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.

4 days is enough time to develop tolerance to the antihistamine sedation, but not to the adrenergic effects. Tolerance to yohimbine takes two weeks.

It's not often you find effective treatments for negative symptoms. As a schizoid myself, this looks like a valuable tool. I'd be fascinated to see how LDN and ULDN perform.

Combined with the fact that smoked nicotine is about 50% bioavailable, melatonin in an electronic cigarette should be roughly three times more bioavailable compared to oral.

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.

This is as I'd expect. I'd like to know if there's a dose relationship. I'll also need to see if this translates to clinical significant improvements in things like schizophrenia and CFS.

That's nearly a 15% reduction! It's also comparable to reductions seen in CFS (though CFS was per weight rather than per surface area, they should be comparable metrics). However, this is in comparison to bipolar, who themselves probably lack normal blood volume, so it's possible schizophrenia is a more extreme version of CFS where the blood volume is radically reduced. Will need more studies.

This implies a causal role. The low parasympathetic tone precedes psychosis.

Predictions.

This is virtually identical to pressure cooker conditions. Thus these tips likely apply equally to cooking. Moreover, I take this as evidence that is appropriate for cooking food in the pressure cooker, though it may warp under stresses (so stacking containers may cause warping).

Could administering melatonin earlier in the day counter this effect? Presumably 6 hours before bedtime would maximize phase advance.

± 0.01 aw? That's crazy accurate. Temperature is extremely easy to measure at home, which makes this a perfect technique for home food preservation. In particular, it can be used with sugar-free, salt-free, and other obscure recipes for which water activity is hard to estimate.

Additionally, this accuracy could be run in reverse. Knowing the water activity of ice-cream can tell you the freezing point. Moreover, a mini fridge could keep select food items chilled below 0°C for better preservation. In particular, I plan to dissolve erythritol into unsweetened plant milks and lower my fridge temp accordingly.

That's a substantial fraction of the 11 point lower blood volume in ME/CFS found in one study. Moreover, this was achieved with only 13 days bed rest. I can only imagine the long-term effects of a sedentary lifestyle. It's likely that this is the primary cause of most ME/CFS. Nonetheless, exercise is unlikely to be the optimal treatment.

I notice the standard deviation is low for their sample size. Normally smaller sample sizes increase SD. However, comparing to a study with 30 subject per group, we can see the expected SD for blood volume (ml/kg) in this sample size of 20 should be greater than ±22.

The reason for this small SD is probably that subjects with ME/CFS are scrunched up against the lower end of the curve. The body simply will not allow blood volumes below a certain level. Judging by this study, I'd say around 50 ml/kg is the lowest possible number.

That's an interesting hypothesis. I wouldn't have thought histamine was involved. Though, histamine being a stimulant, it also makes some sense. I'd have thought the primary mechanism is serotonin blockade, which would work in part by dopamine dis-inhibition as mentioned here.

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.

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4:42 "as monks and mediators, we only eat once in the morning." This seems quite plausibly an acquired wisdom, as opposed to a quirk of the practice. While I've not yet read much of the science myself, I've heard a great deal about the benefits of intermittent fasting. Moreover, there's interesting research suggesting that making breakfast your biggest meal provides benefits. I would not be at all surprised if eating only once in the morning is the optimal approach.

Sounds promising, but it's partly because they have kepped dosage to a minimum. They have "miss" is their name, so it appears to be a woman. Men may be able to take a bit more.

It's a dangerous protocol. I couldn't recommend it to anyone who's risk averse. Ideally, one would have a third compound to cycle.

My guess is that this is caused by a sleep surplus. I'd analogize it to the CBT-i recommendation to avoid napping because it will impair sleep drive that night.

DIRECTORY (in progress): This post is my directory. This post will be tagged with all tags I ever use (in chronological order). It allows people to see all my tags, not just the top 50. Additionally, this allows me to keep track. I plan on sorting tags in categories in reply to this comment.

External links:

Tags categories will be posted in comments of this post.

