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Sedatives of the Future

SNR said:
Anyone know of a drug with strongish GABAergic, NMDA Antagonistic, and Mild Anti-Cholinergic properties? Now that would be one hell of a sedative.
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I believe there is. It's called ETHANOL.=D
 
^ I had no idea ethanol did anything besides Gaba. That's interesting. But it doesn't help in the context of future sedatives; sure you can use ethanol to get to sleep - but its not going to be good sleep. I think may of have been down that road before. I don't have any of the Ki numbers for ethanol - does it bind to Gaba much more so than to the other receptors so that sedation is the predominant side effect? I had always figured alcohol withdrawal was mainly due to the Gaba system but NMDA makes sense there.

I've actually not read anything about the hallucinatory effects of zolpidem; I would be interested to here some commentary on what mechanism / sub_unit of Gaba riggers this.
 
^ Here's a good article about ethanol's effect on ion channel receptors (GABA, NMDA):

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC165791/
The 2 major types of membrane-bound proteins that are directly affected by pharmacologically relevant concentrations of ethanol (i.e., concentrations up to 100 mmol/L or 460 mg/dL, at which point ethanol can be lethal in humans) are ligand-gated ion channels (LGICs) and voltage-dependent calcium channels. LGICs are a family of neurotransmitter receptors that are widely distributed in the mammalian CNS and play a major role in synaptic transmission and the regulation of neuronal excitability. In particular, the gamma-aminobutyric acid type A (GABAA), N-methyl-D-aspartate (NMDA), glycine, neuronal nicotinic and 5-hydroxytryptamine type 3 (5-HT3) receptors are LGICs that have been shown to be directly modulated by ethanol. Ethanol does not modulate these receptors in a non-specific fashion; interestingly, it potentiates ligand-gated currents at some receptors but inhibits them at others. For example, it is well documented that acute ethanol exposure potentiates these currents at GABAA and glycine receptors but inhibits them at NMDA receptors. Voltage-gated calcium channels play key roles in neurotransmitter release, hormone secretion, gene regulation and differentiation. Ethanol, when administered acutely, has been shown to block voltage-gated calcium channels at pharmacologically relevant concentrations.
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Volatile anesthetics have pretty much the same mechanism of action, and so do abusable inhalants like toluene and butane.

EDIT: I don't think it's possible to determine a Ki value for ethanol, because there is probably no specific site at the receptor protein where ethanol molecules bind.
 
kaiba said:
Which sedative is better: GABA action or Antihistamine?
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I've always been under the impression that benzodiazepines disrupt sleep architecture and antihistamines do not. This is well established in literature I believe. So if you were to use a GABAergic for sleep, it would be best to use a Z-Drug.

However, I find antihistamines to be much better for sleep. There's a lot of em too! If you wake up a lot, hydroxyzine might be your magic sleep aid. Long(ish) half life, pretty damn sedating. But then there's also the less potent and short acting ones too. I find that as long as I sleep, the drowsiness from the antihistamine wears off as soon as I wake up.

~snr
 
have you used phenibut? while not really comparable to ghb long term, i thought it was like the second coming for the first week of use, which is euphoric like ghb at similar doses ~2000mg, anywhere up to 10000mg. and the effects last for 12 hours or more, but be careful, the full effects take about 3-4 hours to come on, so you can imagine the trouble you can get into being impatient for it to come on. after about 2 weeks and 100grams later, this substance lost all its nice effects and had a terrible unique comedown where NOTHING made me feel better, like coming down off ice, MDMA and LSD at the same time your coming off your 10mg a day xanax habit, for about a week. only oxycontin seemed to help. benzoes didnt work, neither did more phenibut after a certain point.
 
doctors seem to think it has a very lot less abuse potential as they readily dish out immovane and stillnox in australia. (zopiclone and zolpidem) they are great as they have all the effects i want from benzoes, and dont show up in ANY urine tests ive had so far, whether for employment, post detox, or methadone UDS. I guess there like tramadol is to codeine.
 
Mirtazapine is pretty good as a sleep aid. Less is more. Take 3.25-7.5 mg's for full antihistamine effects with the least amount of side effects.
 
There's been some research on the sedative effects of adenosine agonists:

http://jpet.aspetjournals.org/content/220/1/70
Sedative and anticonvulsant effects of adenosine analogs in mouse and rat.

