provides the first evidence that nitrous oxide may have rapid and marked antidepressant effects in patients with TRD. Subsequent studies are required to determine optimal antidepressant dosing strategies and the risk/benefit ratio of nitrous oxide in a larger and more diverse population of patients with TRD.

https://doi.org/10.1016/j.biopsych.2014.11.016

*From the article (including references) here :
 
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Low dose Nitrous Oxide may help some patients with Major Depression, study*

by Claudia López Lloreda | STAT News | 9 Jun 2021

Nitrous oxide gas may be most associated with its use in dentistry, but in recent years, scientists have been inching toward using the chemical for another purpose: depression that defies treatment. The results of a small trial, published Wednesday in Science Translational Medicine, suggest that a low dose of nitrous oxide could help improve depressive symptoms in patients with a severe form of depression that fails to respond to antidepressants.

Researchers at Washington University in St. Louis found that a low dose of nitrous oxide was just as effective at improving depression as a higher dose in patients with treatment-resistant depression, with less adverse side effects after two weeks. Either dose relieved symptoms more than placebo. A larger trial is planned to confirm the results.

Treatment-resistant major depression (TRMD), usually diagnosed after at least two antidepressants fail to help a patient, occurs in about one-third of patients with major depression, adding up to 17 million individuals in the U.S. The field has been plagued by a series of failures, motivating researchers to continue looking for alternatives.

“There hasn’t been a ton of forward progress to the dismay of many people,” said Kara Zivin, a professor of psychiatry at the University of Michigan who wasn’t part of the study.

Beyond antidepressants and therapy, current strategies to treat TRMD include electroconvulsive therapy and anesthetics. One particular breakthrough, ketamine, was found to improve depression symptoms in just a few hours. But experts are looking for more, cheaper, and safer options. “You need multiple alternatives because every brain is different,” said Cristina Cusin, director of the ketamine clinic for treatment-resistant depression at Massachusetts General Hospital, who wasn’t involved in the study.

In search of these alternatives, researchers looked to test other anesthetics, like nitrous oxide, a chemical typically used to sedate individuals undergoing medical and dental procedures.

A previous study showed that nitrous oxide gas improved depression symptoms one day after treatment. In the new study, the researchers wanted to see whether those effects were long-lasting and whether a lower dose could work as well.

To do this, they recruited 24 patients with TRMD, who were randomized in a crossover study to receive placebo, the low dose, or the high dose of nitrous oxide for one hour. In following sessions, each participant was again randomized to a different treatment group. Researchers then evaluated depressive symptoms of the 20 participants who completed all three sessions with a variety of questionnaires up to two weeks after each treatment.

After receiving either dose of nitrous oxide treatment, participants reported having less depression symptoms than those who did not. In one specific questionnaire, depression symptoms dropped between five and seven points, on a 65-point scale, with nitrous oxide compared to placebo two weeks after treatment. However, the high dose, 50% nitrous oxide, resulted in side effects like nausea and vomiting. The lower dose had much less frequent and less severe side effects. After the entire study was completed, depression symptoms had dropped about 11 points from their baseline levels.

“I work with these people for so many years, I don’t expect to see new things work,” said Charles Conway, professor of psychiatry at Washington University and senior author of the study. “But patients in this trial, some of whom I have known for a long time, got better.”

Nitrous oxide may offer certain advantages over other drugs and treatment strategies. “It’s a good option because it’s already in every hospital and every laboratory,“ said Cusin. It also has less serious side effects than ketamine and it is not metabolized in the body, added Peter Nagele, lead author of the study. “It goes into your body in a few minutes, leaves in a few minutes, and that’s it,” he said. Nagele, an anesthesiologist at the University of Chicago, has filed for a patent for use of nitrous oxide for depression.

However, experts warn that because of the way the anesthetic is typically used, there is a lack of safety data on prolonged use. “We have no idea what happens to a brain that gets exposed [to nitrous oxide] repeatedly over a long period of time,” said Cusin. Other experts agree that, as with other drugs that affect the brain, there is potential for abuse.

Additionally, trial participants were 96% white, raising concerns of how applicable the findings are for other populations, Lisa Harding, a psychiatrist at the Yale School of Medicine who wasn’t involved in the study, pointed out. "In the researchers’ next studies, more individuals from different backgrounds need to be included to prove the efficacy of nitrous oxide in depression in the real world," she said.

Although the results are preliminary and more data are needed, the researchers hope this could become another tool to help treat TRMD in a fast-acting manner.

*From the article here :
 
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Largest study finds Nitrous Oxide safe for women in labor

University of Colorado Anschutz Medical Campus | 29 May 2020

Women in labor who had a prior vaginal birth also had low rates of converting to other pain management techniques such as epidural or opioids.

Researchers at the University of Colorado College of Nursing and the School of Medicine Department of Anesthesiology at the Anschutz Medical Campus found that the use of nitrous oxide (N2O) as a pain relief option for individuals in labor is safe for newborn children and laboring individual, and converting to a different form of pain relief such as an epidural or opioid is influenced by a woman's prior birth history and other factors.

The study, out today in Journal of Midwifery & Women's Health, surveyed 463 women who used nitrous oxide during labor. The study is the largest and first of its kind in the United States to report rates of side effects from N2O use during labor, as well as reasons for women in labor after cesarean to convert to other forms of pain relief. Of the women who began using N2O as an initial pain relief technique, 31% used only N2O throughout labor and 69% transitioned to another pain relief method such as epidural and/or opioids. "Nitrous oxide is a useful, safe option for labor analgesia in the United States. And for some laboring mothers, that's all the pain relief they need. Understanding predictors of conversion from inhaled nitrous oxide to other forms of analgesia may assist providers in their discussions with women about pain relief options during labor," said lead author and Associate Professor with the University of Colorado College of Nursing Priscilla M. Nodine, PhD, CNM.

The reason most often cited (98 percent) for converting from N2O to an alternative therapy was inadequate pain relief. The odds of conversion from N2O increased approximately 3-fold when labor was augmented with oxytocin and when labor was induced. Also, those who had a history of cesarean section and experienced labor post-cesarean had more than a 6-fold increased odds of conversion to neuraxial analgesia or epidural. The odds of conversion to neuraxial analgesia decreased by 63% for individuals who had given birth previously relative to those who were giving birth for the first time.

Approximately 4 million women in the United States give birth each year, and for many, coping with labor is a significant concern. Epidurals and spinal blocks, also known as neuraxial analgesia, are the most frequently used pain management tools in the United States, with the main alternative being systemic opioids, which can be associated with both maternal and fetal adverse effects. Recently reintroduced as a pain relief option during labor in the United States, N2O has a long history of use in many developed nations and is increasingly available in the US. "While there is a fair body of anecdotal evidence of safety and effectiveness for how nitrous oxide affects pain during labor, few systematic analyses of outcomes are available from US-based cohorts," said Nodine.

 
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The Nitrous Oxide Philosopher

by Dmitri Tymoczko | The Atlantic

Do drugs make religious experience possible? They did for James and for other philosopher-mystics of his day. James' experiments with psychoactive drugs raise difficult questions about belief and its conditions

He has short hair and a long brown beard. He is wearing a three-piece suit. One imagines him slumped over his desk, giggling helplessly. Pushed to one side is an apparatus out of a junior-high science experiment: a beaker containing some ammonium nitrate, a few inches of tubing, a cloth bag. Under one hand is a piece of paper, on which he has written, "That sounds like nonsense but it is pure on sense!" He giggles a little more. The writing trails away. He holds his forehead in both hands. He is stoned. He is William James, the American psychologist and philosopher. And for the first time he feels that he is understanding religious mysticism.

The psychedelia of the 1960s was foreshadowed by events in the waning years of the nineteenth century. This first American psychedelic movement began with an anonymous article published in 1874 in The Atlantic Monthly. The article, which was in fact written by James, reviewed The Anaesthetic Revelation and the Gist of Philosophy, a pamphlet arguing that the secrets of religion and philosophy were to be found in the rush of nitrous oxide intoxication. Inspired by this thought, James experimented with the drug, experiencing extraordinary revelations that he immediately committed to paper.
What's mistake but a kind of take?
What's nausea but a kind of -ausea?
Sober, drunk, -unk , astonishment. . . .
Agreement--disagreement!!
Emotion--motion!!! . . .
Reconciliation of opposites; sober, drunk, all the same!
Good and evil reconciled in a laugh!
It escapes, it escapes!
But--
What escapes, WHAT escapes?

This experience, which in James' words involved "the strongest emotion" he had ever had, remained with him throughout his life. In 1882 he first described his experiments with the drug; in 1898 he published an article titled "Consciousness Under Nitrous Oxide" in the Psychological Review; in 1902 he recounted the experience in his greatest work, The Varieties of Religious Experience ; and in 1910, in the last essay he completed, he implied that nitrous oxide had had an abiding influence on his thinking.

When the drug wore off, James found that his mystical insights had disappeared. What remained were incomprehensible words--"tattered fragments" that seemed like "meaningless drivel." Being a philosophical visionary rather than a garden-variety recreational drug user, however, James was not inclined to let his sober consciousness have the final say. On the contrary, he took his experiences with nitrous oxide as evidence that human life was more richly varied than he had previously (and soberly) imagined. "Some years ago," he wrote in Varieties,
I myself made some observations on . . . nitrous oxide intoxication, and reported them in print. One conclusion was forced upon my mind at that time, and my impression of its truth has ever since remained unshaken. It is that our normal waking consciousness, rational consciousness as we call it, is but one special type of consciousness, whilst all about it, parted from it by the filmiest of screens, there lie potential forms of consciousness entirely different.

For James, these alternate forms of consciousness were accessible only by way of artificial intoxicants. Others, he hypothesized, were able to reach them without the aid of drugs: in his view the great religious mystics, and certain mystical philosophers including Hegel, were "unusually susceptible" to these extraordinary forms of consciousness.

James' experiences with nitrous oxide helped to crystallize some of the major tenets of his philosophy. His writings emphasize, for instance, the notion of pluralism, according to which "to the very last, there are various 'points of view' which the philosopher must distinguish in discussing the world." Nitrous oxide had revealed in the most dramatic way possible the existence of alternate points of view. Which was the "real" William James--the drug-addled visionary who spouted meaningless mystical drivel, or the sober, unmystical psychologist whose researches brought him international fame? James' philosophy was based on the thought that the good life--for society and, by extension, for an individual as well--involves a plurality of perspectives, of which the mystical and the scientific are only two. Equally important to the mature Jamesian outlook was the thought that religious experiences are psychologically real--powerful and palpable events that can have important long-term consequences whether the beliefs to which they give rise are true or not. Drugs helped James to understand what religious belief was like from the inside. When he took nitrous oxide, he was for all intents and purposes a religious mystic. ("Thought deeper than speech!" he wrote while on the drug. "Oh my God, oh God, oh God!") Nitrous oxide was the passport that allowed James to see religion from the believer's perspective, traveling between the worlds of science and faith.

Yet James' experiments with nitrous oxide, when they have been noticed at all, have been variously derided. Even in the nineteenth century, skeptical scientists found his interest in exotic mental phenomena misguided, if not reckless. Religious believers tend to resent the comparison of intoxication to religious inspiration. Veterans of the counterculture, who have all had similar if not more-intense drug revelations, tend to think of James as a dabbler. These criticisms are shortsighted, and slight the fact that James was America's first philosophical genius. Perhaps more than any philosopher before him, he succeeded in combining the skepticism of the empirical scientist, the form of consciousness that "diminishes, discriminates, and says no," with the hyperbole of the mystical visionary, the form of consciousness that "expands, unites, and says yes." If drugs helped him to open the doors of consciousness in this welcoming way, perhaps we should rethink some of our assumptions about drug use and its possible role in human life. For example, can drugs play a role in authentic religious experience? And if so, what should be the legal and moral status of religious drug use?

