It's not really that simple either. The real fact of the matter is that we don't understand neurotransmitter systems, or neuroscience in general. It's an incredibly 'young' field, where we haven't even formulated a standard model for many of the most observable features of psychiatry. For instance, sleep disorders; narcolepsy is incredibly obvious, repeatable, and severe, but we don't have a consensus model on what exactly is going on in the brain for it.
For that matter, take sleep itself. We all pass out and are mostly unresponsive for 1/3 of the time, and experience multiple hallucinations every day (most of which we never remember), and we do not understand this phenomenon. We know TONS of facts about sleep, but we just don't have a gears-level understanding of what changes in what cells to make sleep happen or not happen, and we have very little understanding of the changes it makes in our brains.
Asking 'why' in psychiatry is mostly useless because it's asking for an answer from a field that just isn't able to model the behavior you're asking about at all.
FWIW, some developers of AIs have started using "sleep" states to allow the AIs to consolidate memories that deal with more than one context. Not sure of the details, and people aren't AIs, but it's suggestive.
In response to the last paragraph, I would say that is because it takes a mutual understanding of both neurochemistry and psychology to design a model that can answer these questions. You can eat all your nutrients gaining adequate cofactors and amino acids to synthesize the ideal amount of neurochemicals, but you're life's shit you will probably still feel shitty. Flip side if you're life's amazing, you're rich and
Have all of the necessities but your brain chemistry is unbalanced you might as well burn the money ( Assuming it's not something that can be fixed by blowing large amounts of cash, not talking about luxury clothing and a trip on a luxury yacht cause then you will be stranded on an island and no money,, you may be able to spend money to help increase happiness, but you cant buy it)
I'd imagine it's because often "why" is either nightmarishly unclear and complex, and/or knowing "why" doesn't immediately suggest anything one could do differently — i.e., knowing why benzodiazepines and Z-drugs have slightly different effects might not provide any clear way to produce an improvement on either; you're still going to be using benzodiazepines and Z-drugs just how you did before.
It might interest you to know that pyrazolam is an abandoned benzo from the 1970's that recently resurfaced as a grey market designer drug. It is supposedly a2 a3 selective and experience reports confirm that it is primarily anxiolytic with minimal sedation.
No idea, Wikipedia says it was originally developed in the 70s. Reading it again I think it sounds like it just never got picked up moreso than it was abandoned. I think a research team synthesized a ton of benzofiazepene derivatives, confirmed basic properties and then some of them got picked up by pharmaceutical companies for further development and some didn't. This one didn't so it was never technically scheduled so it can be sold semi-legally online. There are so many structural combinations you can do on the benzodiazepene structure that all seem to work to create active drugs so there are a lot of combinations that work just as well as the pharmaceutical ones but fall in this category
After trying many anxiolytic agents, attempting to find 'the holy grail' that has as little sleepiness and cognitive impairment as possible, I can confidently say that pyrazolam is just that.
There is a study out there analyzing online experience reports on designer benzodiazepines and trying to quantify the magnitude of their specific effects. Compared to all the others, pyrazolam was maxed out on anxiolysis and near-zero on other typical effects of it's broader class. Can't say that the methodology of this study was as rigurous as RCTs, but it does seem to represent these experiences 'accurate enough'.
One small caveat: due to it's purely-anxiolytic properties, some people might not feel much & redose. With a seemingly lower threshold dose for blacking out, this is something worth noting.
All that being said, it really is a shame that this has not been developed into a commercially available prescription drug.
Later edit: There's another anxiolytic that could meet the criteria. Chemically it is a benzodiazepine but has no GABAergic mechanism of action. It's called tofisopam but it doesn't have the same (subjective) effectiveness as benzos, but that probably means it doesn't have the typical drawbacks either. It's also slightly nootropic according to at least one study. I know that's not enough, but at least it's good evidence of it at least not impairing cognition.
Can you provide a link / name for this study? I tried several of these grey-market benzos and I... didn't really feel much difference between them, but I'm still curious how they theoretically rank on the scale.
I don't have enough personal experience to cover both, but imo pyrazolam still has some dependence issues and I assume tolerance still develops. I did hear that quitting it is easy in terms of withdrawal symptoms, which probably suggests less 'physical' dependence.
Baikal Skullcap is distantly related to Lavender, which has some better-researched anxiolytic effects. I bought some lavender but haven't got around to trying it, because my ashwagandha works so well (the Himalaya brand stuff from vitamin shoppe).
Scott has mentioned lavender extract, previously. I purchased the Natures Way, Calmaid that he referred to. I believe he said it was used to treat depression? Lavender has some interaction with the serontonergic system as well. (I don't know the details and IIRC, some serontonergic effects can be GABA mediated.) It's certainly interesting, though I don't have anxiety that needs to be treated so I don't usually rely on it.
Oh that reminds me, how did our people taking lavender get on with it? There were mentions of the "lavender burps" but did anyone stick with it long-term? Any results?
I tried it for 6 weeks to no clear qualitative effect, but I did not use an anxiety scoring metric to track changes. I did have lavender burps, which I found fairly enjoyable (unlike my partner).
Tried it for two months, didn't notice any change on my anxiety stats (I rate it on a scale from 0 to 10, where 0 is not anxious at all and 10 is very anxious. The value I take for each day is the worst instance of anxiety during the day).
A quick perusal of the wikipedia page for TPA-023 (https://en.wikipedia.org/wiki/TPA-023) suggests development was stopped 'due to preclinical toxicity (cataract) in long term dosing studies'. There are two references on the wiki page - one has no mention of cataracts I could find, and the other one, 'The rise of a new GABA pharmacology' published in 2011, (scihub link: https://sci-hub.hkvisa.net/10.1016/j.neuropharm.2010.10.020) also mentions cataracts on page 4, but also without a reference as far as I can see.
Does anyone have more information about this? It sounds like an interesting molecule.
Specifically - what was the incidence rate and severity of the cataract issue? A link to some reputable looking source would also be nice. With the information I could find online it is difficult to understand why it is no longer be pursued as a possible anxiolytic. Presumably the cataract issue was deemed too serious, but without actual data I can't assess whether that was a reasonable conclusion.
Some speculation regarding the psychoactive effects of alcohol: I don’t know anything about the specific interactions between ethanol and GABA. But I do know that ethanol increases the permeability of cell membranes. Neurons depend on maintaining particular intercellular/extracellular ion ratios at any given point in their firing cycle, and so anything which allows ions to cross the cell membrane independent of the cell’s ion channels is likely going to effect the cell’s firing threshold.
This effect on membrane permeability is not specific to ethanol; Most organic solvents such as methanol, propanol, ethylene glycol, and diethyl ether do this. Perhaps this is why all solvents have similar psychoactive effects (depending on dose): relaxation, euphoria, delirium, loss of motor function etc.
It’s also not a coincidence that while the effective dosage of most psychoactive drugs is in the milligram range or lower, many grams of ethanol must be consumed before drunkenness occurs. A line of cocaine might be 50 mg, where as a glass of wine contains about 14 g (14,000 mg!) of ethanol. Further, there is an inverse correlation between the hydrophobicity of a solvent (and therefore it’s ability permeabilise membranes) and the dose needed for psychoactive effects. For example, propanol is several times more potent that ethanol.
This leads me to conclude that ethanol and other solvents work by altering the physical properties of the membranes rather than interacting with any receptors. Or if they do interact with receptors, then the effect is caused by altering the function of the receptor on a physical level rather than specific binding and activation/blocking/regulation that we observe with other drugs.
The reason why we drink ethanol and not other solvents is because most other solvents are toxic for reasons unrelated to their psychoactive effects. Methanol causes specific toxicity to the optical nerve and ethylene glycol causes liver failure because of its downstream metabolites.*
*Edit: Methanol also cases toxicity due to downstream metabolites
I wonder if this applies to ether, though. I'm not sure what kind of dose you get through a nice ol' huff of the stuff, but it surely can't be too high...?
It feels way, way better/different* from ethanol (or the higher alcohols, in my limited experimentation with them), too... just IME, heh. If only it lasted longer.
*[Not to dispute that its effects are broadly in the same category, though. It's just much less "toxic" feeling, to me, and stronger — perhaps, as you hypothesize, due to the difference in required dose.]
Ether (LogP 1.05) is much more hydrophobic than ethanol (LogP 0.06), and 1-propanol (LogP 0.56. But not quite as hydrophobic as 1-butanol (Log P 1.12). So ether having a lower active dose than ethanol and/or having stronger effects would fit the hypothesis.
But you're right: At higher doses ether has effects that ethanol doesn't such as dissociation and hallucinations. Its been said that ethanol interacts with GABA and ether interacts with NMDA, so maybe the effects they have in common are due to permeabilization while their unique effects are due to their interactions with specific receptors.
Alcohol was present (via naturally fermenting fruit) in the ancestral environment - if we were as sensitive to it as we are to most drugs, that would have been quite deadly. So evolved defenses seems like a good explanation for alcohol dosage that doesn't require it to have a different mechanism of action.
This is a really interesting point so I did some back of envelope math:
Apparently a very ripe banana contains 0.4 % ethanol. A banana has 1 kcal per gram, so assuming our ancestors ate a 2000 kcal diet of only very ripe bananas that’s 2000*0.004 = 8 g of ethanol per day. If ethanol was originally as potent as cocaine for humans, then I can defiantly believe that we’d evolve to be less effected by it. Of course our ancestors didn’t eat 2 kg of extra ripe bananas a day, but even if they consumed 10 % as much fruit with half the ethanol content that would still be 400 mg, which is a large amount of substance crossing the blood brain barrier.