Abstract
The behavioral and physiological effects of L-phenylisopropyladenosine, cyclohexyladenosine and 2-chloroadenosine were examined in mice and rats. These analogs of adenosine are agonists which bind with high affinity to putative central A1 receptors in vitro. Relatively low doses of these drugs administered i.p. produced marked sedation and hypothermia; higher doses resulted in an almost complete cessation of spontaneous motor activity as well as some ataxia. These analogs also antagonized seizures elicited by a variety of convulsants with different mechanisms of action. The differences observed in the anticonvulsant potencies of the analogs suggest that these effects are not produced by the interaction of these drugs with a single class of adenosine receptor. In particular, 2-chloroadenosine and cyclohexyladenosine appear to be more related to each other pharmacologically than to L-phenylisopropyladenosine. Because some of the anticonvulsant actions of L-phenylisopropyladenosine are not reversed by the adenosine antagonist theophylline, and are not shared by the other analogs, these may reflect actions mediated by other, perhaps nonpurinergic receptors. Although benzodiazepines also have sedative, hypothermic and anticonvulsant properties, responses to benzodiazepines can be clearly dissociated from responses to the adenosine agonists.
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http://www.researchgate.net/publica..._that_suppress_lever_pressing_and_food_intake
Systemic administration of the adenosine A(2A) agonist CGS 21680 induces sedation at doses that suppress lever pressing and food intake

Abstract
Adenosine A(2A) receptors are involved in the regulation of several behavioral functions. Adenosine A(2A) antagonists exert antiparkinsonian effects in animal models, and adenosine A(2A) agonists suppress locomotion and impair various aspects of motor control. The present experiments were conducted to study the effects of low doses of the adenosine A(2A) agonist CGS 21680 on lever pressing, specific parameters of food intake, and sedation. In the first experiment, the effects of CGS 21680 on fixed ratio 5 lever pressing were assessed. In the second experiment, rats were tested in 30 min feeding sessions, and also were observed for drug-induced sedation using a sedation rating scale. CGS 21680 (0.025, 0.05, 0.1 mg/kg IP) produced a dose related suppression of lever pressing, and also reduced the amount of food consumed. The feeding effect was largely dependent upon a slowing of the rate of feeding, and there was only a modest suppression of time spent feeding. Doses of CGS 21680 that suppressed lever pressing and feeding also were associated with sedation/drowsiness. In conjunction with other studies, the present results suggest that sedative effects may play an important role in some of the behavioral effects produced by systemic administration of adenosine A(2A) agonists.
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This is like the opposite of what caffeine does... (caffeine is an adenosine antagonist) Of course no one knows how the effect of these drugs feels subjectively - if its dysphoric, then obviously these compounds are of no interest to us.

Personally, I found the antihistamine hydroxyzine a useful hypnotic in normalizing my sleep rhythm when I got a new job after years of unemployment and staying up all night/sleeping at daytime.
 
While admittedly dated, this is an interesting full-text on an orally active hypnotic neurosteroid, CCD-3693 full. The following is an excerpt:

Taken together, these data suggest that the new orally bioavailable neuroactive steroid CCD-3693 has NREM-promoting potency comparable to the endogenous neuroactive steroid, pregnanolone. Although CCD-3693 potentiates alcohol comparable to benzodiazepine receptor ligands, some notable potential advantages over triazolam and zolpidem were observed: CCD-3693 appeared to be more intrinsically potent in promoting NREM sleep. The neuroactive steroids did not interfere significantly with REM sleep and selectively reduced EEG wakefulness without disproportionate locomotor activity inhibition. In addition, the benzodiazepines ligands showed distinct “rebound” wakefulness after the NREM-promoting effect subsided, although the neuroactive steroids did not.