These questions lead into a fascinating tangle of history and philosophy, much of which has surprising relevance to contemporary policy. Indeed, for more than thirty years courts, legislatures, and philosophers have been debating James' questions, reaching a bewildering variety of incompatible conclusions. Some courts have held that religious drug use is legitimate and even deserves constitutional protection; others--including the Supreme Court--have rejected these arguments. In 1993 Congress passed a law allowing for the sacramental use of peyote, a powerful hallucinogen; yet politicians continue to excoriate "drug use," as if "drugs" were a single sort of unequivocally bad thing. (One wonders how many of the congressional representatives who passed the peyote law would be willing to acknowledge publicly their support for hallucinogenic drug use.) William James thought more clearly about these issues than we are able to think today, and we may want to look to James as we consider the place of drugs in contemporary life.
An "Adamic" Revelation

James' interest in nitrous oxide was prompted by a man named Benjamin Paul Blood. Born in 1832, Blood --a farmer, philosopher, athletic strongman, prodigious calculator, debunker, inventor, mystic, and forgotten visionary, and the author of the pamphlet The Anaesthetic Revelation and the Gist of Philosophy --is a classic figure of nineteenth-century America. By his own confession an idler, a "fraud," haphazardly educated and with little gift for sustained argument, Blood spent his eighty-six years in Amsterdam, a town in upstate New York. But despite his limitations, or perhaps because of them, he devoted his life to philosophy. The bulk of his writing consists of letters to the editors of local papers: the Amsterdam Gazette and Recorder , the Utica Herald , the Albany Times . (Some of these letters were amalgamated for the Journal of Speculative Philosophy.) He published a few poems in Scribner's Magazine . Eventually he wrote a book, Pluriverse: An Essay in the Philosophy of Pluralism.

Blood could multiply large numbers in his head. He could demolish the itinerant lecturers who were a staple of nineteenth-century American popular culture. On one occasion he demonstrated to an astonished crowd how a visiting spiritualist had produced apparently ghostly occurrences. On another he used the doctrines of what was then called modern philosophy to challenge an astronomer's glorification of space: Why, he asked, should we be impressed by the size of the solar system if size is relative to the perceiver? Would not a giant find the universe small? And is it not, therefore, we who make space large, since without us it would be neither large nor small? Amsterdam was not always up to these speculations, but it loved Blood nonetheless. Bewildered newspaper editors cheerfully printed his grandiose contributions. Townspeople spoke in admiring terms of Blood's letters from such luminaries as Ralph Waldo Emerson, Grover Cleveland, and William James. And, as Blood was not above mentioning, in a poll conducted by one of the local papers he placed as "one of the twelve leading citizens" of the town--number six, to be precise.

The outside world, however, was less kind. The portentous letters Blood directed to innumerable nineteenth-century eminentos were for the most part met with polite dismissal. One appeal, it is true, produced an invitation to visit Alfred Lord Tennyson; another resulted in a lengthy and affectionate correspondence with James. But in the main Blood lived his long life alone. Thumbing through the detritus of his "papers," the inconsequential letters and crumbling newspaper clippings that some admirer deposited in Harvard's Houghton Library, one catches the unmistakable whiff of intellectual tragedy. Blood was the very picture of the half-baked American eccentric, a snake-oil salesman with philosophical pretensions. Born in the wrong place and at the wrong time, he knew too little to put his talents to good use, and too much to let them atrophy gracefully.

Blood's obsession with nitrous oxide began at a dentist's office. Nitrous oxide, or "laughing gas," had been discovered in 1772 by Joseph Priestley. Its distinctive psychoactive properties were noticed twenty-seven years later by Sir Humphrey Davy, whose Researches, Chemical and Philosophical, Chiefly Concerning Nitrous Oxide, or Dephlogisticated Nitrous Air, and Its Respiration records a series of attempts to try to find a use for the new drug. Notwithstanding Davy's efforts,the drug was used in the early half of the century primarily for recreation. One nineteenth-century observer wrote that ether, which has similar psychoactive properties, had "long been the toy of professors and students," and noted that "the students at Harvard used to inhale sulphuric ether from their handkerchiefs, and that it intoxicated them, making them reel and stagger." Ether was first put to its modern use in 1846, when, in one of the major triumphs of nineteenth-century medicine, W.T.G. Morton, an American dentist, "administered the vapor of sulphuric ether to a patient, and extracted a tooth, the patient being in a state of entire insensibility." A similar result followed shortly thereafter with nitrous oxide, and the modern practice of anesthesia was born.

Enter Blood. In the preface to his book, Pluriverse, he wrote,
It was in the year 1860 that there came to me, through the necessary [medical] use of anaesthetics, a Revelation or insight of the immemorial Mystery which among enlightened peoples still persists as the philosophical secret or problem of the world. . . . After fourteen years of this experience at varying intervals, I published in 1874 "The Anaesthetic Revelation and the Gist of Philosophy," not assuming to define therein the purport of the illumination, but rather to signalize the experience, and in a résumé of philosophy to show wherein that had come short of it.

Blood held that the great metaphysical philosophers, from Plato to Hegel, had all experienced something like what he had experienced while on nitrous oxide. This "anaesthetic revelation," he argued, was "primordial," "Adamic," and incommunicable. He wrote to James, "Philosophy is past. It was the long endeavor to logicize what we can only realize practically or in immediate experience."

Tireless proselytizing on behalf of his pamphlet--Blood sent copies to virtually everyone he could think of--eventually resulted in the formation of a tiny group of nitrous oxide philosophers, who agreed that the drug produced some sort of incommunicable metaphysical illumination. One was Xenos Clark, a philosopher who died young in Amherst, Massachusetts. (His last days were spent collecting his writings on the "anaesthetic revelation," which he asked James to transmit to posterity.) Other experimenters included some impressive figures: Edmund Gurney, an English spiritualist who had written a heavy two-volume catalogue of telepathic events, hauntings, and other ghostly occurrences (Phantasms of the Living, 1886); J. A. Symonds, the poet, historian, and biographer; Professor William Ramsay, a 1904 Nobel laureate and the discoverer of the inert gases; and, of course, William James. All reported "metaphysical insights" under the influence of nitrous oxide or similar drugs. Even Tennyson, while he was recovering from an experience with ether, blurted out "a long metaphysical term"--unfortunately not recorded.

Many of these figures were associated with the British Society for Psychical Research. Founded in 1882, the society (which still exists) aimed to test with an unbiased, scientific eye reports of a wide variety of unusual experiences not recognized by the academic establishment. Its province was what we would now call parapsychology: claims of hauntings, telepathy, spontaneous mental healings, visions of the dead, and other supernatural occurrences. Members conducted research, collected reports of paranormal activity, and published a journal. Blood's claim--that nitrous oxide reliably produced the experience of metaphysical illumination--engaged the society, and its members immediately set about to verify or disprove it.

James was attracted to the society by its peculiar mixture of scientific caution and romantic optimism. The son of a Swedenborgian, James was permanently suspended between the poles of faith and reason. Although he was uncomfortable with his father's visionary excess, he was scandalized by the neglect of this very quality on the part of the more reputable sciences. He wrote in "What Psychical Research Has Accomplished,"
No part of the unclassified residuum [of human experience] has usually been treated with a more contemptuous scientific disregard than the mass of phenomena generally called mystical. Physiology will have nothing to do with them. Orthodox psychology turns its back on them. Medicine sweeps them out; or, at most, when in an anecdotal vein, records a few of them as "effects of the imagination"--a phrase of mere dismissal, whose meaning, in this connection, it is impossible to make precise. All the while, however, the phenomena are there, lying broadcast over the surface of history.

James even went so far as to compare this disregard to that of a religious believer who refuses to acknowledge scientific considerations that weigh against his or her cause: "Certain of our positivists keep chiming to us that, amid the wreck of every other god and idol, one divinity still stands upright,--that his name is Scientific Truth, and that he has but one commandment, but that one supreme, saying, Thou shalt not be a theist." James wanted a more radical empiricism, a science freed of preconceptions, for which the issue of religious belief had not been foreclosed ahead of the evidence.

It was Blood, more than any other single figure, who embodied this attitude. James' final published essay, "A Pluralist Mystic," was a sustained encomium of Amsterdam's finest philosopher. Blood's work, he wrote, "fascinated me so 'weirdly' that I am conscious of its having been one of the stepping-stones of my thinking ever since." Blood gave James confidence that empirical and mystical sympathies could be combined. James wrote,
One cannot criticize the vision of a mystic--one can but pass it by, or else accept it as having some amount of evidential weight. I felt unable to do either with a good conscience until I met with Mr. Blood. . . . I confess that the existence of this novel brand of mysticism has made my cowering mood depart.

Blood's was a "pluralist mysticism" because it presented his extraordinary mystical experiences simply as experiences, without chaining them to a grand systematic doctrine such as Christianity or Hegelian philosophy. Moreover, it provided others with a key to those experiences, nitrous oxide, with which they could test Blood's claims in controlled and scientific surroundings. It was, in short, a mysticism without dogma or conclusions--just the thing for a Harvard professor with strong religious sympathies.

Did religion begin with drugs?

DRUGS have long been associated with religion. Psychedelic mushrooms were used in Siberia more than 6,000 years ago. The ceremonial use of marijuana among the Scythians dates back almost 2,500 years. Haoma, a sacred drink of the Zoroastrians, and soma, an early Hindu analogue, are both presumed to have been made from psychedelic plants; scriptural references to the drinking of "sacred urine" have led some historians to propose that the plants in question may have included the Amanita muscaria mushroom, whose active ingredient passes into urine without a significant loss of potency. The ancient Greek cult of Dionysus used wine to provoke visions, and other Greek mystery cults may have used psychoactive substances. (The use of wine in Christian rituals may be a remnant of similar practices.) In the New World the religious use of psychedelic mushrooms has been widely practiced--among the Mayans, in the Aztec empire, and today, by many members of the Native American Church. In view of this extensive transcultural association between religion and drug use, at least one scholar--R. Gordon Wasson, an authority on mushroom cults--has proposed that the religious impulse itself originated with drugs, as a confused reaction to intense experiences provoked by the accidental ingestion of psychoactive plants.

James' interest in the connection between drugs and religion was unusual in one crucial respect. Unlike other drug-using mystics, he did not see drugs as a means to understanding higher religious truths; on the contrary, he used drugs because they provided him with access to beliefs that were potentially false. At the time of his experiments with nitrous oxide James thought that religion, though it might be based on untruth from the scientific point of view, was nevertheless good for one. It had survival value: in the long run religion helped human beings to live rich and happy lives. In "Is Life Worth Living?" he offered the analogy of a mountain climber who is stuck in a tight place.
Suppose, for instance, that you are climbing a mountain, and have worked yourself into a position from which the only escape is by a terrible leap. Have faith that you can successfully make it, and your feet are nerved to its accomplishment. But mistrust yourself, and think of all the sweet things you have heard the scientists say of maybes, and you will hesitate so long that, at last, all unstrung and trembling, and launching yourself in a moment of despair, you roll in the abyss.

This analogy, which emphasizes belief's potential usefulness rather than its truth, is utterly characteristic of James, a man who arrived at philosophy by way of medicine and psychology rather than physical science and logic.

At the age of twenty-eight James had fallen into a period of deep depression. Unable to see his way around the determinism of his materialist friends, he felt pessimistic, not just about the possibility of human freedom in a world of physical laws but also about his own aptitude for philosophy. The death of a favorite cousin, coupled with repeated bouts of physical illness, exacerbated his situation. Finally came a crisis. One night, walking into a darkened room, James had a sudden hallucinatory vision: a young man he had once seen, a patient at a mental hospital, black-haired, with "greenish" skin, sitting on a bench against the wall, his legs pressed up against his chest, moving only his eyes. "That shape am I," James wrote: a powerless waif, observing a world he could not change. After this, he said, "the universe changed entirely." He began to wake up each morning with dread in his stomach. For months he was afraid to go into the dark alone. Concealing his condition from the people around him, James quietly contemplated suicide.

