Oddly, the strong adenosinergic pressure from ~20 hours wake combined from caffeine withdrawal didn't lead to increased SWS. Indeed, there was a nonsignificant trend towards a decrease in SWS. One possibility is that caffeine induced SWS surplus accumulation over the previous week, reducing SWS drive. However, this could alternatively be explained by the 60 minute nap.

Withdrawal restored REM sleep under these conditions. The withdrawal condition looks quite similar to placebo (both REM and SWS), which is rather surprising.

This demonstrates that tolerance is possible. However, exposure in humans lasts only several minutes at a time. Let's assume 3 exposures per day lasting 10 minutes each (i.e. 30 minutes total). It would take 68 days to reach 34 hours of exposure. Alternatively, that's a ratio of 1 to 47 exposure to non-exposure. It's unclear whether that would be sufficient for tolerance.

In the 50% exposure group, convulsion score was effectively zero by hour 6 (from full text). This does not mean that withdrawal symptoms were gone. However, it does imply that recovery is rapid. It seems plausible that 20 hours between doses is sufficient to reach baseline, rendering tolerance in humans extremely unlikely. I will need to compare to alcohol withdrawal to confirm.

Edit: Alcohol withdrawal in mice can be induced with 72 hours of alcohol exposure. That implies it is similar to NO. In humans, "the shakes" appear to last 1 or two weeks. In mice, convulsions appear to be half gone in 25 hours, suggesting that they last a few days. Thus, it appears that NO withdrawal is possibly an order of magnitude shorter than alcohol withdrawal.

In conclusion, NO used in a normal fashion is unlikely to be harmful (except for risk of inducing B12 deficiency). Even if it is harmful, the short half life means that it will be apparent very quickly. I'm aware of several reports of B12 deficiency from NO abuse, but I haven't seen any reports of withdrawal symptoms.

Ian Nurmi on Twitter: “In the midst of a global pandemic, @BU_Tweets has just threatened to pull the medical insurance of any graduate student unwilling to teach in the classroom this fall. https://t.co/VPHlskry6A” / Twitter. (n.d.). Twitter. Retrieved June 25, 2020, from https://twitter.com/i_nurmi/status/1275457100454465542

"Just notice the feeling of the need for withdrawal into privateness—without judgement. But be aware of it."

Feeling what we feel without judging it.

"You are withdrawing into privateness that does not allow you to experience the fact that you are embracing always! The suggestion is that you are shutting me out. But know that you are shutting yourself in—self-protective withdrawal into isolation for security that doesn't constitute security, but which constitutes incarceration."