Off the top of my head, I can’t think of any other foreign BBB penetrating chemical, encountered in the EAA, that our ancestors would have been exposed to in such large quantities.
On the other hand, perhaps our evolved tolerance to alcohol occurs in the form of membrane adaptations rather than receptor adaptations: https://pubmed.ncbi.nlm.nih.gov/3526990/
My understanding is that it's pretty widely accepted that human tolerance to alcohol is due to a mutation to Alcohol Dehydrogenase (the enzyme that metabolizes alcohol) which makes it more efficient and significantly reduces its toxicity.
Multiple mechanisms are likely. Alcohol Dehydrogenase decreases the amount of alcohol in the system, and membrane and/or receptor adaptions reduce the sensitivity to whats left.
What is the operational definition of "solvent" here, though? There's a big physical chemical difference between ethanol and diethyl ether, and again between water and THF.
I'm using "solvent" here to mean the set of small, usually volatile, organic molecules which are miscible with membrane lipids. Methanol, ethanol, ethylene glycol, propanol, butanol, propylene glycol, acetone, DMSO, diethyl ether, THF, dichloromethane, ethyl acetate, (potentially) glycerol, and a wide range of hydrocarbons. All of these can disrupt cell membranes at low concentrations, incensing permeability.
I dunno, that seems pretty broad, perhaps almost to the point of uselessness. The range of small molecules that can infiltrate a lipid bilayer is almost infinite. You probably need a definition which is independent of their effect on cognition, rooted in their physical or chemical properties, to avoid the circularity in saying "I mean those molecules that can cross the membrane and also make you feel whacked" -- in order to more seriously evaluate the general hypothesis.
Propranolol was a very effective performance enhancing drug for me while playing Starcraft 2 and I wonder if that had anything to do with its membrane stabilizing effect.
Regarding alcohol, I've read some very fun studies where people were given placebo alcohol in a party setting. Turns out, most of the social effects of alcohol (apart from dizziness and passing out) are essentially placebo effect.
Seriously. I usually drank alone, back when I drank, and the experience wasn't substantially different. The effects of alcohol are significant and I very much doubt that "the dizziness and passing out" can be separated from the "social effects" — the infamous quality of benzos and alcohol both to impair judgment in the "haha fuck it watch this you guys" way also argues against this.
I think the OP's formulation is a misinterpretation of these studies, though. It's not "people acted drunk even with fake alcohol, *therefore its 'social effects' are placebo*", but rather, if we trust these studies at all, something more like "people can be placebo'd into mimicking the effects they're expecting from experience" (i.e. *effects which are otherwise quite real*).
Definitely have seen this in action before though. I'm not going to claim that it's all placebo effect, but it can be a really strong one. I remember one night a friend of mine met a blind date at a bar with a group of us, and it was clear she was only 18 or 19 and had 'forgot her ID'. She tried flirting with the bartender to get served anyway, and he suggested pineapple upside-down shots, then winked at the rest of us secretly as he walked away. I watched him make the completely non-alcoholic shots out of pure pineapple juice with a bit of Grenadine, and proceed to serve a dozen rounds of them, and the girls got absolutely 'hammered', while the rest of us just tried not to laugh too hard at them. At the end of the night, I think he charged us $12 for all the shots, and we tipped him probably 3 times that for the laughs, and my friend never called that girl back again.
The infamous propensity of writers to drink undermines that idea for me. It's one thing to imagine getting a fake buzz off a party atmosphere, it's another when the 'social effects' play out in solitude, between you and a tyrannous blank page.
I think the real effects are: reducing anxiety, dizziness, passing out. (Writers drink to reduce their anxiety.)
But for things like obnoxious behavior, placebo alcohol is enough. I guess the exact mechanism is like this:
People have all kinds of annoying tendencies that they usually control, because they are afraid of punishment. Once drunk, the anxiety reduces, so they actually do the annoying thing. As a consequence, everyone learns that "drunk people do annoying things", so the social punishment for being annoying while drunk is smaller than the social punishment for being annoying while sober. (Though you might get a separate punishment for getting drunk. But this does not happen if everyone gets drunk at the same time.)
Knowing that, people who start drinking know that if they start doing annoying things now, they will be less punished. This works with both real alcohol and placebo alcohol. You only have to believe that other people believe that you are drunk.
That squares with my observations, yeah. In Japan, where sober social norms can still be quite strait-laced, drinking to permit free self-expression is practically codified. And, of course, a notable subset of 'annoying things' are confessions of affection, which can be written off as the booze talking if rejected or treated seriously if accepted.
On the other hand, I once had non-alcoholic wine that tasted almost exactly like normal wine, and felt like I was getting slightly drunk from it. It was kind of like my brain had such a strong expectation of the taste of wine causing drunkness, that it was enough to trigger some of the effects of actual alcohol.
Something kind of similar can happen with drug users: if they take the drug in a familiar setting, their brain knows to expect the effects of the drug and triggers physiological effects that protect against the drug's effect. If the user then takes their normal dose somewhere where they don't usually use drugs, that may cause an overdose since the location-drug conditioning didn't cause those anticipatory responses and their tolerance was lower. (Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1196296/ )
Though it's unclear to me why the location-drug expectation *decreases* the effect of the drug, while the taste-alcohol expectation *increased* the effect of alcohol (to the point of creating an effect where no alcohol was present). Maybe some of what I experienced as slight drunkeness was actually my body triggering anticipatory responses *against* being drunk, which I've learned to interpret drunkeness because they normally always happen when I'm just getting drunk?
Lately, I've been drinking mostly non-alcoholic beer, because I've gotten more sensitive to alcohol. On the label, it's <0.5% alcohol.
Without hyperbole, I can feel it. Not strongly, but it feels perhaps half as strong as a normal beer when finished. Potentially usefully, it's often types like IPAs, which have strong hops flavors, so there's a lot for me to be anchored on.
Yet, I know it's not real in the moment. It's not like I accidentally grabbed a non-alcoholic beer and realized it later. The first time I noticed it, I went aside and focused closely on the body sensations. Slight dizziness, slight euphoria, slight blurriness.
So, there's must be a lot going on. It's reasonable that part of my response is due to my increased alcohol sensitivity (easier to generate the effect internally, perhaps?).
"Someday we will find a selective α5 blocker, gain perfect memory, and storm the gates of Heaven."
I wonder whether anyone's ever checked the handful of hyperthymesiacs we've had for some abnormality of that subunit. There's evidence for anatomical changes in regions of their brains implicated in autobiographical memory and especially for overall better connectivity between the regions (10.1080/13554794.2011.654225, 10.1016/j.nlm.2012.05.002, 10.1037/neu0000410) but what if these were adaptations rather than causes?
Sort of like the result of a built-in Anki deck from hell: being 'forced' to long-term memorise things because they keep obsessively cycling into short term memory.
Deciphering the many different subunits comprising GABA receptors is crucial for understanding basic mechanisms of GABAergic inhibition, and for developing effective new drugs. However, the notion that specific receptors map directly onto specific brain functions is a hypothesis that is unreliable and often incorrect.
Oh they were totally fake manufactured nonsense from the start, but good for a laugh. A bit like The Darkness later on, who were a joke band that got taken seriously for five minutes.
The paucity of actually robust knowledge of what exactly is going on is stunning. We are totally in infancy of understanding basic functions and the complexity.
I find the idea of trying to brain hack basically akin to alchemy. A little bit of knowledge and hubris is dangerous. How this could possible fit into a rationalist program; I am not seeing it.
I find the report of trying doses of baikal skullcap disturbing. It conjures up Russian roulette and the case of David Hahn, a boy scout in the 90s who thought he could build a nuclear reactor in his backyard.
Or maybe let's give junior high school kids CRISPR technology and see what they come up with.
"The first principle is that you must not fool yourself and you are the easiest person to fool." ~ Richard P. Feynman
Life really is not short. Seven or eight decades on average.
Shouldn't risk taking is always be in proportion to benefits?
As to personally agency, I of the thought that we are autonomous trustees of ourselves. A trustee controls something as a fiduciary for the beneficiary. The beneficiary of our self is not just ourself but also all of humanity. We have a duty not only to preserve our self for our self but also for our ability to do good for others.
Agree. We still understand so little about psychopharmacology that brain hacks are risky business. I prefer substances with a track record of many generations. Treating life-threatening disease is something else, of course.
I feel like this post should come w/ a codicil advising extreme caution when it comes to GABAergic drug/supplement use. Basically two classes of drugs will kill you on withdrawal: alcohol and benzos. Compensatory down-regulation and de-sensitization of specific GABA(a) receptor subunits is comparatively quick and long-lasting. That is also somewhat true with the non-ionotropic GABA(b) receptor, so messing around w/ stuff like phenibut/GHB/baclofen long-term really isn't advisable.
GABA-A receptor modulation is one area where I have comparative expertise, and a few notes I'd add are:
-The δ subunit-containing receptors are mostly extrasynaptic and modulate tonic inhibition (the baseline propensity towards excitability) and the subunits 1, 2, 3 and 5 (though a5 are more often associated with tonic inhibition) are mostly synaptic and mediate phasic (acute) inhibition.
