Haas, J. W., Bender, F. L., Ballou, S., Kelley, J. M., Wilhelm, M., Miller, F. G., Rief, W., & Kaptchuk, T. J. (2022). Frequency of Adverse Events in the Placebo Arms of COVID-19 Vaccine Trials: A Systematic Review and Meta-analysis. JAMA Network Open, 5(1), e2143955. https://doi.org/10.1001/jamanetworkopen.2021.43955

Hilda Bastian, PhD. (2021, February 6). Unofficial unnamed AstraZeneca insider says they are doing the interim analysis for the US trial of the Oxford vaccine. AstraZeneca spokesperson says 4-6 weeks till data release. Https://t.co/VUHgbHN02d One is wrong? Or they’ll release only when have FDA minimum follow-up? Https://t.co/LgjfX8AIti [Tweet]. @hildabast. https://twitter.com/hildabast/status/1357862227106095105

Mahase, E. (2022). Covid-19: Sanofi and GSK to seek regulatory authorisation for protein based vaccine. BMJ, 376, o526. https://doi.org/10.1136/bmj.o526

Given how cheap and easy this intervention is, I'd say this is adequate evidence that all ME/CFS patients should be taking these supplements. Moreover. given that the p-value is so low, it is almost certain to be replicated.

That's quite impressive. It's worth noting that benefits accrued throughout the entire study duration. There's likely further benefits over longer durations. I take the benefit to be from antioxidants.

This was achieved by a single size 0 capsule. The benefits would likely be proportionally greater with higher doses. Though, there is probably a cap depending on one's starting antioxidant status. I take it to be antioxidants that are providing the benefit.

Madhi, S. A., Koen, A. L., Izu, A., Fairlie, L., Cutland, C. L., Baillie, V., Padayachee, S. D., Dheda, K., Barnabas, S. L., Bhorat, Q. E., Briner, C., Aley, P. K., Bhikha, S., Hermanus, T., Horne, E., Jose, A., Kgagudi, P., Lambe, T., Masenya, M., … Kwatra, G. (2021). Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 in people living with and without HIV in South Africa: An interim analysis of a randomised, double-blind, placebo-controlled, phase 1B/2A trial. The Lancet HIV, 0(0). https://doi.org/10.1016/S2352-3018(21)00157-0

This disproves my suggestion that 2 mg might increase HRV, but I was looking for 1 mg rather than 2. The 2 mg gum is still plausibly a higher dose than a 7 mg patch. I'm struggling to find studies in the lower doses. This may be because everyone wants to prove the harm of nicotine. There may even be publication bias (especially if there's no effect).

This was with a 14 mg patch. A 21 mg patch would probably reduce HRV given that a 4 mg lozenge does so.

I still expect to find enhance HRV with 7 mg. This study supports that hypothesis to an extent. That it, it shows that 14 mg may be the tipping point between increased or decreased HRV from nicotine.

Assuming a half life of two hours, I calculated a 7 mg per day patch delivers a peak dosage of around 0.8 mg. Given that a 4mg lozenge has a bioavailability of 79%, this is equivalent to a 21 mg patch.

Given that we know anything above a 7 mg patch disrupts sleep (while 7 mg enhances sleep), it's unsurprising that HRV was reduced. I expect that a 1 mg lozenge or gum would increase HRV. Given that the above citation lists the bioavailability of a 2 mg lozenge at 50%, 2 mg may also increase HRV.

Benefits accrued throughout the 8 weeks. I recall reading on Longecity forum that ashwagandha takes a month for benefits to kick in. This study demonstrates that benefits continue to increase over two months. I suspect they continue even further than that.

Interestingly, this is pretty similar to the two placebo controlled studies on antioxidants for sleep. Thus, I wonder of the benefits of ashwaganha extract are largely antioxidant capacity. This would be a bit surprising because the ORAC of dried ashwaganda is just slightly above raw pinto beans. Based on the recommended doses, the extract isn't vastly more potent than the whole root. Though, this comment saying that the Withanolide/Withaferin A (edit: withaferin A is purportedly cytotoxic) reside mostly in the leaves has greatly confused me. Either the extract has more antioxidant activity than I realize (directly or indirectly), or the benefits come primarily from the purported mechanisms of ashwagandha (which include cortisol reduction and GABAergic activity). Edit: the full text mentions a 15 to 1 extract ratio, which is enough to put the antioxidant mechanism back on the table. It's probably a partial explanation, but after seeing the full text I think the benefits are too great to be simply from antioxidants.