PSA: everyone with insomnia should know that there are two recent double-blind, placebo-controlled trials on antioxidant blends for sleep, (1, 2). Given that the blends in each study are completely different, probably any antioxidants will do. I suggest amla powder as a cheap and available antioxidant source. Though, you may want to hedge your bets by adding other antioxidants. Antioxidants synergise, so the fact that they were blends may be important. Note: the benefits appear to take weeks to accumulate.

(1) A Randomized, Double-Blind, Placebo-Controlled Trial of a Polyphenol Botanical Blend on Sleep and Daytime Functioning

(2) Sleep Promoting Effects of IQP-AO-101: A Double-Blind, Randomized, Placebo-Controlled Exploratory Trial

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.

That's what I'd expect, and it's one of the main reasons I don't think CBT will help me. That said, I intent to try CBT. I'm also interested to know if this is the consensus or if it is the opinion of this particular doctor. It seems plausible that some CBT practices have subconscious effects.

This is exactly what one would expect. Though, I'd not be surprised if there were small reductions in RLS severity over time.

Fascinating. I'd expect mu and delta opioids to reduce cortisol, if only indirectly via relaxation.

Likewise, it is important to understand the mechanism by which kappa agonism increases cortisol. Kappa is known for its dysphoric effects, which would naturally increase cortisol. However, kappa agonism is also consistent with extreme euphoria. This is known from reports with Salvia divinorum and Tabernanthe iboga. Whether this euphoria decreases cortisol or if it is, rather, a form of eustress is a very interesting question.

This conflict with this CaymanChem PDF. The PDF states that limonene has a solubility of 20 mg/ml.

This conflicts with the PubChem page, which says limonene is miscible in alcohol. The PubChem page doesn't mention the other solvents.

I'm quite a novice in chemistry. I assume a 9:1 ratio would work with other solvents replacing the 9 parts propylene glycol. That is to say, given that salvinorin A was not soluble in propylene glycol, I'm assuming the propylene glycol plays little to no role.

This is not concentrated enough for ejuice. I imagine the maximum capacity is much higher. DMSO is extremely powerful. Additionally, given that I don't like throat hit, I'd probably swap the PEG for VG. Once I can get pure salvinorin A, I can test if VG hinders solubility somehow.

Edit: Glycerol and DMSO are probably not miscible. This is based on the fact that glycerin and acetone aren't. I may try to see if terpenes and DMSO are miscible.

As with DMSO and propylene glycol, I suspect that the DMSO is doing the dissolving. Given that it appears to only take 10% DMSO to dissolve salvinorin, naturally the 25% works. Unfortunately, I see no mention of whether salvinorin A is soluble in pure PEG-400. I suspect it is not.

Which one it is should be possible to determine by running multiple washes and visually assess how much pigmentation is removed. The idea is to dissolve acetone plant extract, add PEG-400, let the acetone evaporate, pour PEG-400 leaving sediment and/or crystals, then repeat. While I'd probably be doing this with salvia divinorum, any leaf should work for testing chlorophyll washing.

They seem to be saying that PEG dissolved 50% of the chlorophyll? I also don't know what what Ch or DHp means. I'm somewhat outside my wheelhouse.

Assuming PEG-400 does not dissolve salvinorin A, then it may be an excellent option for purification of salvinorin A.

This is incredibly useful information.

I noticed my extract had some bitter taste and some earthy notes. I don't know what salvinorin and chlorophyll taste like, but I assume the taste comes from other impurities. However, I extracted for many minutes (10 or so); next time, I should do only the 3 minutes suggested here (3 times 1 minute).

Incredible. I may have destroyed my current batch. I'll have to start over. Good thing I only made a moderate amount.

This is the first confirmation I've seen of using acetone as a solvent for terpenes. I'd be surprised had acetone not dissolved them.

I'm using a method of adding terpenes to my salvia divinorum extract, then evaporating the acetone. This creates an instant e-juice. It's a relatively crude method, containing large amounts chlorophyll. Nonetheless, the contents should be safe for inhalation.