-Ethanol is generally active at the a4/delta-containing subunit as both an agonist and positive allosteric modulator (PAM). Chronic use can make these neurons (mostly located in thalamic tracts) more prone to excitation, w/ all the attendant problems like insomnia, anxiety, &, most notably, issues w/ smooth pursuit eye movements and a shift towards saccadic vision. Curiously, some inhibitory neuroactive steroids like allopregnanolone also act as PAMs at this specific subunit type (mostly a4b3delta). In a weird way, chronic alcohol use could theoretically improve memory consolidation, but that is probably not the case given its toxic metabolites, broad and systemic effects, and pro-inflammatory nature.
-Comments on the a5 subunit seem confused. Blocking any GABA-A subunit type would probably engender hypermnesic effects but also raise the potential for excitotoxicity b/c you are effectively altering the intracellular chloride- concentration. A5 subunits are mostly located extrasynaptically (tonic inhibition) in the hippocampus, so that is why they might be especially relevant for memory.
It definitely puts a different filter on notions of what I would do in an apocalypse when the answer is 'become incapacitated in 3 days and die one way or another without a clonazepam supply'
Two things that weren’t mentioned here: at the neurobiological level, a1 and a2 are localized to synapses, so they contribute to what we call “phasic inhibition” — i.e. they dampen acute bursts of activity. a4 and a5 are extrasynaptic, so they provide a kind of low-grade, constant level of “tonic inhibition”, probably by catching GABA that spills over from synapses. I have no idea how this translates to their psychiatric effects, as I am a lowly biologist, sorry.
Also, I’m surprised you didn’t mention that most GABA drugs bind not to a single subunit, but to the interface of two subunits, usually two different ones. For instance, diazepam has to bind at an alpha-gamma interface. This probably contributes to some sort of combinatorial code for the effects of different drugs (depending on which subunit combos they bind to and where in the nervous system those receptors are located). This is almost certainly why selective modulation of a single subunit type never seems to work as well as expected.
That is interesting and thanks for the information, that helps me understand better why things work differently when they're expected to be the same.
Biology is not a nice, easy, simple field like physics, where your sub-atomic particles do what they're told and behave as they're supposed to, and if they don't you know you have something new to discover. In biology, everything does as it damn well pleases 😁
I'm trying to find an Phenibut equivalent that I can take more often (really scared about tolerance/addiction), and I've found that taurine seems to work great (though less potent and empathogenic). What I'm wondering is if cycling between taurine and phenibut will help with phenibut tolerance, or will only make it worse. It seems that they're both GABA receptor agonists, but Phenibut seems to be a GABA-b agonist, while Taurine seems to be a GABA-a agonist. I'm a big noob so I don't really know how this works.
This seems like something that can't be determined by knowledge about how these drugs work. You'll have to test it empirically. If you want to get an answer you can trust you'll need to take placebos some of the time.
In the spirit of "Fictional Drugs Banned by the FDA" I propose that TPA-023 dropped off the face of the earth because in early human trials someone lied on their screening questionnaire and took it at the same time as Ambien. In the investigation of their death and the complete trashing of their apartment it was discovered that if you combine these medications it makes the hallucinatory walruses real! The entire incident and the drug itself were immediately classified by the military so that they could investigate the combat potential of a drug that physically manifests hallucinations.
Interesting that Scott got no effect from Scutellaria baicalensis. Should have tried S. lateriflora “Virginia Skullcap”.
I made a tea from just 600mg of fresh leaf of some S. lateriflora I grew and can attest to strong effects. Like getting my brain activity dial turned down to about 10%. Made it hard to read. Neither pleasant nor unpleasant. I could see how it helps in cases of panic or other extreme emotional state. Don’t understand how people find the effects desirable as a departure from ordinary consciousness however.
I had insomnia and anxiety issues about decade ago. My doctor prescribed Trazodone. I'm not sure what interaction it has with the GABA areas (if any), but it's been working beautifully for me all this time.
After reading this email, I felt more confused than enlightened. Here is some additional information that may clariify certain aspects of the topic. GABAergic neurons are mostly interneurons that release synaptic GABA onto postsynaptic neuronal GABA receptors. GABA receptors are ligand-gated ion channels that when activated permit a Cl- (chloride ion) to cross the cell membrane. Cl- currents are mostly inward (i.e. Cl- ions move from outside to inside the cell) and act in opposition to inward sodium (Na+), calcium (Ca+2) currents that are responsible for the action potentials (a transient change in membrane potential) that encodes neuronal signaling). Thus, GABA(a) agonists/positive allosteric modulators down-modulate neuronal signaling and have clinical manifestations as sedatives and hypnotics Conversely, GABA (a) antagonists/negative allosteric modulators up-modulate neuronal signaling and have clinical manifestations as pro-convulsants. As pointed out all GABA receptors are heteromeric pentamers, that share ~30-40% amino acid identity. There are six families of receptor subtypes, several of which have variants: α1- α6, β1-β6, γ1 –γ3, δ1, ε1, ρ1 – ρ3. As found in the brain the α1βγ2 receptor (ratio 2α1: 2β (mixed variants): 1γ2) is the most common receptor. Different receptor subtypes have different pharmacological and electrophysiological profiles. For example, the GABA binding site is located at the α:ß subunit interface, whereas the benzodiazepine binding site requires an α:γ subunit interface. By combining pharmacology, binding stoichometry and electrophysiological profiles, GABA subunit topologies can be predicted.
It was ignored because the owners didn't realize there was a market for sleep until Ambien came along, but then soon after they were perhaps spooked by the strange side effects of Ambien and didn't want to enter that market (summary from my hazy memory of the article).
Wikipedia states that it operates on GABA but in a way different than benzos or Z-drugs.
"These are baicalein and baicalin, flavanoids derived from the Baikal skullcap. I tried very high doses of both of these and can report that they had absolutely no effect on me whatsoever, sorry. I’m not sure how to update my credulity about their selective GABA modulation based on this experience."
You were taking the wrong variety? 😁 I had some vague memory of reading that skullcap was used medicinally, so I looked it up. Seemingly there are two varieties, American and Chinese (the Chinese is the Baikal skullcap version) and it's the *American* one that is used as a sedative and mood-booster:
"American skullcap (Scutellaria lateriflora) is a perennial herb native to North America. In bloom, the plant is covered in tiny, tubular blue flowers, although color can vary.
The leaves of American skullcap have been used in traditional herbal medicine as a sedative and to treat conditions like anxiety and convulsions. The plant was prized by Native Americans for its powerful medicinal properties.
Chinese skullcap (Scutellaria baicalensis) is native to several Asian countries, as well as Russia.
The dried roots of this plant have been used for centuries as a traditional Chinese medicine known as Huang Qin to treat diarrhea, insomnia, dysentery, high blood pressure, hemorrhaging, respiratory infections, and inflammation.
In Asia, Huang Qin is used in herbal remedies, such as Xiao Chai Hu Tang or Sho-saiko-to (SST), a popular formulation used to treat conditions like fevers, gastrointestinal issues, and liver disease.
May boost mood and reduce anxiety
American skullcap has been shown to boost mood and reduce symptoms of anxiety.
A study in 43 people found that those who received 1,050 mg of American skullcap daily for 2 weeks reported significant enhancements in mood compared to a placebo group.
It’s thought that American skullcap positively impacts mood and reduces anxiety by stimulating gamma-aminobutyric acid (GABA), a neurotransmitter that helps calm nerves.
Notably, this plant was used in traditional medicine practices as a sedative and treatment for conditions like insomnia and anxiety."
The site does warn that you shouldn't just go out and guzzle a handful of supplements, since there can be serious side-effects. So - Chinese for inflammation, American for anxiety!
I concur. The American or “Virginia” skullcap is the one used in TWM as an anxiolytic. I’ve grown and consumed it (once). It’s definitely active, though I don’t know enough about the subjective effects of GABAergics to guess at the receptor-level activity.
Thanks for the hint. After reading that post and the comments I'd like to add that opiod addicts with experiences of benzodiazepine versus pregabaline withdrawals told me that getting off pregabaline was even worse. There's a lot of pregabaline abuse among addicts, partly because it´s comparatively easy to get prescriptions for it. Oh, and there seems to be a lot of unmetabolized pregabaline in the urine of users, which probably increases the risk of drowning for gutter rats.
The pharmacology is confusing to me, but in a practical sense, I think the answer is that it's a drug to be used just as cautiously as benzos. Long term usage seems to cause similar problems, like deteriorating memory. Withdrawal from gabapentin and lyrica is almost as unpleasant as from benzos. I'm not sure if gabapentin has the same kindling issues with repeated withdrawals. It's possibly worth the downsides for people with severe nerve pain, but it's probably a bad idea to give it out for all these off label uses like anxiety.
I think we're perhaps just on a long cycle of re-inventing similar sedatives. From alcohol to barbiturates to benzodiazepines to z-drugs to gabapentinoids. At each turn, the new drug is announced to be safer, less harmful, less addictive. Then, people notice that they all have similar problems with addiction, dependence, and withdrawal.
Valium used to be the #1 prescribed drug in America (in the 60's and 70's, I think). Last I checked, Gabapentin is somewhere in the top 10.
I worry about what will happen to all those users, long term. I especially worry what will happen if the medical establishment suddenly decide it's unsafe and doctors all cut their patients off or rapidly taper them.