Over the next few months his melancholia faded somewhat. Then, on April 30, 1870, a dam burst.
I think yesterday was a crisis in my life. I finished the first part of Renouvier's 2nd Essay and saw no reason why his definition of free will--"the sustaining of a thought because I choose to when I might have other thoughts"--need be the definition of an illusion. At any rate I will assume for the present--until next year--that it is no illusion. My first act of free will shall be to believe in free will. For the remainder of the year, I will abstain from the mere speculation & contemplative [meditation] in which my nature takes most delight, and voluntarily cultivate the feeling of moral freedom, by reading books favorable to it, as well as by acting.

James chose to believe in free will not because he thought it was true but because it was necessary to his well-being. Like the mountain climber facing a life-or-death jump, he simply screwed up his courage and told himself that he was free. "In such a case," James wrote about the mountain climber, "(and it belongs to an enormous class) the part of wisdom as well as of courage is to believe what is in the line of your needs, for only by such belief is the need fulfilled."

James' career involved a progressive generalization of this thought. What began as a simple, almost physical necessity--a personal need to believe in free will in order to escape crushing moral paralysis--blossomed into a full-fledged philosophical doctrine. Beliefs, James eventually decided, were adaptations, like the giraffe's long neck or the tiger's claws: they were justifiable only insofar as they helped people to get around in the world. To believe what one needed to believe was no mere sign of weakness, as some of James' contemporaries contended. Rather, it showed a healthy understanding of what the process of believing was all about. In particular James argued that we are not obligated to be determinists, atheists, or materialists just because science might say that those are the correct and true doctrines. Ultimately science itself should be evaluated in terms of a higher moral question: To what extent are scientific beliefs conducive to human happiness?

Positive Illusions

SOME remarkable work by psychologists has recently illuminated James' position. Lyn Abramson, of the University of Wisconsin, and Lauren Alloy, of Temple University, have uncovered a number of "cognitive illusions" to which normal, healthy people are subject. Emotional health, they suggest, involves mildly overoptimistic presumptions and a corresponding insensitivity to failure, which result in a propensity to make straightforwardly false judgments. Perversely, the clinically depressed are often free of these cognitive illusions--they are, to use the subtitle of one of Abramson and Alloy's best-known papers, "Sadder But Wiser." Likewise, Shelley Taylor, a social psychologist, has studied the use of illusions by victims of trauma and illness. She found that like James' mountaineer, those who are unjustifiably optimistic tend to live better-adjusted and happier lives than people faced with similar situations who are thoroughly realistic about their prospects. (Taylor's book, Positive Illusions, provides an introduction to the subject of useful falsehoods.) Finally, Daniel Goleman, the author of Vital Lies, Simple Truths, and other neo-Freudians have argued that repression, the forgetting of unpleasant facts, plays a crucial role in emotional health. Overall, the psychological consensus seems to be that there can be a reasonably widespread conflict between truth and happiness. The best beliefs, as James clearly intuited, are by no means the truest ones. (Toward the end of his life James came to use "true" almost as a synonym for "useful," but the early James had not yet taken this radical step.)

James' life was filled with eloquent demonstrations, both large and small, of this principle. Testifying before the Massachusetts legislature, in 1898, he opposed a bill that would have prohibited Christian Scientists from practicing their "mind-cures." "You are not to ask yourselves whether these mind-curers really achieve the successes that are claimed," he told the lawmakers. "It is enough for you as legislators to ascertain that a large number of our citizens . . . are persuaded that a valuable new department of medical experience is by them opening up." On a more mundane level James supported the philosopher Charles Sanders Peirce, his friend and mentor, with money that was from his own pocket but that James claimed had been collected from Peirce's many "anonymous admirers." This was an ordinary white lie, but in the context of James' lifelong concern for the practical consequences of belief it resonates with unusual grandeur. James' genius can be described as an unwillingness to overlook the numerous instances of benign deception (and self-deception) that mark human life. With inspired audacity he suggested a link between these banal little deceptions and the grand, useful, and possibly false world views that characterize religious belief.

James' interest in drugs needs to be seen in this light. Although as a philosopher James preached the "will to believe," as a man he was not always able to put this idea into practice. Without nitrous oxide he was a cautious scientist whose skeptical nature prevented him from experiencing the religious joys that his philosophy celebrated. "My own constitution," he said, speaking of mystical experiences, "shuts me out from their enjoyment almost entirely." With the drug he became an inspired visionary whose rantings would surely turn a Beat poet green with envy.
No verbiage can give it, because the verbiage is other.
coherent, coherent--same.
And it fades! And it's infinite! AND it's infinite! . . .
Don't you see the difference, don't you see the identity?
Constantly opposites united!
The same me telling you to write and not to write!
Extreme--extreme, extreme! . . .
Something, and other than that thing!
Intoxication, and otherness than intoxication.
Every attempt at betterment,--every attempt at otherment,
--is a--
It fades forever and forever as we move.

Drugs, in short, gave James the theorist who dared people to believe what accorded with their needs the ability to do just that.

The Freedom to Believe

AMERICANS, it is often remarked, are confused about drugs. The image of William Bennett giving up his cigarettes in order to lead the nation's War on Drugs exemplifies this confusion. We tolerate cigarettes and alcohol but prohibit the recreational use of similarly mild intoxicants, including marijuana. We pour billions of dollars into law enforcement but devote only a tiny fraction of this amount to the medical treatment and rehabilitation of drug addicts. Courts impose widely disparate punishments for the possession and use of chemically similar substances, notably crack and powdered cocaine. But perhaps the most egregious area of inconsistency involves religious drug use. Faced with the claim that drug use contributes importantly to religious belief, courts have made a number of confused and conflicting judgments.

In 1964 the California Supreme Court held that members of the Native American Church, an association of Native American groups all of whom use peyote in their religious rituals, had a First Amendment right to use the drug. In subsequent years the Native American Church obtained religious exemption from peyote restrictions in twenty-seven other states, though in a few instances, notably in a case before the Oregon Supreme Court, its arguments were rejected. Meanwhile, non-Native American requests for religious exemption from drug statutes have repeatedly been denied--including those of the Neo-American Church, which in 1968 claimed 20,000 members; the Universal Church of Christ Light, which used marijuana in its rituals; the Church of the Awakening, founded in 1963 by two retired osteopaths; the Native American Church of New York (of whose 1,000 members only a few were in fact Native Americans); Timothy Leary; and the Ethiopian Zion Coptic Church, a syncretic Jamaican group. Finally, in 1990, the U.S. Supreme Court rejected the claim that the First Amendment protected the Native American Church's use of peyote--in part, no doubt, because of the obvious double standard that was being applied. Congress retaliated in 1993 with the Religious Freedom Restoration Act, in effect reinstating both the Native American Church's right to use drugs in its religious rituals and the disturbing double standard.

The reasoning behind decisions that uphold the right to use drugs in a religious context is obvious: drugs play an important, even essential, role in the practice of many religious groups; the Constitution protects the free exercise of religious belief; therefore the Constitution protects the use of drugs. The reasoning behind decisions that reject the same right is that religious action, unlike religious belief, is not absolutely protected by the Constitution. The distinction was definitively articulated by Justice Owen Roberts in Cantwell v. Connecticut (1940). "The [First] Amendment," he wrote, "embraces two concepts--freedom to believe and freedom to act. The first is absolute but, in the nature of things, the second cannot be." Thus the law, though it does not seek to prevent people from having certain religious beliefs, may prevent them from acting on those beliefs. Courts have held, for instance, that prohibitions on polygamy apply to Mormons, and that even Christian snake-handling sects are subject to regulations controlling the treatment of dangerous animals. Since taking drugs is an action, it is thus subject to government regulation.

But is this the right way to look at the situation? William James used drugs not because he had religious beliefs that encouraged him to do so but in order to generate religious or mystical beliefs that he otherwise would not have had.
Looking back on my own experiences [with nitrous oxide], they all converge towards a kind of insight to which I cannot help ascribing some metaphysical significance. The keynote of it is invariably a reconciliation. It is as if the opposites of the world, whose contradictoriness and conflict make all our difficulties and troubles, were melted into unity. . . . This is a dark saying, I know, when thus expressed in terms of common logic, but I cannot wholly escape from its authority. I feel as if it must mean something, something like what the hegelian philosophy means, if one could only lay hold of it more clearly. Those who have ears to hear, let them hear; to me the living sense of its reality only comes in the artificial mystic state of mind.

If we take this claim seriously, and if we also take seriously Justice Roberts's assertion that the "freedom to believe" is absolute, then we need to rethink the prevailing consensus about religious drug use. Taking drugs is an action, certainly, but actions that are necessary for the production of religious beliefs should not be conflated with actions taken because of religious beliefs that could exist regardless. James needed nitrous oxide in order to have his mystical belief. Did he then have a constitutional right to use the drug? Just how absolute is the freedom to believe?

More important, James' philosophy gives us a principled way to think about the relation between religion and drugs. From a Jamesian perspective, religious toleration represents not just a commitment to individual freedom, not simply a hands-off policy on the part of the government toward questions of ultimate truth, but rather an affirmative decision to shelter certain useful though potentially false beliefs. Drug use, from this perspective, represents a similar sort of decision, but on the level of the individual rather than of the society. Just as a society might choose to nurture or tolerate certain sorts of illusions, pluralistically embracing both atheistic and religious subcultures, so, too, might an individual decide--as did James--to divide his or her life into periods of sober rationality and ecstatic religious intoxication. Drugs can allow even the most skeptical people, those who by constitution or upbringing are not susceptible to religious insights, to experience temporary periods of pleasing falsehood. Indeed, this is the real religious significance of drug use, from the Jamesian point of view--that it lets us choose, if only vaguely and temporarily, what to believe.

In 1977 Judge Jack Weinstein, of New York State, wrote,
Neither the trappings of robes, nor temples of stone, nor a fixed liturgy, nor an extensive literature or history is required to meet the test of beliefs cognizable under the Constitution as religious. So far as our law is concerned, one person's religious beliefs held for one day are presumptively entitled to the same protection as the beliefs of millions which have been shared for thousands of years.

These are generous words, and they should make us ask whether James' beliefs--held not for a day but for the mere minutes of his intoxication--warrant comparable charity. Can we learn to look at drug-induced illusion with enthusiastic Jamesian innocence? Is not the degree of self-control that pharmacology has given us remarkable? Prozac promises to change the hand that chemistry has dealt us, altering our moods to suit our needs. For James, drugs served a similar function: using nitrous oxide, he altered the beliefs that science had given him, experiencing if only for a brief time the pleasing illusions of the religious visionary.

Drugs, of course, are dangerous. They can destroy lives, families, and even whole communities. (James' own brother Robertson fought a long and losing battle with alcoholism.) The story of William James shows us how drugs can also contribute to human well-being, fulfilling in some instances an authentic religious need. Of course, our political culture is unprepared to recognize this. No doubt our courts will for the foreseeable future continue to deny that seekers like James might have a compelling religious interest in the use of drugs. Our politicians will continue to make perhaps unnaturally sharp distinctions: between the pleasing illusions of religious belief and those of intoxication; between the Native American's peyote and the non-Native American's nitrous oxide. A century after William James we have yet to catch up with him and his intoxicated nonsense.



