Comprehensive List of GABAA Receptor Anxiolytics That Potentially Produce no Tolerance or Dependence.
- Common misconceptions regarding GABA A Receptor
- Complete List (Pharmaceuticals):
- Complete List (Herbals):
- (Up-)Regulating GABAergic Function: Underutilized Potential Compounds
Research and education, not medical advice.
This is a 7 year old repost from a deleted account. I’m posting it here for discussion purposes.
Common misconceptions regarding GABA A Receptor
Most GABAA positive allosteric modulators(PAM or PAMs), are actually agonists at the benzodiazepine site. Benzodiazepine site itself is a modulatory site of the GABAA receptor’s chloride ion channel. Diazepam, for example, commonly known as valium, act as an agonist at the benzodiazepine site, which in return, ups the efficacy of chloride ion uptake. Ashwagandha, skullcap, and most herbal anxiolytics are believed to perform as a benzodiazepine partial agonist
Direct agonist of GABAA receptors are rare, and they usually induce tolerance and dependence faster than benzodiazepines. So does benzodiazepine agonist or partial agonists = GABAA PAM, yes you can understand it that way. However another misconception is that benzodiazepine antogonists such as flumazenil are stimulatory. No. An antagonist of a modulatory site means that the modulatory site loses its ability at modulating the modulated receptor.
Another misconception, arent all benzodiazepines or GABAergics addictive? No, It depends on the GABAA subunit binding profile of the specific benzodiazepine agonist interact with. Kava and many specific benzodiazepines have shown promise at being anxiolytics without impairing cognition / building tolerance.
Subunits:
- a1 Subunit. Recent research have shown that GABAA a1 to be the most addictive and tolerance building subunit. It leads the tolerance effect as a1 was found to be the subunit where agonists produce most of the downstream changes to your benzodiazepine receptors. a1 is also being the cognitive impairing, sedating, and memory worsening subunit. This means that drugs that avoid this receptor produces no sedating, memory impairing, tolerance, withdrawal, and abuse potential.
- a2 and a3 Subunits. a2 a3 selective agonists have shown to have significantly reduced abuse potential, with their main effects at reducing anxiety and promoting muscle relaxation.
- a5 subunit is involved in memory, agonist has shown memory impairments while inverse agonists have shown memory enhancement.
This beautiful profile of GABAA a1, a2, a3, and a5 subunit brings a new era of pharmacology where anxiolytics with almost no abuse potential and tolerance is possible. A grand table of what effects GABAA a1, a2, a3, a5 subunits are responsible for in terms of their neuropharmacological profile, please see table 1 in this paper
There could be a lot of subunits.
Just to be scientifically accurate, even subunits can be further categorized, such as: a1b2g2, a1b3g2 and a1b2g3, etc. However for the sake of this piece being understandable as well as lack of research in these further sub-categories, we will not talk about it more. Is it possible that 1 of these specific a1 subunits contribute more specific effects than another and therefore we can have 2 drug that are both a1 subunit agonist that produce different rate of sedation, tolerance building, etc.
Complete List (Pharmaceuticals):
- Imidazenil, One of the most promising benzodiazepines in animal studies that have no human studies yet. It is a GABAA a2,a3 Partial agonist, weak to none a1,a4,a5 activities. Zero tolerance building in monkeys and rat studies when chronically high dosed. Pharmacologically speaking, effects should be moderately to strong, in terms of anxiolytic, anti-convulsant effects. Mild to no hypnotic and anti-epileptic effects, and also, mild to none amnesia effects. (Remember, this repost is 7 years old, this may be outdated into)
- MRK-409, aka MK-0343 in past literature, Another promising benzodiazepine. Partial agonist a2,a3, weak a1,a4,a5. Phase I halted due to unexpected sedating effects, it was not very sedating, just more than desired. Since it was designed as a sedation-free anxiolytic. Dosage in human studies was used between 0.1mg-3.0mg, optimum dose seems to around 1.0mg, 2.0mg starts to produce sedation. Tolerance should be none to very slow building.
- L-838,417, Structurally related to MRK-409 and TPA-023, it has almost the same pharmacological profile as MRK-409 but have no human studies. It is a a2,a3,a5 partial agonist, even weaker on a1, and almost none on a4,a6. Effects should be same as MRK-409, maybe slightly more sedating due to partial agonism at a5. Tolerance building should be very slow if any.
- Bretazenil, or Ro16-6028 in past literature, A promising, (Very low to low tolerance building)\[[https://www.ncbi.nlm.nih.gov/pubmed/8162672\]](https://www.ncbi.nlm.nih.gov/pubmed/8162672]) benzodiazepine. Reached Phase III but halted due to sedation. Extremely promising, Extremely safe profile since it reached Phase III and was halted with sedation as only primary side effect - It was designed to be a sedation free anxiolytic. Partial agonist a1,a2,a3,a4,a5,a6. Doses as low as 0.25-0.5mg of bretazenil has shown to improve insomnia and reduce sleep disturbanceBretazenil Synergize with alcohol very well, better than diazepam, infact so well that one should actually not trying mixing them. Effects of this drug should be Moderate in sedation, strong in anxiolytic, and moderate in anticonvulsive and epileptic effects. Ee
- Abecarnil, handful of promising human studies - very slow tolerance building and only mild withdrawal was noted after chronic use (tolerance was only noted in high dosed groups). Extremely promising, large amounts of human data, In humans, seems to cause little sedation, moderate to strong anxiolytic effects. Doses in studies ranged from 5mg to above 30mg.. Looks promising.