Vicodin had a brief stint as the #1 prescribed drug in America (early 2000's, IIRC). That didn't end well, both in terms of overdoses and in terms of addicted users that moved on to worse drugs.
I was prescribed gabapentin for nerve pain in my arm, but the warning leaflet with the drug scared me so badly that I looked it up and found that it was risky, and especially risky for someone with a pre-existing condition that I had (I can't blame my doctor for this, it was a 2019 study that finally came down on the side of "yeah, don't take this if you suffer from that").
So I decided that "you can't take it for immediate pain relief unlike other medications, you have to build up a level in your system first, and you *also* have to build up slowly - or have bad side effects; remain on it - or have bad side effects; and if coming off have to taper off slowly - or have bad side effects" was not worth the candle, and I'd prefer to risk my liver by taking maximum doses of OTC pain relievers (I was lucky enough to obtain via a friend some co-codamol which helped with nighttime pain until the problem resolved itself; I think the nerve probably died or something).
So I can't tell you what gabapentin is like, because the DANGER DANGER WILL ROBINSON warnings scared me off even trying it 😀
I've only taken gabapentin briefly, but I got bad side effects on it and then withdrawal symptoms after only a week of use. I would sooner risk taking an opiate than take it again. And I'd much sooner risk a bit of liver damage from acetaminophen.
It always seemed strange to me that acetaminophen has some centrally acting painkilling effect without a clear mechanism of action. Some newer research suggests that one of its metabolites acts on cannabinoid receptors:
Phenibut makes me feel quite drunk, and Wikipedia says it's a GABA-B receptor agonist. I wonder if anyone has checked if alcohol affects GABA-B? The Wikipedia page for that doesn't contain GABA-B anywhere on it. Also interesting is that phenibut comes with a pleasant 'afterglow' effect the next day, which alcohol notably does not.
If anyone has insomnia issues, I recommend trying oleamide. That stuff absolutely knocks me out, has a stronger effect than Ambien, and does not cause headaches next day. I use it sparingly, only when I need it. I don't know how well it work in general. Here are two interesting papers about it:
Have you tried nervous system management through targeted breathwork? You can activate your parasympathetic nervous system quite easily when you know how. It’s highly effective, and has no side effects 👌
Feel free to check my page out, I’m a breath work facilitator and love to write about it, along with other science backed natural approaches. Have a cracking weekend 👍
I keep wanting something like, a 'users manual for my brain' that says, basically:
- when you feel X
- it is caused by systems A, B, C
- the following are things you can do to reduce/increase the extent of feeling X
Does such a thing exist? Posts like this one make me think... we barely understand these 'brain' things, and mostly know the aggregate statistical results of poking them in various places and with various chemicals, and then we kinda how how things are connected, but not really how it all works.
"we barely understand these 'brain' things, ...but not really how it all works."
To my understanding, this is pretty much how things stand at the moment. Like everything else, it starts off with "with our increasing knowledge and technical sophistication, it'll soon be easy for us to figure out these systems!", leads into "we have now got lots of wonderful new effective drugs that have specific effects on specific problems, total understanding is just around the corner!", skids over "uh, turns out that there are also a lot of gaps in how these drugs work anyway" and crashes on "oh hell nobody knows nothing!" because the more you know, the more you discover that you don't know.
The sedative effect on a1 increases dopamine levels in the mesolimbic dopamine system, which is basically the definition of an addictive drug. Anecdotally, I've talked to a few former heroin addicts who subsequently got hooked on high doses of ambien, perhaps because it's also a fast acting sedative that's rapidly calming and rewarding in a similar way.
The first a2, a3 specific benzo (MRK-409) still had weak activity at a1, which might still be enough to cause the effect. TPA023 seemed more promising because it was an agonist of the a2 and a3 receptors but an antagonist of the a1 receptors. So it should have been a non-sedating, non-addictive anxiolytic. I have no idea what went wrong in the trials.
That said, I'm sure TPA023 would still cause tolerance and dependence, since most psych meds do. It's not just an issue of dopamine, there's also the basic principle of homeostasis -- provide too much of one chemical and the body/brain gradually downregulates the receptors for that. Many different drugs give unpleasant withdrawal, whether that's benzos or SSRI's or beta blockers or zyrtec.
Withdrawal is abnormally bad for benzos, for some reason, but that's not a function of the psychological addictiveness, it's probably more because GABA/glutamate balance is so important to normal brain function. I suspect that quitting TPA023 wouldn't be as bad as normal benzo withdrawal, but you'd probably have weeks or months of horrific rebound anxiety.
Zopiclone/Lunesta do seem to be more benzo-like than the other Z drugs. At least, the withdrawal from them is often benzo level bad, while the withdrawal from ambien usually is not. That might have something to do with the GABA receptor subunits, but it's also just a function of the half life of the drug -- zopiclone has a half-life of 4-6 hours, ambien is closer to 2 hours. So if you take lunesta nightly, you're stimulating the gaba receptors somewhat, at all times. If you take ambien nightly, the receptors return to baseline for most of the day. Halcion is the shortest acting benzodiazepine, with a half-life similar to ambien. The Ashton manual for benzodiazepine withdrawal says that one also has lower dependence than most, and can generally be quit without tapering, unlike the longer acting benzos.
>there are botanicals claiming to have α2- and α3- selective GABA modulation. These are baicalein and baicalin, flavanoids derived from the Baikal skullcap. I tried very high doses of both of these and can report that they had absolutely no effect on me whatsoever, sorry. I’m not sure how to update my credulity about their selective GABA modulation based on this experience.
Flavonoids are notorious for having poor bioavailability as well as a tendency to nonspecifically mess up biochemical assays, so I tend to be skeptical of any research involving them.
The effect on a5 makes sense. For months I was taking a now-out-of-stock GABA-melatonin-l-theanine-CBD pill. During that time, I suddenly felt that my memory was the greatest it has ever been (32-year-old male); it was shocking to me how smooth and automatic my recall was. When I ran out of the pill, I switched to a CBD-melatonin pill, and soon my memory went back to its baseline (or became worse) — to the point of making me feel brain-fogged and frustrated. GABA gave me what felt like a clean 5.5-7 pt IQ increase.
I take Escitalopram (SSRI) since two years now, prescribed for helping me getting to sleep more easily. It improved a lot of my decades long personal issues like angst, endless thought cycles, bad self confidence etc. Then a year ago because of a very toxic work enviroent I started to take Zolpidem for getting even a little sleep at all. Initially I took the full prescribed 10mg dose which played havoc with my mood and temper the next days. I got anxious, my brain worked pretty bad, I was searching a lot for words or concepts, got extremely impatient and showed a lot of nerves the following day. I reduced the dose step by step to 2.5mg which now is working extremely well for me.
I'm not sure if I am a normal guy or an ADHD or an Autistic or a hyper sensible person, but the combination of the above things did virtually change my life.
The experiment is not exactly a RCT and there is quite some coffeeine and ethanol at play as well but just saying...
Because the first attempt at an explanation is always wrong, the second is usually wrong, and the third is hopelessly complex ;)
It's not really that simple either. The real fact of the matter is that we don't understand neurotransmitter systems, or neuroscience in general. It's an incredibly 'young' field, where we haven't even formulated a standard model for many of the most observable features of psychiatry. For instance, sleep disorders; narcolepsy is incredibly obvious, repeatable, and severe, but we don't have a consensus model on what exactly is going on in the brain for it.
For that matter, take sleep itself. We all pass out and are mostly unresponsive for 1/3 of the time, and experience multiple hallucinations every day (most of which we never remember), and we do not understand this phenomenon. We know TONS of facts about sleep, but we just don't have a gears-level understanding of what changes in what cells to make sleep happen or not happen, and we have very little understanding of the changes it makes in our brains.
Asking 'why' in psychiatry is mostly useless because it's asking for an answer from a field that just isn't able to model the behavior you're asking about at all.
FWIW, some developers of AIs have started using "sleep" states to allow the AIs to consolidate memories that deal with more than one context. Not sure of the details, and people aren't AIs, but it's suggestive.
In response to the last paragraph, I would say that is because it takes a mutual understanding of both neurochemistry and psychology to design a model that can answer these questions. You can eat all your nutrients gaining adequate cofactors and amino acids to synthesize the ideal amount of neurochemicals, but you're life's shit you will probably still feel shitty. Flip side if you're life's amazing, you're rich and
Have all of the necessities but your brain chemistry is unbalanced you might as well burn the money ( Assuming it's not something that can be fixed by blowing large amounts of cash, not talking about luxury clothing and a trip on a luxury yacht cause then you will be stranded on an island and no money,, you may be able to spend money to help increase happiness, but you cant buy it)
I'd imagine it's because often "why" is either nightmarishly unclear and complex, and/or knowing "why" doesn't immediately suggest anything one could do differently — i.e., knowing why benzodiazepines and Z-drugs have slightly different effects might not provide any clear way to produce an improvement on either; you're still going to be using benzodiazepines and Z-drugs just how you did before.
It might interest you to know that pyrazolam is an abandoned benzo from the 1970's that recently resurfaced as a grey market designer drug. It is supposedly a2 a3 selective and experience reports confirm that it is primarily anxiolytic with minimal sedation.
Why did they abandon it?