I see no mention of the time of day of administration. I'm assuming it was in the morning, which contrasts with the near bedtime dosing in the antioxidant studies. If I later find out that antioxidants in the morning don't help with sleep, then that will suggest ashwagandha works by other mechanisms. However, I expect antioxidants at any time of day help with sleep. Nonetheless, I'm not discounting that ashwagandha may work by other mechanisms.

I believe this roughly equates to the benefits from an increase in SWS.

Though the effect was stronger in those with lower intake, the effects on mood in those with higher intake were still quite substantial, (full text). That is to say, both groups benefited. Selenium improved anxiety only in the low intake group, (full text).

Interestingly, the high and low intake groups had the same baseline scores. That is to say, it's not that selenium brought the low intake group up to normal, but rather that they were lifted above the high intake group. It's possible that they had adapted to their low intake, be it psychological or physiological adaptation. I recall a similar effect with creatine and cognitive performance in vegetarians.

This raises the question: does the benefit disappear over time as one adapts to their new selenium levels? Perhaps, but I find it more likely that the benefit drops only slightly. That is, I think what may be occurring is a a positive feedback loop where better mood makes you more optimistic, thus improving your mood; I expect this psychological mechanism to fade, leaving the biological component intact.

Of course, there is the possibility that this is a statistical fluke. Nonetheless, I'd expect the above mechanism to occur in general. If I learn more about statistics I could probably run a p-value test.

That is a moderate but worthwhile benefit over placebo.

Not only was is significant, but it was impressive! The 200 μg dose cut the score over 50%, compared to 20-22% reductions in the placebo. Everyone with RLS should be given selenium.

However, I disagree with the authors that this should be a replacement. Multiple treatments are likely necessary to achieve adequate relief.

As expected. This study was placebo controlled, too.

This is not surprising. It seems that L-theanine is clinically useful in the exact ways one would expect.

Ethan Mollick and Nancy Rothbard experiment https://papers.ssrn.com/sol3/papers.cfm?abstract_id=2277103 about gamification in a sales setting shows that gamification only works for those who buy into it.

Is this similar to ideas like the placebo effect or potentially for cases like Eastern Medicine where one might need to buy into it for the effects to matter to them?

Bar-Zeev, N., & Kochhar, S. (2020). Expecting the unexpected with COVID-19 vaccines. The Lancet Infectious Diseases, 0(0). https://doi.org/10.1016/S1473-3099(20)30870-7

the Guardian. ‘Pfizer Vaccine Has 91% Efficacy for up to Six Months, Trial Shows’, 1 April 2021. http://www.theguardian.com/world/2021/apr/01/pfizer-vaccine-has-91-efficacy-for-up-to-six-months-trial-shows.

Isaacson, Walter. ‘Opinion | I Was Part of a Trial for Pfizer’s Covid-19 Vaccine. It’s a Miracle for Genetic Medicine.’ Washington Post. Accessed 6 March 2021. https://www.washingtonpost.com/opinions/i-took-the-pfizer-covid-19-vaccine-its-a-miracle-for-genetic-medicine/2020/11/09/77e652d0-22bf-11eb-952e-0c475972cfc0_story.html.

Carl T. Bergstrom. (2021, January 31). A somewhat technical thread about measuring vaccine efficacy. We’re used to the notion that certain properties of tests for disease depend on prevalence: Positive and negative predictive value do, for example, whereas sensitivity and specificity do not. [Tweet]. @CT_Bergstrom. https://twitter.com/CT_Bergstrom/status/1355762090078703621

Carl T. Bergstrom. (2020, December 5). I don’t have a background in medical ethics but this makes me uncomfortable unless it was very clearly explained to study participants at enrollment, and to some degree even then. H/t @RMCarpiano https://t.co/WUE1mXgjJG https://t.co/yLXkxIa5O8 [Tweet]. @CT_Bergstrom. https://twitter.com/CT_Bergstrom/status/1335152266840424449

CNN, A. V., Holly Yan and Christina Maxouris. (n.d.). FDA won’t ‘cut corners’ to approve a Covid-19 vaccine, commissioner says. CNN. Retrieved 12 August 2020, from https://www.cnn.com/2020/08/10/health/us-coronavirus-monday/index.html

Lipsitch, M., Perlman, S., & Waldor, M. K. (2020). Testing COVID-19 therapies to prevent progression of mild disease. The Lancet Infectious Diseases, 0(0). https://doi.org/10.1016/S1473-3099(20)30372-8

The study. This sounds very similar to the placebo effect, so I wonder if they have checked to see what effects they would find if they picked activities previously classified as neutral.