 
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Nitrous Oxide may offer quick, long-lasting relief from depression

Laughing gas may be far more effective than antidepressants.
  • Standard antidepressant medications don't work for many people who need them.​
  • With ketamine showing potential as an antidepressant, researchers investigate another anesthetic: nitrous oxide, commonly called "laughing gas."​
  • Researchers observe that just a light mixture of nitrous oxide for an hour alleviates depression symptoms for two weeks.​
by Robby Berman | BIG THINK

The usual antidepressants don’t work for everyone. That’s what makes a new study of the antidepressant properties of nitrous oxide so intriguing. It looks like just a single low dose of what your dentist may call “laughing gas” can help alleviate symptoms of depression for weeks afterward.

The study, from researchers at University of Chicago and Washington University-St. Louis, is published in the journal Science Translational Medicine.

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Resistance to anti-depression medications

According to the senior author of the study, Charles Conway, “A significant percentage — we think around 15 percent — of people who suffer from depression don’t respond to standard antidepressant treatment.”

“These ‘treatment-resistant depression’ patients,”
Conway says, “often suffer for years, even decades, with life-debilitating depression. We don’t really know why standard treatments don’t work for them, though we suspect that they may have different brain network disruptions than non-resistant depressed patients. Identifying novel treatments, such as nitrous oxide, that target alternative pathways is critical to treating these individuals.”

“There is a huge unmet need,”
says lead author Peter Nagele. “There are millions of depressed patients who don’t have good treatment options, especially those who are dealing with suicidality.”

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If ketamine can help, can nitrous oxide?

The researchers wondered if some of the anti-depression properties seen in ketamine might also apply to nitrous oxide. Nagele explains, “Like nitrous oxide, ketamine is an anesthetic, and there has been promising work using ketamine at a sub-anesthetic dose for treating depression.”

The researchers conducted a one-hour session — they describe it as a “proof-of-principle” trial — in which 20 individuals with depression were administered an air mixture with 50 percent nitrous oxide. Twenty-four hours later, the researchers found a significant reduction in the participants’ symptoms of depression versus a control group.

However, the individuals also suffered the unpleasant side effects that laughing gas often causes in dental patients: headache, nausea, and vomiting.

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Smaller dose, longer effect

“We wondered if our past concentration of 50 percent had been too high,” recalls Nagele. “Maybe by lowering the dose, we could find the ‘Goldilocks spot’ that would maximize clinical benefit and minimize negative side effects.”

In a new trial, 20 people with depression were given a lighter nitrous oxide mix, just 25 percent, and the individuals tested reported a 75 percent reduction in side effects compared to the a control group given an air/oxygen placebo. This time, the researchers also tracked the effect of nitrous oxide on symptoms of depression for a far longer period, two weeks instead of just 24 hours.

“The reduction in side effects was unexpected and quite drastic,” reports Nagele, “but even more excitingly, the effects after a single administration lasted for a whole two weeks. This has never been shown before. It’s a very cool finding.”

Nagele also notes that, despite its popular renown as laughing gas, even a light 25 percent mix of nitrous actually causes people to nod off. “They’re not getting high or euphoric; they get sedated.”

Delivering help to people with depression

Nagele cautions, “These have just been pilot studies. But we need acceptance by the larger medical community for this to become a treatment that’s actually available to patients in the real world. Most psychiatrists are not familiar with nitrous oxide or how to administer it, so we’ll have to show the community how to deliver this treatment safely and effectively. I think there will be a lot of interest in getting this into clinical practice.”

After all, Nagele adds, “If we develop effective, rapid treatments that can really help someone navigate their suicidal thinking and come out on the other side — that’s a very gratifying line of research.”

 
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Psychedelic effects of a subanesthetic concentration of Nitrous Oxide*

R. I. Block, M. M. Ghoneim, V. Kumar, D. Pathak

The subjective effects of nitrous oxide were examined by administering questionnaires to volunteers (16 men and 16 women) breathing 30% nitrous oxide or 100% oxygen. Nitrous oxide produced a variety of subjective effects, including some that are characteristic of psychedelic drugs, such as happy, euphoric mood changes, changes in body awareness and image, alterations of time perception, and experiences of a dreamy, detached reverie state. The subjective effects, including those of a psychedelic nature, were very similar to the subject effects we observed in a previous study of nitrous oxide. However, euphoric mood changes were more pronounced, and adverse effects were less pronounced, in the present study, possibly due to the shorter duration of gas inhalation or the minimal tests of performance involved. Some other differences in subjective effects between the present and previous studies were identified by a discriminant analysis and seemed related to specific differences in experimental conditions. This suggests that the environment can influence which drug effects emerge, or at least their relative prominence. Clinicians should be familiar with the range of subjective effects that patients inhaling nitrous oxide may experience.
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The subjective effects of nitrous oxide were examined by administering questionnaires to volunteers (16 men and 16 women) breathing 30% nitrous oxide or 100% oxygen. Nitrous oxide produced a variety of subjective effects, including some that are characteristic of psychedelic drugs, such as happy, euphoric mood changes, changes in body awareness and image, alterations of time perception, and experiences of a dreamy, detached reverie state. The subjective effects, including those of a psychedelic nature, were very similar to the subjective effects we observed in a previous study of nitrous oxide. However, euphoric mood changes were more pronounced, and adverse effects were less pronounced, in the present study, possibly due to the shorter duration of gas inhalation or the minimal tests of performance involved. Some other differences in subjective effects between the present and previous studies were identified by a discriminant analysis and seemed related to specific differences in experimental conditions. This suggests that the environment can influence which drug effects emerge, or at least their relative prominence. Clinicians should be familiar with the range of subjective effects that patients inhaling nitrous oxide may experience.

Nitrous oxide in subanesthetic concentrations is widely used in dental and medical practice and is sometimes abused, presumably for its subjective effects. In a previous study, we administered a questionnaire exploring the subjective effects of 30% nitrous oxide and found that the drug produced a variety of subjective effects, including some that are characteristic of psychedelic drugs. Our results were consistent with an earlier study using a similar questionnaire and with the anecdotal descriptions of nineteenth century investigators such as William James. Lysergic acid diethylamide (LSD) is the prototype of the psychedelic drugs. Other drugs that are generally classified as psychedelics include psilocybin, psilocin, dimethyltryptamine, mescaline, and 2,5-dimethoxy-4-methylamphetamine. LSD and other psychedelics produce a multi-faceted pattern of subjective effects which is distinct from that of most other psychoactive drugs. Barber exhaustively reviewed the literature on subjective effects of LSD and classified these effects under categories such as changes in time perception, body image, and mood. In one of the most detailed investigations of subjective effects of LSD, Katz and colleagues developed a Subjective Drug Effects Questionnaire and administered it to subjects receiving LSD (50 ug), amphetamine (15 mg), or placebo. A number of scales on the questionnaire showed subjective effects of LSD that differed from those of both amphetamine and placebo. In contrast, subjective effects of LSD resemble those of other psychedelics. For example, LSD, mescaline, and psilocybin are nearly indistinguishable in most subjective effects, as well as showing considerable cross-tolerance.

It is frequently claimed that subjective effects of a psychedelic nature vary markedly depending on situational factors such as the setting in which a drug is administered. Barber, although indicating that little systematic research had been done, listed a number of factors generally believed to be important in influencing the subjective effects of LSD-type drugs, such as whether the drug is administered in a clinical or experimental setting, the types of activities required of the subject after drug administration, and whether the drug is administered to one subject or to a group. The belief in the importance of setting does psychedelic nature, it has been argued that many potential effects of the drug as typically used might not show up in the traditional "neutral" laboratory setting. Hollister and colleagues examined this question, comparing effects of marijuana smoking in a neutral laboratory setting versus marijuana smoking in a private living room accompanied by pleasant visual, auditory, and other sensory stimulation. Rated euphoria and scores on the hallucinogen and marijuana scales of the Addiction Research Center Inventory were sensitive to marijuana but not to environmental conditions. The authors concluded that, "The actual environment in which the drug is taken seems to play little, if any, role." Similarly, Atkinson and colleagues found that the subjective effects of 40% nitrous oxide were very similar in two studies, one involving administration in a small, plain laboratory room, with subjects lying supine, and the other involving administration in a larger, attractively decorated room with a homelike atmosphere, with subjects sitting in an upholstered recliner.

In the present study, to investigate the consistency of the subjective effects of nitrous oxide under differing experimental conditions, we had subjects complete the same questionnaires assessing subjective drug effects and sedation that we used in our previous study. The present and previous studies were very similar with respect to drug administration and the population from which subjects were drawn, but differed in test procedures, the previous study focusing on memory testing and the present one on measurement of skin conductance. We wanted to see if nitrous oxide produced a consistent pattern of subjective effects in the two studies and to see if any differences in subjective effects seemed related to differences in experimental conditions, which might provide some clues as to how setting modulates subjective effects.

DISCUSSION

The correlational analyses indicated that the subjective effects of nitrous oxide were very similar in the present and previous studies. Nevertheless, some subjective effects differed in the two studies and the three items that were selected as the best discriminators in the discriminant analysis seemed plausibly related to differences in experimental conditions. Memory impairment was a prominent subjective effect of nitrous oxide in the previous study, in which subjects received numerous memory tests, but not in the present study, in which memory testing was a minor feature. Funny or strange feelings in the hands or feet were a prominent subjective effect in the present study, in which electrodes were attached to the subject's hand for measurement of skin conductance, but not in the previous study, which did not involve this procedure; the electrodes may have heightened subjects' attention to their hands. "Calm vs. Excited" ratings showed a treatment effect in the present study but not in the previous one, mainly because subjects receiving oxygen rated themselves as more excited in the present study than the previous one. This excitement could have been related to the loud noise that was presented as part of the skin conductance assessment in the present study. The maximal skin conductance responses elicited by the noise were larger for subjects who rated themselves as more excited, and these subjects also rated the noise as more unpleasant during gas inhalation. Nitrous oxide may have attenuated excitement from this source, since it reduced both the rated unpleasantness of the noise and the size of the skin conductance responses that it elicited.

Given a drug like nitrous oxide with numerous potential subjective effects, the results of the discriminant analysis suggest that environmental conditions can influence which effects emerge, or at least their relative prominence. These results must be viewed as tentative, however. A large number of items were considered for selection and slightly different ratings could have caused other items, correlated with those that were selected, to be selected instead. In any case, these results should not obscure the general similarity of most subjective effects of nitrous oxide in the present and previous studies.

In both studies, nitrous oxide produced some subjective effects that are characteristic of psychedelic drugs, i.e., changes in body awareness and image, alterations of time perception, and experiences of a dreamy, detached reverie state. The present and previous studies also agreed with respect to diminished cognitive-motor proficiency; both found that the Drug Effect items were relatively insensitive to this effect, but simultaneously obtained evidence of diminished cognitive-motor proficiency in the Sedation ratings. The fifth category of psychedelic drug effects provided the major difference in results between the studies; happy, euphoric mood changes were more pronounced in the present study, with 90% of these items showing significant drug effects, than in the previous one, where the corresponding figure was 50%. Another discrepancy between studies was consistent with this one. The Drug Effect ratings included 13 items pertaining to possible adverse effects of nitrous oxide examined by Atkinson. Nitrous oxide significantly increased mean ratings on these adverse items in our previous study, but not in the present one; and only two of the individual items showed significant adverse effects of nitrous oxide in the present study, compared to seven in the previous one. Since Atkinson also observed happy, euphoric mood changes and minimal adverse effects from nitrous oxide, we suggested in our previous study that the more positive experiences of Atkinson's subjects relative to ours could have been related to various procedural differences including the higher concentration of nitrous oxide, the shorter duration of gas inhalation (20 min), or the absence of performance tests in Atkinson's study. The present results are consistent with the latter two possibilities, since our present study resembled Atkinson's more closely than our previous one with respect to the duration of gas inhalation and the minimal performance tests involved.