Because neuroactive steroids are naturally synthesized in the brain by enzymes in situ (Baulieu, 1981) and potently facilitate GABA-dependent chloride flux (Gee et al., 1988), it is plausible that these compounds are endogenous physiological regulators of brain excitability with diffuse action throughout the CNS. Neurotransmitters such as adenosine have similar diffuse inhibitory action and, on that basis, are postulated to be involved in normal sleep regulation (Benington and Heller, 1995). In this sense, the efficacy and therapeutic application of CCD-3693 as a sedative hypnotic could also constitute a pharmacological modification of a natural sleep-promoting physiological mechanism.
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In regards to adenosine reuptake inhibitors/modulators; this article touched upon an important factor that is of great importance in regards to the activity of sedative-hypnotics as a whole: Cl- channel modulation of ionotropic GABA(a). From what I gather, adoRI's are limited in regard to their potential as hypnotics due to dose dependent Cl- channel interruptions (ex, meprobamate). Sure, directly binding can occur with these drugs, but their less than favorable SEP latency and amplitude spikes make them less than desirable in my opinion. In a clinical setting these issues can be controlled; etomidate is an invaluable anesthetic, but utterly unpleasant at subanesthetic doses (much unlike propofol, which is quite pleasant). However, while I am admittedly unfamiliar with any highly specific adenosinergic inhibitors, I am not particularly optimistic with that 'pathway' so to speak (in respect to promising hypnotics, or to be frank; hypnotics with abuse potential). If this message doesn't make sense I will revise it later.
 
Those adeonsine agonists don't sound too good...

not sure how they would actually affect humans but, "Relatively low doses of these drugs administered i.p. produced marked sedation and hypothermia; higher doses resulted in an almost complete cessation of spontaneous motor activity as well as some ataxia. ", this sounds a bit extreme to me. Its one thing to induce sedation but at the risk of causing hypothermia, ataxia, and antagonizing seizures; seems like the side affects majorly outweigh the benefits.
 
In regards to Mirtazipine; I was never able to try dosages that small. I could easily do 7.5mg (the 15mg bars were scored) but I never tried cutting up one of the halves of the 15mg to get a smaller (~3mg) dose.

It worked alright for me but some mornings were awful, heavy body load, dehydration, incredible grogginess. Perhaps at 3mg these side affects would be only minor. I'll see if I still have any around that are not expired. Its been some time since I used them actively as an Rx.

Overall I'm not thrilled about Anti-depressants or Anti-psychotics as sedatives, at least in so much as they mediate sedation mainly via anti-histamine action. I'd rather just take benadryl, doxyl-amine, etc if I were to take an anti-histamine. Perhaps that's just my own biased opinion though. I never gave mirtazipine enough of a shot; trazadone was an utter failure however.
 
Yellobello said:
Qetiapine is soo nasty!
I remember taking the prolong form as a sleep aid and, I can tell you I was totally useless the following day for even the simplest tasks.
Antipsychotic brain nailer at its best. Maybe the problem was the prolong formulation that carried blood levels to the next day.

What I wanted to contribute to this thread is Erythrina vera or Mulungu.
Since Kratom is the Herbal OTC opioid , this would equal the herbal OTC Benzodiazepine.
25-30g of bark brewed as a tea produce very noticeable effects which totally remind me on benzos. Even the afterglow feels like a benzo hangover. Does anyone have some deeper insight on its active compounds?
Since it is totally available and definitely active it should be mentioned here.
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Mulungu is actually quite a nice sedative. I would like to be able to find more documentation on exactly how it works. It does not take away my benzodiazepine withdrawals, which tells me that it doesn't bind to GABA but trying to find information E. Mulungu is pretty damn difficult. I have tried it and it is such a calm and relaxing, slightly euphoric experience. It is everything that kava kava promised but couldn't deliver on and a whole lot more. It lasts awhile too. I got a 20x extract (smelled like cinnamon almost but like woody... hard to explain) and put about 300-400mg in a capsule and took it not expecting anything and I was totally floored. My GAD went away for about 8 hours. I will admit that was concurrent with my usage of Xanax but Xanax doesn't last more than 2 or 3 hours and is TERRIBLE for GAD... Any info on Erythrina Mulungu would absolutely fascinate me. I have tried Valerian extracts and they *DO* stop benzo withdrawal but you have to take so damn much and it makes the whole house smell like rotten cheese... Plus as the levels you have to take it for any noticeable GABA influence it becomes quite expensive. If I could wean myself off of benzos and onto mulungu I would but I want to know more about what makes it tick first.