No idea, Wikipedia says it was originally developed in the 70s. Reading it again I think it sounds like it just never got picked up moreso than it was abandoned. I think a research team synthesized a ton of benzofiazepene derivatives, confirmed basic properties and then some of them got picked up by pharmaceutical companies for further development and some didn't. This one didn't so it was never technically scheduled so it can be sold semi-legally online. There are so many structural combinations you can do on the benzodiazepene structure that all seem to work to create active drugs so there are a lot of combinations that work just as well as the pharmaceutical ones but fall in this category
After trying many anxiolytic agents, attempting to find 'the holy grail' that has as little sleepiness and cognitive impairment as possible, I can confidently say that pyrazolam is just that.
There is a study out there analyzing online experience reports on designer benzodiazepines and trying to quantify the magnitude of their specific effects. Compared to all the others, pyrazolam was maxed out on anxiolysis and near-zero on other typical effects of it's broader class. Can't say that the methodology of this study was as rigurous as RCTs, but it does seem to represent these experiences 'accurate enough'.
One small caveat: due to it's purely-anxiolytic properties, some people might not feel much & redose. With a seemingly lower threshold dose for blacking out, this is something worth noting.
All that being said, it really is a shame that this has not been developed into a commercially available prescription drug.
Later edit: There's another anxiolytic that could meet the criteria. Chemically it is a benzodiazepine but has no GABAergic mechanism of action. It's called tofisopam but it doesn't have the same (subjective) effectiveness as benzos, but that probably means it doesn't have the typical drawbacks either. It's also slightly nootropic according to at least one study. I know that's not enough, but at least it's good evidence of it at least not impairing cognition.
Can you provide a link / name for this study? I tried several of these grey-market benzos and I... didn't really feel much difference between them, but I'm still curious how they theoretically rank on the scale.
Sure!
https://doi.org/10.1177/0269881119901096
Paywalled but easily found on SciHub / LibGen.
How does it compare to classical benzos when it comes to dependence and tolerance with chronic use?
You mean the pyrazolam or the tofisopam?
I don't have enough personal experience to cover both, but imo pyrazolam still has some dependence issues and I assume tolerance still develops. I did hear that quitting it is easy in terms of withdrawal symptoms, which probably suggests less 'physical' dependence.
In a similar vein, I'm curious about (deu-)etifoxine, which seems to act selectively on b2- and b3-containing gaba receptor complexes.
etifoxine - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293506/
deu-etifoxine (deuterated) - https://atai.life/programs/deu-etifoxine/
Thanks a lot for the links — very interesting.
Baikal Skullcap is distantly related to Lavender, which has some better-researched anxiolytic effects. I bought some lavender but haven't got around to trying it, because my ashwagandha works so well (the Himalaya brand stuff from vitamin shoppe).
Scott has mentioned lavender extract, previously. I purchased the Natures Way, Calmaid that he referred to. I believe he said it was used to treat depression? Lavender has some interaction with the serontonergic system as well. (I don't know the details and IIRC, some serontonergic effects can be GABA mediated.) It's certainly interesting, though I don't have anxiety that needs to be treated so I don't usually rely on it.
There are about 200 different species of baikal skullcap.
And related toxicity. Don't play Russian roulette.
I would not eat any organism with a name that ominous.
Oh that reminds me, how did our people taking lavender get on with it? There were mentions of the "lavender burps" but did anyone stick with it long-term? Any results?
I tried it for 6 weeks to no clear qualitative effect, but I did not use an anxiety scoring metric to track changes. I did have lavender burps, which I found fairly enjoyable (unlike my partner).
lavender burps should be the name of a band
Tried it for two months, didn't notice any change on my anxiety stats (I rate it on a scale from 0 to 10, where 0 is not anxious at all and 10 is very anxious. The value I take for each day is the worst instance of anxiety during the day).
A quick perusal of the wikipedia page for TPA-023 (https://en.wikipedia.org/wiki/TPA-023) suggests development was stopped 'due to preclinical toxicity (cataract) in long term dosing studies'. There are two references on the wiki page - one has no mention of cataracts I could find, and the other one, 'The rise of a new GABA pharmacology' published in 2011, (scihub link: https://sci-hub.hkvisa.net/10.1016/j.neuropharm.2010.10.020) also mentions cataracts on page 4, but also without a reference as far as I can see.
Does anyone have more information about this? It sounds like an interesting molecule.
Specifically - what was the incidence rate and severity of the cataract issue? A link to some reputable looking source would also be nice. With the information I could find online it is difficult to understand why it is no longer be pursued as a possible anxiolytic. Presumably the cataract issue was deemed too serious, but without actual data I can't assess whether that was a reasonable conclusion.
Following thread
Some speculation regarding the psychoactive effects of alcohol: I don’t know anything about the specific interactions between ethanol and GABA. But I do know that ethanol increases the permeability of cell membranes. Neurons depend on maintaining particular intercellular/extracellular ion ratios at any given point in their firing cycle, and so anything which allows ions to cross the cell membrane independent of the cell’s ion channels is likely going to effect the cell’s firing threshold.
This effect on membrane permeability is not specific to ethanol; Most organic solvents such as methanol, propanol, ethylene glycol, and diethyl ether do this. Perhaps this is why all solvents have similar psychoactive effects (depending on dose): relaxation, euphoria, delirium, loss of motor function etc.
It’s also not a coincidence that while the effective dosage of most psychoactive drugs is in the milligram range or lower, many grams of ethanol must be consumed before drunkenness occurs. A line of cocaine might be 50 mg, where as a glass of wine contains about 14 g (14,000 mg!) of ethanol. Further, there is an inverse correlation between the hydrophobicity of a solvent (and therefore it’s ability permeabilise membranes) and the dose needed for psychoactive effects. For example, propanol is several times more potent that ethanol.
This leads me to conclude that ethanol and other solvents work by altering the physical properties of the membranes rather than interacting with any receptors. Or if they do interact with receptors, then the effect is caused by altering the function of the receptor on a physical level rather than specific binding and activation/blocking/regulation that we observe with other drugs.
The reason why we drink ethanol and not other solvents is because most other solvents are toxic for reasons unrelated to their psychoactive effects. Methanol causes specific toxicity to the optical nerve and ethylene glycol causes liver failure because of its downstream metabolites.*
*Edit: Methanol also cases toxicity due to downstream metabolites
Methanol's toxicity is due to metabolites too, specifically formic acid.
Interesting! That actually makes a lot more sense.
I wonder if this applies to ether, though. I'm not sure what kind of dose you get through a nice ol' huff of the stuff, but it surely can't be too high...?
It feels way, way better/different* from ethanol (or the higher alcohols, in my limited experimentation with them), too... just IME, heh. If only it lasted longer.
*[Not to dispute that its effects are broadly in the same category, though. It's just much less "toxic" feeling, to me, and stronger — perhaps, as you hypothesize, due to the difference in required dose.]
Ether (LogP 1.05) is much more hydrophobic than ethanol (LogP 0.06), and 1-propanol (LogP 0.56. But not quite as hydrophobic as 1-butanol (Log P 1.12). So ether having a lower active dose than ethanol and/or having stronger effects would fit the hypothesis.
There's a chart here that shows the dose relationship between anesthetics (such as ether) and hydrophobicity: https://en.wikipedia.org/wiki/Nitrogen_narcosis#/media/File:The_Meyer-Overton_correlation.png
But you're right: At higher doses ether has effects that ethanol doesn't such as dissociation and hallucinations. Its been said that ethanol interacts with GABA and ether interacts with NMDA, so maybe the effects they have in common are due to permeabilization while their unique effects are due to their interactions with specific receptors.
Alcohol was present (via naturally fermenting fruit) in the ancestral environment - if we were as sensitive to it as we are to most drugs, that would have been quite deadly. So evolved defenses seems like a good explanation for alcohol dosage that doesn't require it to have a different mechanism of action.
This is a really interesting point so I did some back of envelope math:
Apparently a very ripe banana contains 0.4 % ethanol. A banana has 1 kcal per gram, so assuming our ancestors ate a 2000 kcal diet of only very ripe bananas that’s 2000*0.004 = 8 g of ethanol per day. If ethanol was originally as potent as cocaine for humans, then I can defiantly believe that we’d evolve to be less effected by it. Of course our ancestors didn’t eat 2 kg of extra ripe bananas a day, but even if they consumed 10 % as much fruit with half the ethanol content that would still be 400 mg, which is a large amount of substance crossing the blood brain barrier.
Off the top of my head, I can’t think of any other foreign BBB penetrating chemical, encountered in the EAA, that our ancestors would have been exposed to in such large quantities.
On the other hand, perhaps our evolved tolerance to alcohol occurs in the form of membrane adaptations rather than receptor adaptations: https://pubmed.ncbi.nlm.nih.gov/3526990/
My understanding is that it's pretty widely accepted that human tolerance to alcohol is due to a mutation to Alcohol Dehydrogenase (the enzyme that metabolizes alcohol) which makes it more efficient and significantly reduces its toxicity.
https://en.wikipedia.org/wiki/Alcohol_dehydrogenase
Multiple mechanisms are likely. Alcohol Dehydrogenase decreases the amount of alcohol in the system, and membrane and/or receptor adaptions reduce the sensitivity to whats left.
Apparently the gut microbiome produces a few g of ethanol per day.
What is the operational definition of "solvent" here, though? There's a big physical chemical difference between ethanol and diethyl ether, and again between water and THF.