Overall, in the present study, 76% of the items in these five categories of psychedelic drug effects were influenced significantly by nitrous oxide, compared to only 30% of the remaining Drug Effect items. This preponderance of psychedelic effects was stronger in the present study than the previous study and provides further support for Atkinson's suggestion that nitrous oxide produces a moderate, incomplete psychedelic experience. This suggestion is also supported if one considers only items which were significant in both of our studies and which in this sense maybe the most reliable effects of nitrous oxide; 48% of the psychedelic items but only 24% of the remaining items meet this criterion.

Subjects in the present study assessed the effects of nitrous oxide retrospectively, i.e., after recovery from these effects. We assumed that subjects would be able to remember and report subjective effects retrospectively with acceptable accuracy. This assumption seems plausible, but it would be interesting to test it systematically, by having subjects make repeated ratings of subjective effects, both during gas inhalation and retrospectively.

It would also be interesting to compare the subjective effects of nitrous oxide in patients undergoing dental surgery or other minor operations with those reported by our healthy volunteers. The minimal performance test involved and the occurrence of an aversive stimulus (the loud noise) in the present study give it a slightly greater resemblance to the surgical setting than our previous study. On the basis, patients might be predicted to report subjective effects more similar to those found in the present study than the previous one. But the "set" or expectations of patients with respect to drug effects might be different from volunteers and might influence their experience.

Since subanesthetic concentrations of nitrous oxide are commonly used in dental and medical practice, dentists and physicians should be familiar with the variety of subjective effects produced by the drug. These should be communicated to patients to alleviate possible anxiety and promote full compliance during administration.​

*Full text available here :
 
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Nitrous Oxide as a Treatment for Depression*

by Clare Wilson | New Scientist | 9 June 2021

Nitrous oxide, also known as laughing gas, has shown promise as a treatment for depression. When people inhaled a low dose as part of a small study, their depression improved over the next two weeks.

It has long been known that nitrous oxide can give a short boost to mood as well as relieving pain, but the effect is thought to wear off quickly. Nitrous oxide is one of the most common anaesthetics, used by hospitals, dental surgeries and paramedics, as well as being available illegally in small capsules for recreational use.

The gas seems to chiefly affect the brain by blocking molecules on nerve cells called N-methyl-D-aspartate (NMDA) receptors. This is the same thing targeted by the stronger anaesthetic ketamine, which also relieves depression; a similar chemical to ketamine has recently been approved as a new intranasal spray treatment.

It isn’t known how NMDA receptors change mood. But as the antidepressant effects of ketamine started to emerge, Peter Nagele, then an anaesthetist at Washington University School of Medicine in St Louis, Missouri, wondered if nitrous oxide had similar potential.

In 2014, he and his colleagues found that one hour’s inhalation of nitrous oxide reduced symptoms for up to a day in people with depression who hadn’t improved after trying standard antidepressant medicines, but the study didn’t record whether the effect lasted any longer.

Prolonged nitrous oxide use can can lead to nausea and headaches. So, in the latest study, Nagele’s team looked at 24 people with treatment-resistant depression and gave them half-dose nitrous oxide, a full dose or a placebo mixture of air and oxygen. They were given one treatment a month for three months.

After two weeks, depression symptoms for those with the half-dose treatment had reduced by an average of five points on a commonly used depression rating scale, compared with those who had the placebo, which is a significant benefit. After the full-dose treatment, depression symptoms reduced a little more, although the difference was so small that it could have arisen by chance. The half-dose group also had a much lower incidence of side effects, such as nausea, headaches and light-headedness.

"As with ketamine, nitrous oxide has the benefit of improving mood quickly," says Nagele, who is now at the University of Chicago in Illinois. “Something happens in the brain – it’s like flipping a switch. But how this works, no one knows.”

Journal reference: Science Translational Medicine, DOI: 10.1126/scitranslmed.abe1376

*From the article here :​
 
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"The reduction in side effects was unexpected and quite drastic, but even more excitingly,
the effects after a single administration lasted for a whole two weeks,"
says Peter Nagele.
"This has never been shown before."

One Nitrous Oxide session relieves severe depression quickly*

by Alison Caldwell | FUTURITY

A single inhalation session with 25% nitrous oxide gas can rapidly relieve symptoms of treatment-resistant depression, according to new research.

The new study, published in Science Translational Medicine, also shows that the effects last much longer than previously suspected, with some participants experiencing improvements for upwards of two weeks.

The findings bolster the evidence that non-traditional treatments may be a viable option for patients whose depression is not responsive to typical antidepressant medications. It may also provide a rapidly effective treatment option for patients in crisis.

Nitrous Oxide is frequently used as an anesthetic that provides short-term pain relief in dentistry and surgery.

In a prior study, the investigators tested the effects of a one-hour inhalation session with 50% nitrous oxide gas in 20 patients, finding that it led to rapid improvements in patient’s depressive symptoms that lasted for at least 24 hours when compared to placebo. However, several patients experienced negative side effects, including nausea, vomiting, and headaches.

“This investigation was motivated by observations from research on ketamine and depression,” says Peter Nagele, the chair of anesthesia and critical care at the University of Chicago Medicine.

“Like nitrous oxide, ketamine is an anesthetic, and there has been promising work using ketamine at a sub-anesthetic dose for treating depression. We wondered if our past concentration of 50% had been too high. Maybe by lowering the dose, we could find the ‘Goldilocks spot’ that would maximize clinical benefit and minimize negative side effects.”

In the new study, the investigators repeated a similar protocol with 20 patients, this time adding an additional inhalation session with 25% nitrous oxide. They found that even with only half the concentration of nitrous oxide, the treatment was nearly as effective as 50% nitrous oxide, but this time with just one quarter of the negative side effects.

Furthermore, the investigators looked at patients’ clinical depression scores after treatment over a longer time course; while the previous study only evaluated depression symptoms up to 24 hours after treatment, the new study conducted additional evaluations over two weeks.

To their surprise, after just a single administration, some patients’ improvements in their depression symptoms lasted for the entire evaluation period.

“The reduction in side effects was unexpected and quite drastic, but even more excitingly, the effects after a single administration lasted for a whole two weeks,” says Nagele. “This has never been shown before. It’s a very cool finding.”

These results indicate promise for nitrous oxide as a rapid and effective treatment for those suffering from severe depression that fails to respond to other treatments, such as SSRIs, a common type of antidepressant medication.

“A significant percentage— we think around 15%—of people who suffer from depression don’t respond to standard antidepressant treatment,” says coauthor Charles Conway, professor of psychiatry and director of the Treatment Resistant Depression and Neurostimulation Clinic at Washington University School of Medicine.

“These ‘treatment-resistant depression‘ patients often suffer for years, even decades, with life-debilitating depression. We don’t really know why standard treatments don’t work for them, though we suspect that they may have different brain network disruptions than non-resistant depressed patients. Identifying novel treatments, such as nitrous oxide, that target alternative pathways is critical to treating these individuals.”

Despite its “laughing gas” reputation, patients who receive such a low dosage actually fall asleep. “They’re not getting high or euphoric, they get sedated,” Nagele says.

While it remains challenging to get non-traditional treatments for depression accepted in the mainstream, researchers hope that these results, and other similar studies, will open the minds of reluctant physicians toward the unique properties of these drugs.

“These have just been pilot studies,” says Nagele. “But we need acceptance by the larger medical community for this to become a treatment that’s actually available to patients in the real world. Most psychiatrists are not familiar with nitrous oxide or how to administer it, so we’ll have to show the community how to deliver this treatment safely and effectively. I think there will be a lot of interest in getting this into clinical practice.”

With broader public acceptance, Nagele hopes that these results can open doors for those patients who are struggling to find adequate therapies for their depression.

“There is a huge unmet need,” he says. “There are millions of depressed patients who don’t have good treatment options, especially those who are dealing with suicidality. If we develop effective, rapid treatments that can really help someone navigate their suicidal thinking and come out on the other side—that’s a very gratifying line of research.”

Source: University of Chicago

Original Study DOI: 10.1126/scitranslmed.abe1376

*From the article here :
 
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How nitrous oxide inspired early psychedelic literature

A conversation with author Mike Jay on nitrous oxide's remarkable history.

by Patrick Lyons | VICE

I love jotting down nonsensical snippets of conversation I overhear at music festivals, parties, and other drug-friendly gatherings. I've catalogued trustafarian musings like "At our core, we're interstellar beings," "Dog feet are a good idea," and most spectacularly, "I feel like a deer that for some reason has the ability to travel in and out of heaven."

Imagine for a second that these quotes came from respected members of Victorian society—powdered wigs and all—and you've got the focus of Oh Excellent Air Bag: Under the Influence of Nitrous Oxide 1799-1920. This anthology of original accounts from the earliest days of laughing gas (out now via The Public Domain Review) features poets, scientists, and philosophers offering such musings as "I felt like the sound of a harp," "He seemed… to be bathed all over with a bucket full of good humour," and "It would require a pen, made of a quill, plucked from an angel's wing, to describe half the pleasures arising from this source."

This manner of speech was wholly new in the early 19th century, well before our culture's current surplus of armchair philosophers and aspiring gonzo journalists. Even Thomas Beddoes, who owned the first lab in which nitrous oxide was synthesized, prefaced his own sensory descriptions with the following parenthetical: "Why should one fear to use ludicrous terms when they are expressive?"

Indeed, Oh Excellent Air Bag's curators believe that their findings comprise some of the earliest-known psychedelic literature. Author Mike Jay, who previously explored nitrous oxide's beginnings in his book The Atmosphere of Heaven, penned an introduction to this chronological collection of essays, scientific observations, and poetry, as well as assisted with its curation. VICE spoke with him about the drug's remarkable history.

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How prevalent was the use of other recreational drugs during this time period?

Mike Jay: Opium was used very widely, and it was a medication that most people were familiar with—but it wasn't thought of as a mind-altering drug until Thomas De Quincy's Confessions of an English Opium-Eater. People didn't use opium for philosophical investigations, though. There's also a bit of writing about hashish—particularly in the French tradition—which was becoming known in the West by 1850. Baudelaire and the French decadent poets were taking it, and some scientists experimented with it too. Ether was also very popular.

There wasn't really a category of illegal drugs like we have now. These drugs were all seen as medicines with interesting and odd effects. We still have things like that— Parkinson's disease medicines give people bizarre hallucinations, but we don't think of them as mind-altering drugs.

What differed in the way nitrous oxide entered the fold?

In the 19th century, nitrous oxide was the go-to drug for what we might now call psychedelic science. There was no LSD or other psychedelics. It all started when [Beddoes' assistant] Humphrey Davy synthesized nitrous oxide in a laboratory in 1799. He inhaled it and had this really bizarre, extraordinary experience of consciousness alteration. The chemical reaction by which he did it was simple, so anybody who was set up with a laboratory could have a go at it.

[Nitrous oxide] raised all of these extraordinary questions, like: How could a gas isolated in a laboratory have this effect on the human mind? How could it make you suddenly feel happy and euphoric for no reason? Why did it make you laugh? Why did it give you this feeling of cosmic revelation? What's the connection between mind and body? Where do ideas and feelings come from? The 19th century was the great century for discovering the mind, so for anybody who was interested in these ideas during this time, nitrous oxide was the go-to drug to investigate further.

What differentiates these writings on nitrous oxide from Paris' mid-19th century "drug literature" scene?

They follow different cultural threads. Nitrous oxide got involved with anesthesia halfway through the century. But because of the drug's many dimensions, early on Davy and Beddoes brought on was members of other disciplines—poets, artists, literary figures—to get the nitrous experience. [The feeling from nitrous oxide is] intense, and it's obvious while you're having it, but it's really hard to describe. Davy figured all that out and said, "We need a new language of feeling to describe our state of consciousness when we take this gas."