These are the effects I was expecting to find. cGMP plays a role in SCN nighttime signalling, though I expect it has other mechanisms as well.

This is probably due to nasal congestion.

It's hard to say what this tells me about my hypothesis that the 7 mg patch increases HRV. It really depends on their blood levels. The second-hand smoke machine is extremely unrealistic. They were exposed to 30 puffs of 1.8% nicotine e-juice in the first measurement interval. Assuming 150 puffs per ml, that's 3.6 mg smoked in a single 15 minute interval! I've not read the full study to confirm this calculation. Nonetheless, it's clear that these insane conditions require scrutiny. That's not even counting the fact that there's no placebo (Or even control). How am I supposed to know if this is not just an effect of being concern about inhaling e-smoke? I'm still searching for studies on low concentration of nicotine and HRV.

This confirms that thyroid function probably lacks any (direct) effect sleep. Of course, not this evidence alone, but rather this combined with "Effects of Supraphysiological Doses of Levothyroxine on Sleep in Healthy Subjects: A Prospective Polysomnography Study"

Odd they don't mention vitamin E or other antioxidants. They do cite that placebo-controlled vitamin E study in diabetics. I ought to see what other important information they've left out of the abstract.

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.

I'll need to review this later. This is a more precise figure than I was familiar with. I think I read somewhere between 20% and 50%; I believe I cited that figure in one of my college papers.

This may partly represent the salvia "afterglow". It also demonstrates how rapidly tolerance-like mechanism can occur.

I find it odd that 0.32 mg/kg had little prolonged effect when twice that dose had a very large effect. I'd expect more of a gradient. The graph (figure 4) shows a nonsignificant drop in KOR binding of ~13% at 1 hour at 0.32 mg/kg, which I'm certain would become statistically significant in a larger sample. Still, that's nowhere near the 45% seen at 0.6 mg/kg. At 0.18 mg/kg, we see ~9%.

I calculated the human equivalent dose to be 6.8mg (0.6mg0.16270). This is an very high dose, so likely does not represent an accurate dose conversion.

That's quite interesting. I have a vague memory of reading that morphine tolerance upregulates KOR, but that memory may be mistaken. Alternatively, it could be that KOR was upregulated in this study, but it took greater KOR agonism due to mu/delta not providing baseline analgesia due to downregulation. Lastly, there is also the possibility that it takes simultaneous mu and delta agonism to upregulate KOR; this possibility seems likely.

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.

I'm considering switching back to amla for this reason. Amla is cheaper due to its potency. While I don't like the taste of amla, it's easily tolerable provided I know why I'm taking it.

This effect was quite substantial. It was over 100 minutes greater increase than in the placebo, for both healthy subjects and insomniacs. Total Sleep Time (TST) increased in the placebo group by 1 hour in healthy subjects and 2 hours in insomniacs. Of course, most of that was probably not placebo, but rather getting used to the sleeping conditions. As I said, ashwagandha increased sleep time 100 minutes more than that. In real world conditions, I think it's reasonable to expect an hour increase after 8 weeks of ashwagandha. Indeed, this effect implies it's not just an antioxidant, as antioxidants didn't have an effect that significant on TST.

Edit: actually, the increase in TST appears not to be that great, assuming the graph is to be trusted. Given that TST was reported as such low numbers, I had assumed it must be change in TST from baseline. However, the graphs show a 20 or so minute increase. The reported numbers in the table are all messed up. Sleep onset latency is reported as 85 in the healthy group taking ashwagandha. Time in bed is reported as 20 minutes. None of it makes sense, and none of it matches up with the graphs. That table isn't trustworthy. Best to go by the graphs, which show decent but more realistic benefit.

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.

This supports that study on vitamin E in diabetics.

This was most likely morning and bedtime. 300 mg times 15 equals 4.5 grams. In other words, they administered the equivalent of 9 grams ashwagandha root per day.