I'm using "solvent" here to mean the set of small, usually volatile, organic molecules which are miscible with membrane lipids. Methanol, ethanol, ethylene glycol, propanol, butanol, propylene glycol, acetone, DMSO, diethyl ether, THF, dichloromethane, ethyl acetate, (potentially) glycerol, and a wide range of hydrocarbons. All of these can disrupt cell membranes at low concentrations, incensing permeability.
I dunno, that seems pretty broad, perhaps almost to the point of uselessness. The range of small molecules that can infiltrate a lipid bilayer is almost infinite. You probably need a definition which is independent of their effect on cognition, rooted in their physical or chemical properties, to avoid the circularity in saying "I mean those molecules that can cross the membrane and also make you feel whacked" -- in order to more seriously evaluate the general hypothesis.
Most solvents are 1. liquid at room temperature 2. have 1-6 carbon atoms.
Propranolol was a very effective performance enhancing drug for me while playing Starcraft 2 and I wonder if that had anything to do with its membrane stabilizing effect.
"Methanol causes specific toxicity to the optical nerve"
Is this the reason people sometimes went blind after drinking illegal hooch during Prohibition?
Regarding alcohol, I've read some very fun studies where people were given placebo alcohol in a party setting. Turns out, most of the social effects of alcohol (apart from dizziness and passing out) are essentially placebo effect.
I would sooner believe that science is fake
Seriously. I usually drank alone, back when I drank, and the experience wasn't substantially different. The effects of alcohol are significant and I very much doubt that "the dizziness and passing out" can be separated from the "social effects" — the infamous quality of benzos and alcohol both to impair judgment in the "haha fuck it watch this you guys" way also argues against this.
I think the OP's formulation is a misinterpretation of these studies, though. It's not "people acted drunk even with fake alcohol, *therefore its 'social effects' are placebo*", but rather, if we trust these studies at all, something more like "people can be placebo'd into mimicking the effects they're expecting from experience" (i.e. *effects which are otherwise quite real*).
Definitely have seen this in action before though. I'm not going to claim that it's all placebo effect, but it can be a really strong one. I remember one night a friend of mine met a blind date at a bar with a group of us, and it was clear she was only 18 or 19 and had 'forgot her ID'. She tried flirting with the bartender to get served anyway, and he suggested pineapple upside-down shots, then winked at the rest of us secretly as he walked away. I watched him make the completely non-alcoholic shots out of pure pineapple juice with a bit of Grenadine, and proceed to serve a dozen rounds of them, and the girls got absolutely 'hammered', while the rest of us just tried not to laugh too hard at them. At the end of the night, I think he charged us $12 for all the shots, and we tipped him probably 3 times that for the laughs, and my friend never called that girl back again.
The infamous propensity of writers to drink undermines that idea for me. It's one thing to imagine getting a fake buzz off a party atmosphere, it's another when the 'social effects' play out in solitude, between you and a tyrannous blank page.
I think the real effects are: reducing anxiety, dizziness, passing out. (Writers drink to reduce their anxiety.)
But for things like obnoxious behavior, placebo alcohol is enough. I guess the exact mechanism is like this:
People have all kinds of annoying tendencies that they usually control, because they are afraid of punishment. Once drunk, the anxiety reduces, so they actually do the annoying thing. As a consequence, everyone learns that "drunk people do annoying things", so the social punishment for being annoying while drunk is smaller than the social punishment for being annoying while sober. (Though you might get a separate punishment for getting drunk. But this does not happen if everyone gets drunk at the same time.)
Knowing that, people who start drinking know that if they start doing annoying things now, they will be less punished. This works with both real alcohol and placebo alcohol. You only have to believe that other people believe that you are drunk.
That squares with my observations, yeah. In Japan, where sober social norms can still be quite strait-laced, drinking to permit free self-expression is practically codified. And, of course, a notable subset of 'annoying things' are confessions of affection, which can be written off as the booze talking if rejected or treated seriously if accepted.
But the real effects are real, all the same.
Weren't those studies done with mainly teens who plausibly were unfamiliar with the actual physical effects of ethanol?
I expect if you tried the same with a bunch of 50-year olds at a football party they'd figure out they weren't drinking real beer.
On the other hand, I once had non-alcoholic wine that tasted almost exactly like normal wine, and felt like I was getting slightly drunk from it. It was kind of like my brain had such a strong expectation of the taste of wine causing drunkness, that it was enough to trigger some of the effects of actual alcohol.
Something kind of similar can happen with drug users: if they take the drug in a familiar setting, their brain knows to expect the effects of the drug and triggers physiological effects that protect against the drug's effect. If the user then takes their normal dose somewhere where they don't usually use drugs, that may cause an overdose since the location-drug conditioning didn't cause those anticipatory responses and their tolerance was lower. (Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1196296/ )
Though it's unclear to me why the location-drug expectation *decreases* the effect of the drug, while the taste-alcohol expectation *increased* the effect of alcohol (to the point of creating an effect where no alcohol was present). Maybe some of what I experienced as slight drunkeness was actually my body triggering anticipatory responses *against* being drunk, which I've learned to interpret drunkeness because they normally always happen when I'm just getting drunk?
Lately, I've been drinking mostly non-alcoholic beer, because I've gotten more sensitive to alcohol. On the label, it's <0.5% alcohol.
Without hyperbole, I can feel it. Not strongly, but it feels perhaps half as strong as a normal beer when finished. Potentially usefully, it's often types like IPAs, which have strong hops flavors, so there's a lot for me to be anchored on.
Yet, I know it's not real in the moment. It's not like I accidentally grabbed a non-alcoholic beer and realized it later. The first time I noticed it, I went aside and focused closely on the body sensations. Slight dizziness, slight euphoria, slight blurriness.
So, there's must be a lot going on. It's reasonable that part of my response is due to my increased alcohol sensitivity (easier to generate the effect internally, perhaps?).
I can confirm that for me personally, the social effects of alcohol can be had without alcohol. I get the same party buzz even when I don’t drink.
I think part of it is being tired but not sleeping. The rest may be empathy since everyone else is drinking.
A mafia boss tells his goons "Slip a placebo into his drink, as a warning."
Can you link to the study? What are its limitations?
In general, studies with such a surprising result don't replicate or have methodological flaws.
"Someday we will find a selective α5 blocker, gain perfect memory, and storm the gates of Heaven."
I wonder whether anyone's ever checked the handful of hyperthymesiacs we've had for some abnormality of that subunit. There's evidence for anatomical changes in regions of their brains implicated in autobiographical memory and especially for overall better connectivity between the regions (10.1080/13554794.2011.654225, 10.1016/j.nlm.2012.05.002, 10.1037/neu0000410) but what if these were adaptations rather than causes?
Sort of like the result of a built-in Anki deck from hell: being 'forced' to long-term memorise things because they keep obsessively cycling into short term memory.
Deciphering the many different subunits comprising GABA receptors is crucial for understanding basic mechanisms of GABAergic inhibition, and for developing effective new drugs. However, the notion that specific receptors map directly onto specific brain functions is a hypothesis that is unreliable and often incorrect.
GABA GABA HEY!
Oh good, I'm not the only one who automatically thinks of The Ramones everytime GABA is mentioned!
Now Rock Lobster is playing in my head. Thanks a shit for mentioning the Ramones, you two.
I don't understand. Why triggers mentioning the Ramones a B52s song?
Brain convolutions.
And now you have *me* playing the B-52s in my head, which naturally led on to the Stray Cats.
Dang it, now the 90s will be on loop all night 😁 And for the last hurrah of the 80s, does anyone else remember Sigue Sigue Sputnik?
https://www.youtube.com/watch?v=_LKMT5d9iqo
Eh. I always thought Sigue Sigue Sputnik was a glam ripoff of the far better Art of Noise.
Oh they were totally fake manufactured nonsense from the start, but good for a laugh. A bit like The Darkness later on, who were a joke band that got taken seriously for five minutes.
Could be some of the a5 receptors make memory better, and some make it worse. There may be a5 receptor subtypes.
Or a5 receptors in one part of the brain make it better, and others make it worse.
Or it's involved in part of the memory pathway, so it keeps you from making new memories but helps you remember old ones. Or vice versa. Or something.
The paucity of actually robust knowledge of what exactly is going on is stunning. We are totally in infancy of understanding basic functions and the complexity.
I find the idea of trying to brain hack basically akin to alchemy. A little bit of knowledge and hubris is dangerous. How this could possible fit into a rationalist program; I am not seeing it.
I find the report of trying doses of baikal skullcap disturbing. It conjures up Russian roulette and the case of David Hahn, a boy scout in the 90s who thought he could build a nuclear reactor in his backyard.
Or maybe let's give junior high school kids CRISPR technology and see what they come up with.
"The first principle is that you must not fool yourself and you are the easiest person to fool." ~ Richard P. Feynman
Did you actually mean *lack* of hubris?
Good catch. Was typing fast. Have edited
Where is your sense of adventure? Life is short and our bodies are falling apart anyways. May as well take some agency and risk with it.
Life really is not short. Seven or eight decades on average.
Shouldn't risk taking is always be in proportion to benefits?
As to personally agency, I of the thought that we are autonomous trustees of ourselves. A trustee controls something as a fiduciary for the beneficiary. The beneficiary of our self is not just ourself but also all of humanity. We have a duty not only to preserve our self for our self but also for our ability to do good for others.
Agree. We still understand so little about psychopharmacology that brain hacks are risky business. I prefer substances with a track record of many generations. Treating life-threatening disease is something else, of course.