At the time, Davy was very friendly with early Romantic poets Samuel Taylor Coleridge and Robert Southey, who were trying to find ways to talk about states of mind and emotions that nobody had ever talked about before. So Davy got everybody involved in the experiments to write about their experiences. Those writings have never been reproduced before, so it's great to see them—it's kind of the beginning of psychedelic literature. When the hashish experiments in Paris started in the mid-19th century, the doctor who convened them looked back and read all of Davy's work, said "This is what I'm trying to do," and convened a similar group of scientists, artists, and poets.

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It's interesting that all of these inter-disciplinary minds converged on the scene immediately. How did that happen?

Beddoes was a guru figure to Coleridge and Southey, and he also brought Davy in as his lab assistant, so they all met during the course of the project. Beddoes is a real interesting figure—a political revolutionary, very much on the radical edge of British culture, he brought a lot of interesting people together. They had great medical ambitions for nitrous oxide, but it was hard to interest the medical profession because nobody had any idea of how this stuff might work, or what the therapeutic applications might be. Also, they were a marginal, radical group of people who you didn't want to associate with.

Oddly enough, the writings became popular, and people got the idea that it was this extraordinary gas that had strange effects. You'd have nitrous oxide demonstrations as an evening's entertainment, or scientific lectures, or variety shows with magic and hypnotism. That's when it got the name "laughing gas." It was discovered by dentists when they watched people taking it in public and not feel any pain until the gas wore off—a big problem with dentists' business model at the time was that nobody wanted the pain of dental procedures and tooth extractions. So nitrous oxide went from philosophical experiments, to the seamy world of carnivals and fairgrounds, and then it was accepted as a great medical breakthrough.

Had nitrous oxide been discovered and tested more recently, do you think it would have still been explored for medical use?

Pretty much everything we think of now as an illicit drug once had medical or therapeutic applications in a clinical setting before becoming part of a public scene. If something gets known as a street drug nowadays, it becomes much harder for it to become accepted in medicine—we're seeing that with everything from psilocybin to ketamine. It's always an uphill battle to get approval.

The first mention of psilocybin mushrooms in European medical writing also occurred in England in 1799. Was there something about the state of British science, medicine, or culture at the time that led people to be more curious about mind-altering substances?

The end of the 18th century was the great age of classification, when everybody started trying to nail down all kinds of things that, in the past, had been labeled as folklore, mythology, or weird superstition. In the 1760s, famed taxonomist Carl Linnaeus wrote a book called Inebriantia, which was the first catalog of intoxicants. He rounded up everything from all over the world— coca leaf and tobacco from the Americas, betel nut and opium and hashish and different types of alcohol—which nobody had listed at that point. Linnaeus looked around the world and said, "Every culture has their own favorite intoxicants," which was an idea that I don't think anybody would've had before that time.

The identification of psilocybin mushrooms was interesting. It was random that there happened to be a doctor around to write and publish a report when people [who ate psilocybin mushrooms] started acting strangely. People always believed there were poisonous mushrooms—ones that had strange effects or made you delirious—but no one nailed down which exact species. At the same time, the discovery of nitrous oxide was part of Beddoes' program of isolating and testing different gases. They're both part of the same process of classification.

A Review of the book Oh Excellent Air Bag: Under the Influence of Nitrous Oxide 1799-1920 can be found here.

Follow Patrick Lyons on Twitter.

*From the article here :
 
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The role of Nitrous Oxide nanoparticles in combating COVID-19*

S. Manigandan, T. R. Praveenkumar, Kathirvel Brindhadev

The lives of human individuals and groups around the globe have changed drastically due to the emergence of novel corona virus in late 2019. The significant part of CoV-19 from the global point is transmission rate, and therefore, it is mandatory to identify and isolate the affected persons even with the mild infection. To stop the rapid transmission of virus to drastic manner, it is essential to follow the hygienic practices, identification of potential vaccines and proper health care management systems to combat the novel virus. Despite the serious mortality rates and high confirmed cases, at present, there is no proven treatment and vaccine to treat the pandemic coronavirus.

Nature of SARS-CoV-2 (COVID-19)

Corona Viruses include a large family of Viruses found in nature. They belong to the Family Coronaviridae and order Nidovirales possessing single stranded, positive sense RNA genome. The technical name of corona virus is SARS-CoV-2. Corona Viruses are named for their crown like spikes protruding from their surfaces. The most common symptoms are fever, dry cough, tiredness, difficulty in breathing and chest pain. Based on the study by UK Kings College London, there is a possibility of six different types of strains cause’s different type’s symptoms such as Flu (with and without fever), fatigue, and gastrointestinal, abdominal and respiratory issues. The common things between all strains are breathing difficulties. Incubation period refers to the time between being exposed to the disease and when the actual symptoms start to show up.​

Role of nitrous oxide (NO) nanoparticles in combating COVID-19

Virus usually constitutes variable size ranges from 10 to 850 nm. NO is known to combat various fungi, bacteria, virus and tumor cells. Nitrous oxide combined with nanoparticles can be used for various applications. NO can act as an antimicrobial agent because of its anti fungal and antibacterial properties. In addition to those properties, it can able to modulate foreign agents. NO had considered to be a vital agent to treat corona virus and other lung-related ailments.

NO can be administered with some other medicines can be effectively used to cure MERS-CoV affected patients and showed positive impacts with very less side effects . Inhalation of NO treatment has been assessed for COVID patients in two nations, United States of America and China. Previously, NO was effectively used to treat lung-related ailments caused by certain virus. The studies found that NO compounds have potential to combat SARS-CoV replication. Nitrous oxide donor S-nitroso-N-acetyl penicillamine was effective in inhibition of SRS-CoV replication mechanism. Several researchers tried to assess the effects of NO against SARS-CoV-2 and NO donors were considered to important medical treatment. NO can be used as an alternative to tackle the current pandemic. Ultraviolet radiation promotes the NO generation and it is stored in skin and releases into blood, thereby reducing the blood pressure.

*From the article (including references) here :
 
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At-home Nitrous Oxide may ease pain in severe DEB*

by Patricia Inacio PhD | EB NEWS | 25 Feb 2022

At-home inhalation of nitrous oxide, a colorless gas commonly used for sedation, may help reduce pain during wound dressings in patients with severe recessive dystrophic epidermolysis bullosa (DEB), a case report shows.

For a 28-year-old man in Italy with spontaneous and frequent blisters due to severe DEB, “the beneficial effects of conscious sedation are evident,” according to the researchers, who described treating the patient with nitrous oxide given through a nasal mask.

"The patient reports a significant acute-pain reduction, reduction in anticipatory pain and anxiety before the procedure, … and less fatigue after the dressing session, which allows him to enjoy and perform multiple activities during the day,” the researchers wrote.

Additionally, for the man’s caregivers, “their burden has been significantly reduced in parallel with the reduction in patient suffering,” the team reported.

The report, titled “Procedural analgesia with nitrous oxide at home for epidermolysis bullosa: A case report,” was published in the journal Medicine.

DEB, one of the major types of epidermolysis bullosa, is characterized by very fragile skin, prone to blisters and tearing, and often associated with pain. Current pain management strategies include psychological support, along with medication and local wound care.

However, improvements in pain management are limited due to a lack of studies on the subject for EB.

In this case report, the team of researchers described the case of a DEB patient requiring daily blister treatment who used inhaled nitrous oxide, sometimes called laughing gas, at home as a pain management strategy.

He constantly developed spontaneous blisters, following skin rash and itching. His medical history showed tiny bone fractures as a result of severe osteoporosis, celiac disease — an immune reaction to eating gluten, damaging the small intestine — and a severe episode of bleeding inflammation of the blood vessels following an infection.

He underwent several surgeries to correct his hand deformities and improve hand dexterity.

Standard therapies for pain control, administered after other alternatives, had proven inadequate. Denosumab, a therapy for osteoporosis (sold as Prolia) was administered monthly.

The man also required daily treatment consisting of lancing blisters with a needle and emptying them by compression, and had an average of three full-body dressings per week. His wound care was deemed very painful, particularly in the feet and armpits.

He complained of intense burning pain during wound cleansing of such intensity that it impaired cleansing by his caregivers. As a result, the patient had anxiety before the procedure. Topical options were ineffective for pain relief.

Immediate-release oral morphine, which is the only form of morphine allowed in Italy to manage pain in non-cancer patients, made him feel sleepy, drowsy, or lightheaded.

As a result, the patient requested a short-acting, effective pain relief strategy that would have no side effects and minimal long-term consequences.

He started inhalation of nitrous oxide as a pain management strategy, advised by pain therapy experts. The gas was delivered using the IntelliFlux equipped with a gas mixer.

Nitrous oxide has been reported to act as a partial activator of opioid receptors, prompting pain relief.

An experienced anesthesiologist was present to supervise the first administration of the gas. The second administration was attended by a physician with airway management skills and basic life-support certification. The procedure was conducted in a room in the patient’s home, prepared in advance, that was cleaned, ventilated, and equipped with emergency devices.

The first dressing under nitrous oxide was completed in about one hour from a prior duration of 3.5–4 hours — a marked decrease of 25–40%.

Additional benefits included a significant easing of acute pain, as well as pain and anxiety reduction prior to the dressings. He also required fewer medications and was less tired.

“The domestic device allows greater flexibility of schedules, allowing less effort for caregivers,” the scientists wrote.

Medium-term benefits included a marked easing in the bad smell of wounds up to its disappearance.

The patient’s vital signs remained stable, with no episodes of low oxygen, rapid heartbeat, or low blood pressure. Pain score using the Numeric Pain Rating Scale — higher scores mean more severe pain — showed a score reduction from 10 to 1 after nitrous oxide was given.

Since nitrous oxide may deplete vitamin B12, regular follow-up was conducted to assess this vitamin’s levels as well as neurological complications. The patient received a standard multivitamin supplement daily. At the time of the study’s completion, he was performing regular daily social activities.

"Overall, this case report suggests that nitrous oxide-mediated pain relief is safe and effective, resulting in a significant reduction in procedural pain and an improvement in the quality of life of patients and their caregivers,” the investigators concluded.

*From the article here :
 
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Nitrous Oxide helps ease young patients’ anxiety during painful medical procedures

A small group of Twin Cities providers has been offering nitrous oxide to anxious patients since around 2009. Fairview is the first major health-care provider in the region to make it readily available.

by Andy Steiner | MINNPOST

Most of the time Ava Jay is a happy kid. But when she has to go to the doctor’s office, her mood changes.

“When Ava thinks doctors, she thinks shots,” explained her mother, Micky Jay. “And when Ava thinks about shots, her anxiety just takes over.”

A little bit of whining or even a tear or two might be OK, Jay said, but Ava’s outsized reaction to medical procedures — especially those involving needles — can be distressing.

Not so long ago, Jay took Ava, 7, to the pediatrician’s office to investigate some ongoing stomach issues. She knew that at this appointment came with a vaccination and a blood draw, so she steeled herself: The visit could be hard for her daughter — and for her, too.

Once Ava and her mother arrived for their doctor’s appointment in Burnsville after a long drive from their home in Rush City, it didn’t take long for Ava’s anxieties to make themselves known.

“Ava’s on high alert when she’s in a doctor’s office,” Jay said. “As soon as the doctor said, ‘I think we need to do some tests,’ I saw her face change. And when she realized that there’d be needles involved, Ava was crying and crying, almost hyperventilating. She was so scared.”

Even the pediatrician’s offer to apply a special numbing cream on her arm and her mother’s calm reassurance that everything would be OK did not help Ava feel less anxious. Jay, who’d in the past had to hold her daughter down so she could get a shot, had the sinking feeling that she’d have to do the same thing again.