This is likely the standard. It is a sufficient ratio to give it a high ORAC, meaning the antioxidant mechanism is back on the table. Nonetheless, the benefits appear greater than that of mere antioxidants.

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

There was a trend towards increased SWS. I suspect this will bear out in larger or otherwise better studies.

There seems to be an error in reporting of SWS. The reported increase was actually fairly substantial. It was reported as 19.2 in the CGA compared to 15.7 in the placebo, but I'm sure that must be missing a digit or something. In any case, assuming it is otherwise accurate, that would be a 22% increase.

This is plausibly the reason why antioxidants enhance sleep. Though it is likely that there are other mechanisms as well, such as reduced neuroinflammation. Come to think of it, given that ME/CFS appears to be caused by high sympathetic tone during sleep, antioxidants are the perfect treatment. Antioxidants are proven in placebo-controlled trials to help with sleep in healthy subjects and insomniacs alike. I doubt that antioxidants can cure ME/CFS, but I'm confident they will help.

This suggests measurable enhancements in sleep architecture.

I suspect near bedtime is optimal, but I'd be interested to see effects of daytime administration.

That is indeed unexpected. However, this may be explained by a nap, mentioned in an article which appears to be based on the same data.

Edit: they measured on day 9, whereas the first placebo was administered on day 8, so the may have accumulated SWS surplus on night 8.

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.

I see. I believe this could possibly explain the lack of increase in SWS. They don't mention taking any measurements during this nap.

Appears to be proven incorrect.

This aligns with intuition. However, they only tested a single night in each condition. The harm of eating at night may be a zeitgeber effect, taking multiple days to accumulate.

These results bring into question advice about avoiding food at night. Food quality likely plays a critical role. It remains unclear whether eating before bed is advisable, but this data gives reason to at least avoid making recommendations against it.

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.

Interesting. They were using full naltrexone doses, not LDN. I'd expected full doses would make movement disorders worse.

Thus, your typical selenium supplement will not provide this benefit. I wonder, however, if higher doses might. Indeed, it is often closer to toxic doses that are effective against cancer (for various compounds).

Good. I thought 400 was likely safe. Though I'm considering taking 400 mcg daily, 200 mcg is probably more than adequate.

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.

Not sure why 50 instead of 200. Though the superiority of 200 μg was not statistically significant, I doubt there is any risk to such a dose.

As expected. This study was placebo controlled, too.

This study doesn't say much given that they only included smokers.

This is supported by a single-blind study on nicotine for akathisia.

I'd be interested to see the effect of a 7 mg patch. 14 mg is too high for sleep, so I wonder if it is also too high for akathisia.

Unsurprising. This supports my hypothesis that ADHD is a sleep disorder. This hypothesis should hold sound regardless of EEG. That said, I also expect to find EEG disturbance during sleep in ADHD.

I concur. This merits human analysis. I'd be curious to know the subjective effects of combining the two. In particular, I'm wondering if mirtazapine reduces "wanting" while enhancing "liking".

The main reason I'd been thinking this is due to comparison to similar drug combos in humans. I'd heard that combining hydroxyzine and opioids was sometimes prescribed to enhance the effectiveness of opioids and/or use lower opioid doses; I'd also read on some harm reduction forum that some people enjoy combining opioids with antihistamines. Given that mirtazapine is to a large extent just hydroxyzine but with added adrenergic effects, it seems likely that much of these data can be cross-applied (between mirtazapine and hydroxyzine in particular).

This is the highest dose of L-theanine I've seen taken. At one dolar per 10 grams, It's actually reasonably affordable to take daily for medical purposes. I may try it, but I'm unlikely to implement it long term. If it's a significant effect, it would be a useful tool. However, I'd be concerned about tolerance.

In contrast, sildenafil appears not to provide any acute benefit, (study). I'd only expected benefit due to sleep enhancement, so lack of acute benefit was unsurprising to me.

Given that risperidone was likely taken at night, and sildenafil was likely taken at the same time, it's my opinion that the benefits in this study were due to sleep improvement. This may be via the circadian clock, or a more direct effect on sleep, or both.