I feel like this post should come w/ a codicil advising extreme caution when it comes to GABAergic drug/supplement use. Basically two classes of drugs will kill you on withdrawal: alcohol and benzos. Compensatory down-regulation and de-sensitization of specific GABA(a) receptor subunits is comparatively quick and long-lasting. That is also somewhat true with the non-ionotropic GABA(b) receptor, so messing around w/ stuff like phenibut/GHB/baclofen long-term really isn't advisable.
GABA-A receptor modulation is one area where I have comparative expertise, and a few notes I'd add are:
-The δ subunit-containing receptors are mostly extrasynaptic and modulate tonic inhibition (the baseline propensity towards excitability) and the subunits 1, 2, 3 and 5 (though a5 are more often associated with tonic inhibition) are mostly synaptic and mediate phasic (acute) inhibition.
-Ethanol is generally active at the a4/delta-containing subunit as both an agonist and positive allosteric modulator (PAM). Chronic use can make these neurons (mostly located in thalamic tracts) more prone to excitation, w/ all the attendant problems like insomnia, anxiety, &, most notably, issues w/ smooth pursuit eye movements and a shift towards saccadic vision. Curiously, some inhibitory neuroactive steroids like allopregnanolone also act as PAMs at this specific subunit type (mostly a4b3delta). In a weird way, chronic alcohol use could theoretically improve memory consolidation, but that is probably not the case given its toxic metabolites, broad and systemic effects, and pro-inflammatory nature.
-Comments on the a5 subunit seem confused. Blocking any GABA-A subunit type would probably engender hypermnesic effects but also raise the potential for excitotoxicity b/c you are effectively altering the intracellular chloride- concentration. A5 subunits are mostly located extrasynaptically (tonic inhibition) in the hippocampus, so that is why they might be especially relevant for memory.
It definitely puts a different filter on notions of what I would do in an apocalypse when the answer is 'become incapacitated in 3 days and die one way or another without a clonazepam supply'
Thank you.
I am not sure I'm totally with you on ETOH withdrawal. But I understand the sentiment.
Two things that weren’t mentioned here: at the neurobiological level, a1 and a2 are localized to synapses, so they contribute to what we call “phasic inhibition” — i.e. they dampen acute bursts of activity. a4 and a5 are extrasynaptic, so they provide a kind of low-grade, constant level of “tonic inhibition”, probably by catching GABA that spills over from synapses. I have no idea how this translates to their psychiatric effects, as I am a lowly biologist, sorry.
Also, I’m surprised you didn’t mention that most GABA drugs bind not to a single subunit, but to the interface of two subunits, usually two different ones. For instance, diazepam has to bind at an alpha-gamma interface. This probably contributes to some sort of combinatorial code for the effects of different drugs (depending on which subunit combos they bind to and where in the nervous system those receptors are located). This is almost certainly why selective modulation of a single subunit type never seems to work as well as expected.
That is interesting and thanks for the information, that helps me understand better why things work differently when they're expected to be the same.
Biology is not a nice, easy, simple field like physics, where your sub-atomic particles do what they're told and behave as they're supposed to, and if they don't you know you have something new to discover. In biology, everything does as it damn well pleases 😁
I'm trying to find an Phenibut equivalent that I can take more often (really scared about tolerance/addiction), and I've found that taurine seems to work great (though less potent and empathogenic). What I'm wondering is if cycling between taurine and phenibut will help with phenibut tolerance, or will only make it worse. It seems that they're both GABA receptor agonists, but Phenibut seems to be a GABA-b agonist, while Taurine seems to be a GABA-a agonist. I'm a big noob so I don't really know how this works.
This seems like something that can't be determined by knowledge about how these drugs work. You'll have to test it empirically. If you want to get an answer you can trust you'll need to take placebos some of the time.
In the spirit of "Fictional Drugs Banned by the FDA" I propose that TPA-023 dropped off the face of the earth because in early human trials someone lied on their screening questionnaire and took it at the same time as Ambien. In the investigation of their death and the complete trashing of their apartment it was discovered that if you combine these medications it makes the hallucinatory walruses real! The entire incident and the drug itself were immediately classified by the military so that they could investigate the combat potential of a drug that physically manifests hallucinations.
Interesting that Scott got no effect from Scutellaria baicalensis. Should have tried S. lateriflora “Virginia Skullcap”.
I made a tea from just 600mg of fresh leaf of some S. lateriflora I grew and can attest to strong effects. Like getting my brain activity dial turned down to about 10%. Made it hard to read. Neither pleasant nor unpleasant. I could see how it helps in cases of panic or other extreme emotional state. Don’t understand how people find the effects desirable as a departure from ordinary consciousness however.
I had insomnia and anxiety issues about decade ago. My doctor prescribed Trazodone. I'm not sure what interaction it has with the GABA areas (if any), but it's been working beautifully for me all this time.
You can read about the mechanism of action here:
https://en.wikipedia.org/wiki/Trazodone
It doesn't affect GABA, it's mostly working on adrenergic receptors, but it's also weakly working on H1 histamine receptors.
After reading this email, I felt more confused than enlightened. Here is some additional information that may clariify certain aspects of the topic. GABAergic neurons are mostly interneurons that release synaptic GABA onto postsynaptic neuronal GABA receptors. GABA receptors are ligand-gated ion channels that when activated permit a Cl- (chloride ion) to cross the cell membrane. Cl- currents are mostly inward (i.e. Cl- ions move from outside to inside the cell) and act in opposition to inward sodium (Na+), calcium (Ca+2) currents that are responsible for the action potentials (a transient change in membrane potential) that encodes neuronal signaling). Thus, GABA(a) agonists/positive allosteric modulators down-modulate neuronal signaling and have clinical manifestations as sedatives and hypnotics Conversely, GABA (a) antagonists/negative allosteric modulators up-modulate neuronal signaling and have clinical manifestations as pro-convulsants. As pointed out all GABA receptors are heteromeric pentamers, that share ~30-40% amino acid identity. There are six families of receptor subtypes, several of which have variants: α1- α6, β1-β6, γ1 –γ3, δ1, ε1, ρ1 – ρ3. As found in the brain the α1βγ2 receptor (ratio 2α1: 2β (mixed variants): 1γ2) is the most common receptor. Different receptor subtypes have different pharmacological and electrophysiological profiles. For example, the GABA binding site is located at the α:ß subunit interface, whereas the benzodiazepine binding site requires an α:γ subunit interface. By combining pharmacology, binding stoichometry and electrophysiological profiles, GABA subunit topologies can be predicted.
An excellent article on Gaboxadol, the perfect sleep aid: https://harpers.org/archive/2013/08/gaboxadol
It was ignored because the owners didn't realize there was a market for sleep until Ambien came along, but then soon after they were perhaps spooked by the strange side effects of Ambien and didn't want to enter that market (summary from my hazy memory of the article).
Wikipedia states that it operates on GABA but in a way different than benzos or Z-drugs.
"These are baicalein and baicalin, flavanoids derived from the Baikal skullcap. I tried very high doses of both of these and can report that they had absolutely no effect on me whatsoever, sorry. I’m not sure how to update my credulity about their selective GABA modulation based on this experience."
You were taking the wrong variety? 😁 I had some vague memory of reading that skullcap was used medicinally, so I looked it up. Seemingly there are two varieties, American and Chinese (the Chinese is the Baikal skullcap version) and it's the *American* one that is used as a sedative and mood-booster:
https://www.healthline.com/nutrition/skullcap#benefits
"American skullcap (Scutellaria lateriflora) is a perennial herb native to North America. In bloom, the plant is covered in tiny, tubular blue flowers, although color can vary.
The leaves of American skullcap have been used in traditional herbal medicine as a sedative and to treat conditions like anxiety and convulsions. The plant was prized by Native Americans for its powerful medicinal properties.
Chinese skullcap (Scutellaria baicalensis) is native to several Asian countries, as well as Russia.
The dried roots of this plant have been used for centuries as a traditional Chinese medicine known as Huang Qin to treat diarrhea, insomnia, dysentery, high blood pressure, hemorrhaging, respiratory infections, and inflammation.
In Asia, Huang Qin is used in herbal remedies, such as Xiao Chai Hu Tang or Sho-saiko-to (SST), a popular formulation used to treat conditions like fevers, gastrointestinal issues, and liver disease.
May boost mood and reduce anxiety
American skullcap has been shown to boost mood and reduce symptoms of anxiety.
A study in 43 people found that those who received 1,050 mg of American skullcap daily for 2 weeks reported significant enhancements in mood compared to a placebo group.
It’s thought that American skullcap positively impacts mood and reduces anxiety by stimulating gamma-aminobutyric acid (GABA), a neurotransmitter that helps calm nerves.
Notably, this plant was used in traditional medicine practices as a sedative and treatment for conditions like insomnia and anxiety."
The site does warn that you shouldn't just go out and guzzle a handful of supplements, since there can be serious side-effects. So - Chinese for inflammation, American for anxiety!
I concur. The American or “Virginia” skullcap is the one used in TWM as an anxiolytic. I’ve grown and consumed it (once). It’s definitely active, though I don’t know enough about the subjective effects of GABAergics to guess at the receptor-level activity.
Can you please comment on Gabapentin and Pregabalin?
https://slatestarcodex.com/2019/07/18/know-your-gabapentinoids/
It's worth checking Scott's back-catalogue, especially when it comes to psychopharmaceuticals, growth mindset and papal elections.