“I really don’t like holding her down,” Jay said, adding that she felt that a forced approach to medical treatments only served to intensify Ava’s anxieties: “As a mom, it is a horrible feeling.”

As the tension in the exam room began to build, the nurse took Jay aside.

“She asked, ‘Would you be interested in having Ava try some nitrous oxide?’” Jay said. She knew about dentists using nitrous oxide, or “laughing gas,” to calm nerves during fillings (she’d even used it herself), but she’d never heard of nitrous being used for medical procedures. Fairview, the nurse explained, had recently begun to use doses of the gas mixed with oxygen to help anxious young patients reduce their anxiety. Jay jumped at the opportunity.

“I said, ‘If if this could make it OK for Ava to have a blood draw or a shot, I’m doing it,’” she recalled.

A new use for an old option

Kelly Fichmeller, RN, a pediatric nurse who was part of the group that started the nitrous oxide program at Fairview Ridges Hospital, explained that using doses of the gas to help anxious young patients cope with medical procedures is becoming more common worldwide.

“Nitrous has been used for a long time in the dental world,” Fichmeller said, adding that it is generally accepted as safe for use in children as young as 6 months. “My supervisor and I were at a pediatrics conference a few years ago and we learned about nitrous being used for anxiety in medical procedures. As we looked more into that we thought it was a good idea. We decided we wanted to bring it here.”

A small group of Twin Cities health care providers has been offering nitrous oxide to anxious patients since around 2009, Fichmeller said. Fairview is the first major health-care provider in the region to make it readily available to all who request its use.

Some medical procedures, including lab draws, IV starts, lumbar punctures and catheterizations, cause anxiety for many children. And for a smaller group of kids, almost any medical procedure can be anxiety provoking.

Help for patients — and providers

While nitrous oxide can help a child feel better about undergoing a procedure, it can also help a doctor or nurse perform their job in a safer manner, Fichmeller said.

More involved procedures that do not require general anesthesia but still require a patient to remain calm and still, like CT scans or X-rays, can be performed quickly and easily when an anxious child has been given a dose of nitrous.

“It takes the worry away,” she said. “And it creates a bit of amnesia, where they don’t truly remember what’s going on. During treatment, patients are in this fuzzy state. They can respond appropriately to questions and stimulation, but they don’t care so much. Afterward, most don’t really have a clear memory of what happened.”

Amy Feeder, Fairview certified child life specialist, added that while parents can stay close to provide a comforting touch during some stressful procedures, there are other situations where parents have to step away. This can be particularly traumatic for children prone to anxiety.

“The great thing about nitrous from my perspective is we can use it whenever we have to do a test or procedure for kids in the hospital where we are limited in the types of comfort measures we can offer. There is a certain population of kids that get hyper-fixated on the procedure so it gets hard for them to relax or cope with it. Nitrous helps take them away from those worries.”

And nitrous oxide is a relatively inexpensive option for sedation, Feeder added.

“From a child-life perspective, it’s really hard if a kid’s anxiety spirals out of control. Sometimes you’ll have physicians who want to just do the procedure and get it over with or want to do a full sedation. That takes a long time and is expensive. Nitrous is an extra option that we have now. It is quick and easy. It helps that population of kids relax. They are awake, they know what is going on, but they are calmer and the doctor can do their job.”

How laughing gas works

How nitrous oxide helps users stay calm is mysterious.

“Researchers haven’t been able to figure exactly out how it works,” Fichmeller said. “They don’t know what properties it has or how it physiologically affects the body. The Fairview physician who educated us on its use said they haven’t been able to explain what nitrous does to make people less anxious. It just helps.”

Nitrous oxide is safe, Fichmeller said. “It is not metabolized by the body. It goes in in the same form that it comes out. When you are finished using it, you replace it with 100 percent oxygen. Kids aren’t fully sedated with it. So there is no risk there. We only use nitrous in combination with oxygen to create a calm demeanor.”

In the article, “Efficacy and Safety of Nitrous Oxide in Alleviating Pain and Anxiety During Painful Procedures,” published in the Archives of Disease in Childhood, researchers studied the use of nitrous oxide for 99 children requiring complex medical procedures including lumbar puncture, bone marrow aspiration, venous cannulation, or dressing changes. The study’s authors concluded that, “Inhalation of nitrous oxide is effective in alleviating distress during painful procedures, with minimal side effects and short recovery time.”

Nitrous oxide does not have to be administered by a doctor, which also reduces its cost. At Ridges, pediatric nurses administer nitrous in the emergency department or for an outpatient blood draw.

“If we assess that the child is pretty anxious, we can call pediatrics and offer it right away,” Fichmeller said. “Or parents can walk in and share their child’s experiences with prior procedures and see what options are available.”

Child-centered treatment

To get an anxious child comfortable with using nitrous oxide, nurses will often begin with “medical play,” Fichmeller said. The nitrous oxide is mixed with oxygen and delivered via a child-sized mask that goes around the child’s nose and mouth: “We take it out and touch it and play with it. We do this with children as young as 18 months, just to recognize that this equipment isn’t scary. We talk about how they are going to breathe in and out to help their body stay calm and relaxed.”

Some young patients don’t respond well to nitrous, Feeder said. “A few older kids told me they didn’t really like the way it made them feel. That’s the way they expressed their experience. But the majority of our kids who use nitrous literally sing through their procedures, no matter how big they are. It just puts them in a more relaxed state.”

That was the case for Ava. After a few deep breaths of the nitrous oxide/oxygen combination, her anxiety level dropped dramatically, her mother said.

“When she finally had her blood drawn, she was playing games,” Jay said. “It was such a good experience.”

When the procedure was completed, recovery from the nitrous oxide was almost instantaneous, Jay said.

“As soon as they switched the nitrous oxide off and started running 100 percent oxygen, she was normal and good to go in a matter of minutes. The rest of the day, she kept saying, ‘I want my blood drawn again.’ The fear had disappeared.”

Tough enough?

Does offering children an easy way to escape their anxieties about common medical procedures create a generation unable to face up to life’s hard realities?

Feeder said that she believes that helping kids ease their fears actually makes them more able to face tough times later on.

“For kids who have a really hard time emotionally with medical procedures, nitrous is a great option,” Feeder said. “We need to get kids to a point where they can cope without using nitrous, but teaching them that pain is part of life is an old-school mentality. A lot of us grew up with that attitude: I don’t think it actually made us stronger. We want to teach kids that doctor’s offices and hospitals aren’t scary, that they can trust health care professionals to help them feel better.”

Feeder and Fichmeller share the conviction that helping children build a positive association with medicine will only help them grow into mentally healthy adults.

“We want to do everything we can to provide the best possible experience for infants, toddlers and younger kids so they are able to build off that experience in the medical setting for their future medical interactions,” Feeder said. “It’s hard to undo trauma, but simple things like comfort holds, numbing cream and nitrous oxide can really help to reduce or eliminate trauma in the first place.”

Micky Jay said she thinks some people are just born anxious and pain sensitive.

“Ava has always been this way,” she sighed. “A finger prick really hurts her feelings. I have an older daughter who never balked about medical procedures, but Ava is different.”

Though Ava has already had some negative experiences at the doctor’s office during her young life, her mother is hoping that positive experiences going forward might erase the some of those fears and anxieties.

“I grew up on a farm,” Jay said. “I’m all about tough love, but Ava has so much anxiety. This treatment helps her deal with it, so I’m OK with that. She needs to go back to the doctor soon: She keeps talking about it, but she never brings up blood draws or shots. I think that the nitrous helped build up her self-confidence. Now she knows she can do it. And if she has a few more good experiences like that one, she might not need to use nitrous again.”

 
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Nitrous Oxide

Nitrous oxide is an atypical dissociative substance that is found in the form of an inhalable gas. The exact mechanism of action of nitrous oxide is unknown, but it is thought to have an effect on GABA and NMDA receptors in the brain.

Nitrous oxide was first identified in 1772 by the British chemist Joseph Priestly. In the 19th century, it was discovered to have anesthetic properties which made it suitable for dental and surgical procedures. It was given the name "laughing gas" by the British chemist Humphry Davy due to its exhilarating and laughter-inducing effects. Today, it is widely used in surgery and dentistry for its anaesthetic and analgesic effects, and in motorsports for its performance boosting effect on internal combustion engines. Additionally, it has a number of industrial uses and is commonly sold as a whipped cream propellant in kitchen and household stores.

Subjective effects include sedation, pain relief, motor control loss, anxiety suppression, conceptual thinking, euphoria, and dissociation.

Nitrous is considered to have low to moderate abuse potential and low toxicity when used in moderation. However, frequent and/or chronic use can cause vitamin B12 depletion, which may lead to severe nerve damage. Additionally, improper use puts the user at risk of oxygen deprivation. It is highly advised to use harm reduction practices if using this substance.

History and culture

Nitrous oxide gas was first synthesized in 1772 by English natural philosopher and chemist Joseph Priestley. He published his findings in the book Experiments and Observations on Different Kinds of Air (1775), describing the synthesis of the gas by heating iron filings dampened with nitric acid. In 1800, Humphry Davy, an assistant at the Pneumatic Institute, published a book about nitrous oxide in 1800. In the book, there is the following passage;
"As nitrous oxide in its extensive operation appears capable of destroying physical pain, it may probably be used with advantage during surgical operations where too great an effusion of blood does not take place."

Davy notes the analgesic effect of nitrous oxide and its potential for use in surgical operations. Davy coined the name "laughing gas" for nitrous oxide. Beginning in 1799, nitrous oxide was used as a recreational drug at "laughing gas parties." They became an immediate success within the British upper class. Despite Davy's discovery of nitrous' potential for anesthesia, doctors did not attempt to use it for nearly half a decade.

The discovery of ether in 1830 led nitrous to fall out of popularity as a recreational drug. It was not until 1844 that American dentist Horace Wells noticed the anesthetic properties of the gas. With the assistance of Gardner Quincy Colton and John Mankey Riggs, he demonstrated insensitivity to pain during a tooth extraction. The practice was not immediately adopted by other dentists, as Wells' first public demonstration had been partly unsuccessful. In 1863, Gardner Quincy Colton began to administer the gas to patients in all of his "Colton Dental Association" clinics, administering nitrous oxide to over 25,000 patients over three years. This brought the practice into general use.

Nitrous oxide was not found to be a strong enough anesthetic for major surgeries in hospital settings, but it became useful as an initiator for stronger anesthetics like ether or chloroform. Hospitals would initiate treatment with a mild flow of nitrous oxide, and then gradually increase the flow of the stronger anesthetic. This technique of initiating anesthesia is still used in hospitals today.

Nitrous is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.

Chemistry

Nitrous oxide, or dinitrogen monoxide, was first synthesised by heating ammonium nitrate in the presence of iron filings and then passing the gas that came off (NO) through water. Now it is commonly synthesised by gently heating ammonium nitrate to decompose it into nitrous oxide. It is an oxide of nitrogen.

Nitrous has a linear molecular structure. It can be thought as existing in two "resonance structures":​
  • The central nitrogen atom is triple bonded to the other nitrogen atom and single bonded to the oxygen atom.​
  • The central nitrogen atom double-bonded to both the other nitrogen atom as well as the oxygen atom.​
In practice, the atom will almost exclusively exist in between these two states almost all the time, and the electrons will be delocalised across the molecule. Each of the resonance forms can be thought of as having a positive and negative charge, giving a neutral molecule overall.

Nitrous is used as an oxidiser in rocketry and in motor racing to increase the power output of engines. At elevated temperatures, nitrous oxide is a powerful oxidizer similar to molecular oxygen.

At room temperature, nitrous is a colorless and non-flammable gas with a slightly sweet odor and distinctive sweet taste.

