The sources are patents. 2014a and 2014b.

It is interesting that the benefits were retained over a large dose range. Oddly, full doses (when combined with benzos) can help treat tardive dyskinesia. Thus, it seems plausible that the benefits for RLS are retained at even higher doses. I've not yet checked the sources to see if higher doses were tested. That is, doses over 1 mg. I doubt they were, because it would probably have been mentioned here.

https://en.wikipedia.org/wiki/Paradox_of_tolerance

Best known example of gene-culture coevolution - co-evolution of pastoralism and lactose intolerance - the adoption of dairying set up a modified niche - in which the ability to digest lactose into adulthood was an advantage. - ancestors who were lactose tolerant could take advantage of a new source of calories. - Hence it is the learned acquisition of dairying which explains the natural selection of genes favoring lactase persistence, - the continued production of the enzyme lactase beyond weaning - Dual inheritance theory (Gene-culture coevolution) typically uses this example to explain - Dairying is inherited via a cultural channel - lactase persistence is inherited via a genetic channel - Recent supporters of this also make recent claims that it is not possible to distinguish between - what is biological from what is cultural

What features would be design society towards? Stability? Freedom? Wealth? Tolerance?

How might long term evolution work for societies that maximized for tolerance given Popper's paradox of tolerance?

https://en.wikipedia.org/wiki/Paradox_of_tolerance

Ben Thompson argues that it is precisely culture that has now changed, seemingly in favor of being less tolerant towards the expression of certain opinions.

Ben Thompson by highlighting an argument made by Pat Kerr, that free speech (although lacking a widely accepted definition) is about the tolerance we show others in expressing their opinions, equates it to culture.

Kinderimpfstoff gegen Corona: Stiko-Chef Mertens würde eigene Kinder jetzt nicht impfen lassen. (2021, December 2). FAZ.NET. https://www.faz.net/aktuell/politik/inland/stiko-chef-mertens-wuerde-eigene-kinder-nicht-gegen-corona-impfen-17662194.html

James Mumford says that therapists took the idea that they shouldn't talk to patients about right and wrong (to help create a safe space) morphed into: there IS no right and wrong.

I would add that this seems to have bled over into society.

Sinclair, Alyssa H., Morgan Taylor, Freyja Brandel-Tanis, Audra Davidson, Aroon T. Chande, Lavanya Rishishwar, Clio Maria Andris, et al. ‘Counteracting COVID-19 Risk Misestimation with an Interactive Website’. PsyArXiv, 9 February 2022. https://doi.org/10.31234/osf.io/v8tdf.

Townsend, L., Dyer, A. H., Naughton, A., Kiersey, R., Holden, D., Gardiner, M., Dowds, J., O’Brien, K., Bannan, C., Nadarajan, P., Dunne, J., Martin-Loeches, I., Fallon, P. G., Bergin, C., O’Farrelly, C., Cheallaigh, C. N., Bourke, N. M., & Conlon, N. (2021). Longitudinal Analysis of COVID-19 Patients Shows Age-Associated T Cell Changes Independent of Ongoing Ill-Health. Frontiers in Immunology, 12. https://www.frontiersin.org/article/10.3389/fimmu.2021.676932

Vega-Oliveros, D. A., Grande, H. L. C., Iannelli, F., & Vazquez, F. (2021). Bi-layer voter model: Modeling intolerant/tolerant positions and bots in opinion dynamics. The European Physical Journal Special Topics, 230(14–15), 2875–2886. https://doi.org/10.1140/epjs/s11734-021-00151-8

Deepti Gurdasani. (2021, December 23). Some brief thoughts on the concerning relativism I’ve seen creeping into media, and scientific rhetoric over the past 20 months or so—The idea that things are ok because they’re better relative to a point where things got really really bad. 🧵 [Tweet]. @dgurdasani1. https://twitter.com/dgurdasani1/status/1474042179110772736

Kan, U., Feng, M., & Porter, M. A. (2021). An Adaptive Bounded-Confidence Model of Opinion Dynamics on Networks. ArXiv:2112.05856 [Physics]. http://arxiv.org/abs/2112.05856

This suggests to me that it is the opioid tolerance itself that determines cocaine sensitivity. To test this, I'd like to see a study that administers a KOR agonist after tolerance to opioids has been established, and see if this reverses cocaine sensitivity.

Just confirming what I believed to be the case. I couldn't remember whether I'd read results of this specific sort, so I figured I should look it up. Chronic KOR agonism appears to be an ideal opioid hack.

agencies, G. staff and. (2021, August 6). CNN fires three employees for coming to work unvaccinated. The Guardian. http://www.theguardian.com/media/2021/aug/05/cnn-fires-employees-covid-unvaccinated-office

i was going to ask what good it is having a cable that has power, but not the data center behind it.

i guess the situation is that the fiber optic cable also has power cables running along it too, powering the repeaters, and it's the power cables that might break. in this case, having single ended power would be very useful.

i'm most curious to know how power is sent. is this 48V dc? higher? how much? kV?