Thanks for the hint. After reading that post and the comments I'd like to add that opiod addicts with experiences of benzodiazepine versus pregabaline withdrawals told me that getting off pregabaline was even worse. There's a lot of pregabaline abuse among addicts, partly because it´s comparatively easy to get prescriptions for it. Oh, and there seems to be a lot of unmetabolized pregabaline in the urine of users, which probably increases the risk of drowning for gutter rats.
I thought gabapentin was supposed to be non-addictive.
Pregabaline, what I was talking about, is not gabapentin and seems to be more addictive.
Thanks.
The pharmacology is confusing to me, but in a practical sense, I think the answer is that it's a drug to be used just as cautiously as benzos. Long term usage seems to cause similar problems, like deteriorating memory. Withdrawal from gabapentin and lyrica is almost as unpleasant as from benzos. I'm not sure if gabapentin has the same kindling issues with repeated withdrawals. It's possibly worth the downsides for people with severe nerve pain, but it's probably a bad idea to give it out for all these off label uses like anxiety.
I think we're perhaps just on a long cycle of re-inventing similar sedatives. From alcohol to barbiturates to benzodiazepines to z-drugs to gabapentinoids. At each turn, the new drug is announced to be safer, less harmful, less addictive. Then, people notice that they all have similar problems with addiction, dependence, and withdrawal.
Valium used to be the #1 prescribed drug in America (in the 60's and 70's, I think). Last I checked, Gabapentin is somewhere in the top 10.
I worry about what will happen to all those users, long term. I especially worry what will happen if the medical establishment suddenly decide it's unsafe and doctors all cut their patients off or rapidly taper them.
Vicodin had a brief stint as the #1 prescribed drug in America (early 2000's, IIRC). That didn't end well, both in terms of overdoses and in terms of addicted users that moved on to worse drugs.
I was prescribed gabapentin for nerve pain in my arm, but the warning leaflet with the drug scared me so badly that I looked it up and found that it was risky, and especially risky for someone with a pre-existing condition that I had (I can't blame my doctor for this, it was a 2019 study that finally came down on the side of "yeah, don't take this if you suffer from that").
So I decided that "you can't take it for immediate pain relief unlike other medications, you have to build up a level in your system first, and you *also* have to build up slowly - or have bad side effects; remain on it - or have bad side effects; and if coming off have to taper off slowly - or have bad side effects" was not worth the candle, and I'd prefer to risk my liver by taking maximum doses of OTC pain relievers (I was lucky enough to obtain via a friend some co-codamol which helped with nighttime pain until the problem resolved itself; I think the nerve probably died or something).
So I can't tell you what gabapentin is like, because the DANGER DANGER WILL ROBINSON warnings scared me off even trying it 😀
I've only taken gabapentin briefly, but I got bad side effects on it and then withdrawal symptoms after only a week of use. I would sooner risk taking an opiate than take it again. And I'd much sooner risk a bit of liver damage from acetaminophen.
It always seemed strange to me that acetaminophen has some centrally acting painkilling effect without a clear mechanism of action. Some newer research suggests that one of its metabolites acts on cannabinoid receptors:
https://www.sclabs.com/tylenol-s-analgesic-effect-is-mediated-by-cannabinoid-receptors/
That begs the question whether other cannabinoids could be used as non-addictive painkillers without the liver damage.
Thanks
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Phenibut makes me feel quite drunk, and Wikipedia says it's a GABA-B receptor agonist. I wonder if anyone has checked if alcohol affects GABA-B? The Wikipedia page for that doesn't contain GABA-B anywhere on it. Also interesting is that phenibut comes with a pleasant 'afterglow' effect the next day, which alcohol notably does not.
If anyone has insomnia issues, I recommend trying oleamide. That stuff absolutely knocks me out, has a stronger effect than Ambien, and does not cause headaches next day. I use it sparingly, only when I need it. I don't know how well it work in general. Here are two interesting papers about it:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1573315/
https://pubmed.ncbi.nlm.nih.gov/11561096/
Have you tried nervous system management through targeted breathwork? You can activate your parasympathetic nervous system quite easily when you know how. It’s highly effective, and has no side effects 👌
Yes, I have, thanks. Breathwork is excellent at mitigating anxiety.
Great to hear 👌
Feel free to check my page out, I’m a breath work facilitator and love to write about it, along with other science backed natural approaches. Have a cracking weekend 👍
I have found theanine plus tryptophan to be very effective.
I keep wanting something like, a 'users manual for my brain' that says, basically:
- when you feel X
- it is caused by systems A, B, C
- the following are things you can do to reduce/increase the extent of feeling X
Does such a thing exist? Posts like this one make me think... we barely understand these 'brain' things, and mostly know the aggregate statistical results of poking them in various places and with various chemicals, and then we kinda how how things are connected, but not really how it all works.
"we barely understand these 'brain' things, ...but not really how it all works."
To my understanding, this is pretty much how things stand at the moment. Like everything else, it starts off with "with our increasing knowledge and technical sophistication, it'll soon be easy for us to figure out these systems!", leads into "we have now got lots of wonderful new effective drugs that have specific effects on specific problems, total understanding is just around the corner!", skids over "uh, turns out that there are also a lot of gaps in how these drugs work anyway" and crashes on "oh hell nobody knows nothing!" because the more you know, the more you discover that you don't know.
Well here's a rough map of what we know so far:
http://biochemical-pathways.com/#/map/1
I've read that benzo addiction can be assigned to the effect on the a1 subunits:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020178/
The sedative effect on a1 increases dopamine levels in the mesolimbic dopamine system, which is basically the definition of an addictive drug. Anecdotally, I've talked to a few former heroin addicts who subsequently got hooked on high doses of ambien, perhaps because it's also a fast acting sedative that's rapidly calming and rewarding in a similar way.
The first a2, a3 specific benzo (MRK-409) still had weak activity at a1, which might still be enough to cause the effect. TPA023 seemed more promising because it was an agonist of the a2 and a3 receptors but an antagonist of the a1 receptors. So it should have been a non-sedating, non-addictive anxiolytic. I have no idea what went wrong in the trials.
That said, I'm sure TPA023 would still cause tolerance and dependence, since most psych meds do. It's not just an issue of dopamine, there's also the basic principle of homeostasis -- provide too much of one chemical and the body/brain gradually downregulates the receptors for that. Many different drugs give unpleasant withdrawal, whether that's benzos or SSRI's or beta blockers or zyrtec.
Withdrawal is abnormally bad for benzos, for some reason, but that's not a function of the psychological addictiveness, it's probably more because GABA/glutamate balance is so important to normal brain function. I suspect that quitting TPA023 wouldn't be as bad as normal benzo withdrawal, but you'd probably have weeks or months of horrific rebound anxiety.
Zopiclone/Lunesta do seem to be more benzo-like than the other Z drugs. At least, the withdrawal from them is often benzo level bad, while the withdrawal from ambien usually is not. That might have something to do with the GABA receptor subunits, but it's also just a function of the half life of the drug -- zopiclone has a half-life of 4-6 hours, ambien is closer to 2 hours. So if you take lunesta nightly, you're stimulating the gaba receptors somewhat, at all times. If you take ambien nightly, the receptors return to baseline for most of the day. Halcion is the shortest acting benzodiazepine, with a half-life similar to ambien. The Ashton manual for benzodiazepine withdrawal says that one also has lower dependence than most, and can generally be quit without tapering, unlike the longer acting benzos.
>there are botanicals claiming to have α2- and α3- selective GABA modulation. These are baicalein and baicalin, flavanoids derived from the Baikal skullcap. I tried very high doses of both of these and can report that they had absolutely no effect on me whatsoever, sorry. I’m not sure how to update my credulity about their selective GABA modulation based on this experience.
Flavonoids are notorious for having poor bioavailability as well as a tendency to nonspecifically mess up biochemical assays, so I tend to be skeptical of any research involving them.
The effect on a5 makes sense. For months I was taking a now-out-of-stock GABA-melatonin-l-theanine-CBD pill. During that time, I suddenly felt that my memory was the greatest it has ever been (32-year-old male); it was shocking to me how smooth and automatic my recall was. When I ran out of the pill, I switched to a CBD-melatonin pill, and soon my memory went back to its baseline (or became worse) — to the point of making me feel brain-fogged and frustrated. GABA gave me what felt like a clean 5.5-7 pt IQ increase.
I always thought that alcohol is an NMDA antagonist, like ketamine.
I'm not sure that perfect memory it is the power necessary to storm the gates of heaven :)
I take Escitalopram (SSRI) since two years now, prescribed for helping me getting to sleep more easily. It improved a lot of my decades long personal issues like angst, endless thought cycles, bad self confidence etc. Then a year ago because of a very toxic work enviroent I started to take Zolpidem for getting even a little sleep at all. Initially I took the full prescribed 10mg dose which played havoc with my mood and temper the next days. I got anxious, my brain worked pretty bad, I was searching a lot for words or concepts, got extremely impatient and showed a lot of nerves the following day. I reduced the dose step by step to 2.5mg which now is working extremely well for me.
I'm not sure if I am a normal guy or an ADHD or an Autistic or a hyper sensible person, but the combination of the above things did virtually change my life.
The experiment is not exactly a RCT and there is quite some coffeeine and ethanol at play as well but just saying...