My remaining question is whether sildenafil improves sleep in healthy subjects. I'm especially interested in combining sildenafil with 100 to 300 mcg melatonin. Will they have synergistic effect? I expect so.

I'm somewhat surprised. I was under the impression that cAMP signalled the wake phase, and cGMP signalled the sleep phase. I thus expected cGMP to increase parasympathetic tone (and therefore increase HRV)

That's important. It seems what we should care about is the effect in severe cases.

This could potentially be explained due to variation in Tmax. That is to say, it may not be that half life varies dramatically. Rather, absorption into the bloodstream after intramuscular injection may be the cause. I'm no expert on IM injections.

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

Data like this seems to be definitive proof that nicotine is nothing like tobacco. I'm not aware of any evidence that nicotine itself is addictive, save for a few anecdotes. I don't put much stock in these anecdotes because people also report habit-withdrawal symptoms when they quit zero nicotine e-juice. That is to say, without placebo controls we cannot conclude drug withdrawal is the cause because it can also be explained by psychology.

That said, I'm reasonably certain that nicotine contributes to tobacco addiction. While I think nicotine is fairly non-addictive, I believe it enhances the addictiveness of other drugs. I think this is partly due to an entourage effect that alters the high, and also a memory-enhancing effect so one remembers the high more vividly.

From the full text, they used 5 micrograms of naltrexone. Naltrexone dose is very finicky. There's low dose (LDN), very low dose (VLDN), and ultra-low dose (ULDN). This is a ULDN. I believe the type of effects I'm looking for occur at VLDN and LDN doses. If I recall correctly, I think 2 mg is optimal for analgesia, but I don't remember whether this was with or without morphine. 0.125 mg and 0.25 mg are effective in opioid withdrawal when combined with methadone. Thus, it's not too surprising that 5 mcg had little effect. At those doses, the effects it does have are like mediated by different mechanisms.

I think this may be the best review of salvinorin A that I have ever looked at. I definitely need to sit down and read the full article at some point.

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.

That's not a large enough sample to draw conclusions out subtypes. Interesting nonetheless.

Low incidence of side effects certainly sounds superior to atypical antipsychotics and tricyclic/tetracyclic antidepressants.

This may mean ritanserin is superior. Amitriptyline is a dirtier drug affecting more than just serotonin receptors. Therefore, ritanserin likely has fewer side effects. However, I'm not currently aware of any studies demonstrating this.

30:55 Ibuprofen rescue. Interesting concept, though I am somewhat skeptical.

18:03 Loneliness leads to microarousals. Could this be a potential root cause of ME/CFS.

Sounds like withdrawal. Why is information like this so hard to find?

This supports my speculation from another study, found here.

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.

I'm not sure what conclusions I should draw from this.

An acute effect. Interesting but not particularly consequential. It does mean, however, that I need to be wary of studies using withdrawal as a netric when combining PDE5 inhibitors with opioids.

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.

Interesting. It is not clear the ideal time/order of administration.

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.

That's a shame. I still need to find out the long term effects on mood. There seem to be only three human studies on calcium channel blockers combined with opioids. I infer that from google search results plus the review that lead me here.

Morphine Benzedrine Group (ARCI-MBG) scale was designed to measure benzodiazepine-induced mood elevation.

https://pubmed.ncbi.nlm.nih.gov/11417943/

There is still the question of subjective effects. Given that I'm primarily interested in this combination as a psychological treatment and as a transhuman upgrade, increased pain is not a deal-breaker. It's also not quite clear how this holds up in the long term. That is, do the effects of L-CCBs on pain change after supersensitization to opioids?

This is getting very odd. It is hard to draw useful conclusions. This is partly because I'm out of my depth.

Shame. It may prevent tolerance partly by reducing the subjective effects. Though, there are other possible explanations.

Interesting hypothesis.

I wish they would expand on that. I may have to read the full text later to see what they mean.

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.

Worth noting.