Pharmacology

Further information: NMDA receptor antagonist

Although N2O affects quite a few receptors, its anesthetic, hallucinogenic, and euphoriant effects are likely caused predominantly or fully via its effects as an NMDA receptor antagonist.[19][20] NMDA receptors allow for electrical signals to pass between neurons in the brain and spinal column; for the signals to pass, the receptor must be open. Dissociatives close the NMDA receptors by blocking them. This disconnection of neurons leads to loss of feeling, difficulty moving, and eventually the famous “hole.”

The pharmacological mechanism of action behind N2O in medicine is not entirely known. However, it has been shown to directly modulate a broad range of receptors and this likely plays a significant role in many of its effects. It moderately blocks β2-subunit-containing nACh channels, weakly inhibits AMPA, kainate, GABAA-rho, and 5-HT3 receptors and slightly potentiates GABAA and glycine receptors. It has also been shown to activate two-pore-domain K+ channels.

Physical effects
  • Spontaneous physical sensations - The nitrous oxide "body high" starts off as the sensation of a diverse mixture of cold, warm, sharp, and soft tingles which begin across the head and face at lower dosages but spread out across the body at higher dosages.​
  • Changes in felt bodily form - This usually occurs with higher dosages and can be described as feelings that in a non-painful fashion your body's physical form is being stretched into infinity, compressed into a singularity, or split into two separate halves.​
  • Dizziness - Although uncommon, some people report dizziness under the influence of nitrous.​
  • Headaches - Although uncommon, a certain subset of people report headaches during the offset of nitrous oxide.​
  • Motor control loss - A loss of gross and fine motor control alongside balance and coordination is prevalent within nitrous oxide and becomes especially active at higher dosages. This means that one should be sitting down before the onset unless they are experienced in case of falling over and injuring oneself.​
  • Perception of bodily lightness - This creates the sensation that the body is floating and has become entirely weightless. It is often accompanied by feelings of slowly falling or drifting.​
  • Physical euphoria - This effect can range between mild pleasure to powerfully all-encompassing bliss. Anecdotal reports show that this sensation, which is taken advantage of by recreational users during sexual activities, can greatly enhance orgasm.​
  • Tactile suppression - This effect partially to entirely suppresses one's sense of touch, creating feelings of numbness within the extremities. It is responsible for the anesthetic properties of this substance.​
  • Vitamin deficiency - Repeated doses may induce vitamin B12 deficiency. However, this can be prevented with B12 supplements.​

Cognitive effects

  • Amnesia - At high dosages, it is often common for one to experience amnesia and memory loss after the experience has occurred. This is especially prevalent alongside ego death.​
  • Déjà vu - Although uncommon and inconsistent, a certain subset of people report strong feelings of deja-vu consistently when under the influence of nitrous oxide.​
  • Cognitive euphoria - This can be described as feelings of mild to intense happiness and general positivity.​
  • Laughter fits - This effect is markedly pronounced with nitrous oxide and can be described as sudden bouts of intense laughter and giggling.​
  • Memory suppression - At higher dosages, level 3 ego death is an all-encompassing effect within nitrous oxide. In comparison to other hallucinogens, it is unique in style due to its rapid onset and quick comedown. This creates the experience that one's sense of self is rapidly disintegrated and then suddenly re-stacked through a process of regaining one's long-term memory. This is a remarkably identical process every time the experience is undergone.​

Auditory effects

The auditory effects found with nitrous oxide, although simplistic, are widely known to be particularly intense and consistent in their manifestation when compared to other hallucinogens. These effects include:
  • Distortions - These distortions are very powerful and loud enough in their volume to make the original sound completely unrecognizable. They include phasers, white noise, high pitch tones and notes, flanging, changes in pitch, echo effects, and stuttering. In particular, the frequency of the stuttering is proportionally related to the intensity of the effects, especially ego death which occurs when the stuttering becomes continuous.​
  • Suppression - This effect can be described as a muffling and quieting of externally sourced sound which results in it sounding more indistinct and distant than it would usually be.​

Multi-sensory effects

  • Synaesthesia - This effect is reported to occur most commonly with auditory stimuli, like music translating into visual stimuli within closed eye visuals.​

Transpersonal effects

  • Unity and interconnectedness - During high dosage states of ego death, this component is a common but inconsistent accompanying effect. It occurs at level 4 - 5 and creates experiences of becoming one with the greater whole. In comparison to other hallucinogens which induce this effect, it can be described as comparatively simpler and less profound due to its more basic accompanying cognitive effects.​
  • Perception of interdependent opposites - During moderate to high doses, the effect may be described as having insight into the nature of two conflicting ideas, "battling" each other to maintain natural balance.​
Combinational effects

Nitrous is commonly combined with other hallucinogens for it which it acts as a brief but profound potentiator of their effects.​
  • Psychedelics - When taken in combination with a psychedelic such as LSD or psilocybin mushrooms, the effect will be a sudden and dramatic increase in perceived geometry to its maximum level of 8A or 8B. This is alongside a sudden and dramatic ego death.​
  • Dissociatives - When taken in combination with a dissociative such as MXE or DXM, the effect will be a sudden and dramatic increase in disconnective effects and the triggering of a sudden internal hallucinatory scenario.​
  • Cannabis - When taken in combination with cannabis, the overall effects of the nitrous itself are potentiated more so than the cannabis' effects.​
  • Alcohol - When taken in combination with alcohol, adverse side effects such as confusion, dizziness, and headaches are often significantly increased.​
Experience reports

Anecdotal reports which describe the effects of this compound within our experience index include:​
Available forms
  • Canned whipped cream - These are found in any grocery store. They contain very minimal gas with one or two uses before the cream comes out.​
  • Chargers - These are readily available and cheap to purchase online. They are small metal canisters that can be used by a nitrous cracker to fill a balloon full of gas which is then inhaled. Some varieties contain industrial residue and strength vary (as it is food grade).​
  • Medical tanks - These are hard to find and dangerous without a professional. They are occasionally seen at music festivals being used to fill balloons for sale.​
Toxicity and harm potential

Nitrous oxide has been safely used as a mild anesthetic for over 150 years. The exact toxic dosage is unknown. Problems with its use come primarily from carelessness. Potential problems include:​
  • Brain injury and suffocation can result from lack of oxygen. When used as an anesthetic, nitrous is always administered in combination with oxygen. Never use nitrous in any manner that does not provide for adequate oxygen intake.​
  • Very cold temperatures of the gas can freeze the lips and throat if taken directly from a tank or whippet. Releasing the gas into a balloon first allows the gas to warm before being administered.​
  • Nitrous temporarily inhibits methionine synthase, a B12-dependant enzyme responsible for many important functions in the body.[25] Heavy and frequent long-term use can deplete vitamin B12 in the body and lead to serious and unpleasant neurological problems. Users may experience numbness and tingling in the fingers, toes, lips, et al. In more severe cases, there will be numbness of all extremities.[26] Taking B12 supplements, especially in combination with a multivitamin and complete amino acid supplements, may help alleviate this problem. If one experiences these symptoms, nitrous use should be ceased immediately, and if the symptoms persist, medical attention should be sought after.​
  • Nitric oxide, a toxic industrial gas, is occasionally mistaken for nitrous oxide. Users should be careful they know what they are inhaling. Inhaling Nitric Oxide can permanently damage the lungs or kill.​
  • The gas from whippets can contain a range of impurities, such as industrial grease left over from manufacturing, and tiny particles of steel from the pierced metal. Users can filter them through a piece of cloth or clothing to reduce the amount of impurities inhaled. Regular cleaning of nitrous dispensing devices can also reduce the harm posed by impurities.​
It is strongly recommended that one use harm reduction practices when using this substance.

Dependence and abuse potential

As with other dissociatives, the chronic use of nitrous oxide can be considered mildly addictive with a moderate potential for abuse.

Tolerance to many of the effects of nitrous oxide develops with prolonged and repeated use. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about 3 - 7 days for the tolerance to be reduced to half and 1 - 2 weeks to be back at baseline (in the absence of further consumption). Nitrous oxide does not produce cross-tolerance with other dissocatives, meaning that after the use of nitrous oxide other dissociatives will not have a reduced effect.

Dangerous interactions

Warning: Many psychoactive substances that are reasonably safe to use on their own can suddenly become dangerous and even life-threatening when combined with certain other substances. The following list provides some known dangerous interactions (although it is not guaranteed to include all of them).

Always conduct independent research (e.g. Google, DuckDuckGo, PubMed) to ensure that a combination of two or more substances is safe to consume. Some of the listed interactions have been sourced from TripSit.
  • Alcohol - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Memory blackouts are likely.​
  • GHB - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Memory blackouts are likely.​
  • GBL - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Memory blackouts are likely.​
  • Opioids - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Memory blackouts are likely.​
  • Tramadol - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. While unconscious, vomit aspiration is a risk if not placed in the recovery position. Memory blackouts are likely.​
*From the article (including references) here :
 
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Nitrous Oxide found to provide relief for Treatment-Resistant Depression*

by Lo Styx | Vetry Well Mind | 17 Jun 2021​
  • A recent clinical trial showed nitrous oxide, or laughing gas, alleviated symptoms of treatment-resistant depression.​
  • There's often stigma around "party drugs" as treatment for psychiatric disorders, even after these options are deemed effective.​
A recent clinical trial revealed that the substance Nitrous Oxide could, perhaps unsurprisingly, serve as an effective treatment for depression.

Researchers from the Washington University School of Medicine in St. Louis and the University of Chicago conducted a phase two clinical trial that included 24 individuals with severe treatment-resistant depression. This means the depression symptoms these participants had been experiencing hadn't improve after multiple standard antidepressant treatments.

Each participant was randomly assigned one of three treatments: a single one-hour inhalation with 50% nitrous oxide, 25% nitrous oxide or an oxygen placebo. Each participants received three treatments roughly one month apart. During the first treatment, individuals inhaled the 50% solution, in the second, the 25%, and in the third, the placebo.

The findings, published in Science Translational Medicine, revealed that a single one-hour treatment rapidly improved symptoms of depression for 55% or participants, and that these benefits can last for weeks. Forty percent of participants even considered themselves in remission. While the 50% dosage had greater antidepressant effects post-treatment, the 25% dosage resulted in fewer unpleasant side effects—nausea being the most common.

Nitrous oxide interacts with different receptors in the brain than traditional antidepressant treatments, and it works more quickly. This could explain some of its success.

"It's very important to find therapies to help these patients," said one of the study's senior investigators, Charles Conway, MD, in a statement.

"That we saw rapid improvements in many such patients in the study suggests nitrous oxide may help people with really severe, resistant depression."

This isn't the first time Nitrous Oxide has been studied as a treatment for depression. A previous proof-of-principle study showed that inhaling nitrous oxide produced immediate antidepressant effects for individuals with treatment-resistant depression, but it did not determine its effectiveness after 24 hours. The dosage of nitrous oxide tested was also high enough to increase the risk of nausea and other unwanted side effects.

“Our primary goals in this study were twofold: to determine whether a lower dose of nitrous oxide might be just as effective as doses we’d tested previously—and it was for most patients—and we also wanted to see how long the relief lasted,” said the study's co-senior investigator Peter Nagele, MD, in a statement.2 “In a proof-of-concept study several years ago, we assessed patients for 24 hours. In this study, we continued to assess them for two weeks, and most continued to feel better.”

"The bias is more in the public because it defies their own logic to have something that officials say 'This is harmful, don’t use this,' and then people say use it because it is good."
— Tiago Reis Marques, PhD

Inhaling nitrous oxide recreationally can have dangerous effects, but when taken as prescribed by a medical professional, it's completely safe.

Nitrous oxide is just one among a plethora of drugs, including ketamine, being tested to treat severe depression. And while this particular study does have limitations, such as its small sample size, it is a step toward more accessible and effective treatments.

*From the article (including references) here :
 
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