Fascinating and useful stuff. This is close to what I was expecting. Though, I was expecting chronic exposure to upregulate dopamine beyond baseline. If I'm understanding this correctly, it was upregulated in the sense that it enhanced the dopaminergic effects of cocaine. I've not yet read the full study.

This is important because it suggests mood-brightening. Contrast this with combining L-type calcium channel blockers with opioids, which appears to limit tolerance to opioid analgesia that does not correspond to mood brightening.

Nurit Nobel. (2021, April 19). Meanwhile, in Europe... 🦗 [Tweet]. @nuritnobel. https://twitter.com/nuritnobel/status/1384121792122425345

Looks promising. It's odd that theophylline had a lesser effect.

It's not clear if this has relevance to the subjective effects. I'm starting to think that I won't get an answer anytime soon.

This is analgesia, so is not necessarily relevant for my purposes. Nonetheless, there implies some relevance of cGMP, but the direction isn't yet clear.

If they mean what I think they mean, then this implies that chronic KOR is useful. I'll need to check citation 27.

PAT is apparently an herbal medicine I should look into. They also imply that KOR agonists act as I expect they do, but I'll need to read the full study to be sure.

Edit: yup, it appears that chronic KOR agonism is probably a good idea.

from full text "Utility of KOR agonists is a promising pharmacological tool for attenuating morphine tolerance (Pan, 1998), however, it is difficult to find effective KOR agonists that are devoid of dysphoric and psychotomimetic adverse effects in humans"

This is the cited study.

Fascinating. However, this provides no insight into the subjective effects. However, it does reduce my certainty that any given combination of drugs (sharing these mechanism) will work. There doesn't seem to be consistent results with these L-CCBs plus opioid studies.

Yes. That also means that most of the rat studies I've been reading are useless for my purposes.

Weird and surprising.This plausibly implies that L-type calcium channel blockers may not be as effective as it first appears.

Consistent with rat data. This is from 1998. I'm sure there's more evidence by now. It's been a while since i researched this, but I think I've previously seen at least one other study.

Excellent. This implies that theobromine may help prevent opioid tolerance.

AirBnB ostensibly failed to realize that if you accept unacceptance, you're shooting yourself in the foot.

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.

Fan, Y., Orhun, A. Y., & Turjeman, D. (2020). Heterogeneous Actions, Beliefs, Constraints and Risk Tolerance During the COVID-19 Pandemic (Working Paper No. 27211; Working Paper Series). National Bureau of Economic Research. https://doi.org/10.3386/w27211

This is what I'd expect for tobacco, but it tells me little about nicotine. Most of the subjective effects are not from tobacco, so It's still plausible that nicotine does not develop tolerance. Indeed, the effects that don't go away are the effects expected from nicotine.

"Zero Tolerance" its main goal is to deter and punish at a very high cost the families that are seeking a safe place to live. to send a message to those who are contemplating to come to the US to stop or they will take their children.

"Patient self-control; restraint and tolerance" (OED).

This is good for my purposes. It means high doses can be taken for brain effects without disturbing stomach acidity. The question remains, of course, whether coinciding CNS tolerance develops.

The question, then, is whether the opioid receptors are involved at all in this upregulation. For example, it could be mediated by TLR4 or filamin A.

I would not expect doses this small to impact the opioid receptors.

Symptoms in the treatment group continually improved, whereas symptoms in the placebo group plateaued. Thus, I'm interested in seeing a longer treatment period. Projecting from symptom scores, elimination of symptoms would occur in about 10 days.

I've found elsewhere that mu agonism combined with delta antagonism provides analgesia while minimizing tolerance.

Nimodipine reduced morphine dose in already tolerant patients.

This book is not about religion, although I talk about religion. It's about religious tolerance and the fight for human rights; the first battlefront in public discourse about human rights.

Freedom of religion was the first base upon which other understandings of freedom have been built upon.

This is the story of 16th century Europe, and the political earthquake that was protestantism. The overarching historical narrative unfolds around the lives of fictional characters who might have lived in this historic period.

Follett's literary reenactment explores the intricacies of the Protestant Reformation through a cast of strategically diverse characters, whose stories span across multiple continents, nations, and cities. Each character is an important harbinger of larger historical trends. Within the masterfully established geo-political reality, each of their decisions serve to gradually reveal their distinct personalities and temperaments, belief systems and ideologies, and cultural identities.

Reminiscent of our current geo-political climate. The extended cycles of history.

Resources for countering Islamophobia.

The only counter-argument that comes to mind for me didn't form itself until I had read this last paragraph a few times.

If your identity marker connotes tolerance then it hopefully has the opposite effect. Insofar as the experience of marginalization promotes empathy such identities might be good evidence for intelligence, and I do think individuals who feel oppressed or marginalized tend to empathize with others who suffer for different, marginalized identities.

These identities will only breed stupidity if the individual feels a competition for scarce resources that overwhelms their empathy, whence the perniciousness of the belief in zero sum attention economics as a greater threat to activism than inaction, ignorance, and exhaustion.