EDIT: Oh and I have to add this... if you want to have your lights knocked out, get 20mg of Geodon shot into your hip... Took awhile to kick in (they gave it to me to calm my nerves after they cold-turkeyed me off of a 2mg a day Klonopin habit and my nerves were on fire and I was angry and throwing shit) but when it did... I started tripping out then I conked out for like 9 hours and woke up perfectly fine (although I ran right up to the nurse and asked for my morning 20mg Geodon pill so I could go eat breakfast without wanting to rip my clothes off)... Then again... don't do that... Geodon was like crack for me... I still sometimes feel like filling my prescription for it because I love the feeling of it so much :P

EDIT2: Actually I just found some articles... the first one has a depiction of the alkaloids that maybe someone here can make a SAR portrait of... http://www.nrcresearchpress.com/doi/pdf/10.1139/v81-400

I can tell you that I am EXTREMELY tolerant to EVERYTHING but amphetamines and cathinones and the dose of mulungu extract I took should not have had me as twisted as I was so there's something unique about the alkaloid structure for sure. I need to get all these apps that yall have so I can inlay molecules over each other and figure this stuff out of my own...

EDIT3: To actually add something that might be somewhat constructive to the thread... wouldn't it be smarter to look into anticholinergics and antihistamines than looking at GABA models? Hasn't pretty much every GABAergic drug been extremely addictive? I know that interfering with acetylcholine transfer can have its own issues but are they not better than GABA issues? I mean there has to be a reason why so many pharmacists recommend Vistaril and Benedryl combos over taking Ambien, right? Many psych hospitals use that combo not just for sleep but for anxiety, particularly in detox but also in general - over anything else - that and mirtazapine (which doesn't do crap for me - give me trazodone and I'm out for the night though). I think exploring that avenue would be the way to look at sedatives. Look at Zyprexa. Its a non-BZD but the withdrawal is EXACTLY like withdrawing from a benzo... We need to move past the GABA model or look for something that enhances the effect of GABA while simultaneously tricking the brain into continuing to produce GABA so there is no discontinuation. The problem with that is obvious though - over-sedation. I'm just shooting ideas out of my ass but hasn't the antihistamine/acetylcholine model worked for so long? If we could get something with that activity in a long term formulation (about 6-8 hours) along with something that has a release upon waking that *slightly* stimulates norepinephrine and also has a choline modulator built into it - that would take 6-8 hours to dissolve in the body so it would hit right when we needed to wake up - would that be a good way to go?
 
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sounds like your asking a bit much there - longterm antihistamine/acetylcholine mediated sedation, norepinephrine stimulation to aid wakefullness upon waking up as well as choline modulation.
You could get combinations to do what you're after there but getting that all bound up into one pill seems a bit much.

I haven't spent too much time trying different anticholinergenic meds in terms of sedation, but as far as antihistamines go I don't see how they are much better than GABA based sedatives in terms of tolerance / addiction; edit - I guess what I mean is you can end up addicted to both but imo gabas work better; sure withdrawing from benzos is far worse than withdrawing from diphenhydramine, but either way you end up with rebound insomnia
 
mgrady3 said:
sounds like your asking a bit much there - longterm antihistamine/acetylcholine mediated sedation, norepinephrine stimulation to aid wakefullness upon waking up as well as choline modulation.
You could get combinations to do what you're after there but getting that all bound up into one pill seems a bit much.

I haven't spent too much time trying different anticholinergenic meds in terms of sedation, but as far as antihistamines go I don't see how they are much better than GABA based sedatives in terms of tolerance / addiction; edit - I guess what I mean is you can end up addicted to both but imo gabas work better; sure withdrawing from benzos is far worse than withdrawing from diphenhydramine, but either way you end up with rebound insomnia
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I'm sure they could figure something out... And yeah you get rebound insomnia but I wasn't aware that DPH had a huge tolerance problem, that's news to me. Then again I guess the body gets tolerant to ANYTHING if you take it for too long. I just think the GABA-mediated model is obviously a piss poor way to go about making sedatives. When they c/t me off of 2mg of Klonopin I think every nerve in my body was on fire... It was like EVERY system in my body from the head down was completely fucked.
 
ebola? said:
Anti-histamines have a much shallower tolerance curve and much milder withdrawal than GABAnergics; Mgrady is fundamentally mistaken.

ebola
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That is what I had originally thought which was part of my reasoning for exploring that route for sedation. Thank you for the confirmation.
 
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