- FG-8205 (AKA, L-663,581): almost exact profile as bretazenil, however less researched.
- TPA023, Dont try this one, Phase I and II showed cataract building up in several participant, extremely promising profile, but unfortunate side effects means this drug has no human potential.
- TPA023B, Structurally very similar to MRK-409 and L-838,417. a2,a3 partial agonism. Extremely similar profile and dosing as well as effects.
- TPA123, Tolerance building but slower than traditional benzodiazepines due to partial agonism of a1,a2,a3,a5.. Animal studies but lacking human studies. Should be a moderate sedative and strong anxiolytic.
- TPA003, Somewhere between agonist and partial agonist on a3, no action on a1 and very weak a5. Should be a strong anxiolytic and very weak hypnotic. I actually wrote a paper debating GABAA a3 to be strongly involved in anxiolytic effects of benzodiazepines, as most studies concluded that a2 was the “sole” contribution to anxiolytic effects. My understanding is that in a2 studies, mice “seemed” to be have less anxiety because they’re seem calm, but they’re only calm because a2 is also the strongest subunit target for myorelexation. TPA003 is definitely one of the most interesting compounds I have personally came across.
- EVT-201, has successful Trials, more ongoing. Low tolerance building, moderate to strong hypnotic, moderate to weak anxiolytic. Partial agonist at alpha1. Seems to be like a slightly better and less adictive version of current Z-Drugs. See more on my past post
- PWZ-029, unique one, partial agonist a3, weak a1,a2, inverse agonist a5. PWZ-029 Improved memory and reduce anxiety at the same time in animal models. Human dosage unknown.
- Ocinaplon, Care on this one, people with sensitive and liver problems should not try this as the entire Phase III was halted by a single participant whos liver enzyme spiked after this drug. strongest action at a3, with interesting metabolites that are also similar in profile. Otherwise seems extremely promising with good profile. Strong anxiolytic activites and weak hypnotic. Human studies dosed 90mg 3 times a day, total 270mg/day, with good results, no side effects reported
- PF-06372865. Another a2/a3 PAM. This one is being developed by Pfizer Inc. Pfizer’s researchers have published promising animal studies with ongoing trials A study link: https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.14119
- AZD7325, Another a2/a3 PAM. Binding affinity is high at GABAAα1, α2 and α3 (Ki of 0.5, 0.3 and 1.3nM, respectively), but not GABAAα5 (230nM). AZD7325 is being studied in humans, its been administered orally to healthy volunteers at single doses of up to 100mg and repeated doses up to 50mg QD for 7 days. Adverse events were CNS in nature, and included dizziness, feeling of relaxation, euphoric mood, somnolence, and headache. “Two Ph2a General Anxiety Disorder studies have been conducted. In the first, AZD7325 was dosed at either 2 or 5mg BID or 10mg QD for 28 days achieving compound plasma exposures of ~4 x Ki. In the second, it was dosed at either 5 or 15mg BID for 28 days and compared with lorazepam. While the primary objective of greater efficacy vs. placebo and/or lorazepam, as assessed by the Hamilton Anxiety scale, were not met at any of the doses tested, the placebo response rate was considered to be high and reduction in other anxiety endpoints at 10mg and depression MADRS score were noted.”
- Emapunil (aka AC-5216, or XBD-173), Emapunil is a ligands of the translocator protein \[18 kilodaltons (kD)\]. It may promote the synthesis of endogenous neurosteroids, which exerts fast-acting anxiolytic agent, both in animals and humans, which lacks the unwanted side effects of benzodiazepines. Repeated administration shows lack of tolerance and dependence.
- SB-205,384. SB-205,384 seems to binds preferentially to α3, α5, and α6 subunit containing subtypes, animal models showed that it produces anxiolytic effects with minimal sedation.
- RWJ-51204. Unclear GABAA binding profile, but sedative effects only come after 20x the dose required for anxiolytic effects.
Complete List (Herbals):
- Baicalin. Baicalin is a herbal compound found in Skullcap or Scutellaria-Baicalensis and Scutellaria lateriflora. Baicalin showed significant preference for alpha2- and alpha3-containing subtypes compared to alpha1- and alpha5-containing subtypes in whole-cell patch clamp studies. Its effects should be mildly anxiolytic without sedating or memory-impairing effects.
- Wogonin. Wogonin’s GABAA profile is unclear, but mild sedative efffects were noted on top of anxiolytic and anti-convulsant effects.
- K36. K36 is interesting because it is the most potent plant-derived benzodiazepine agonist to date. It is reported to be an agonist at the a3 subunit, however, it also showed some effect at a1 although less potent. In animal models, results are promising as K36 showed anxiolytic effects without motor-impairment / sedative effects. Potentially hinting that its a1 efficacy is rather weak.
- Valerenic Acid. Not completely profiled, but shows a2 preferance over a3 and a5, and low to none efficacy at a1. Anxiolytic effects were noted in animal studies with no indication for sedation induced by valerenic acid.
- Apigenin. Mild partial agonsit at a1, no complete profile. Low potency. Seems to be similar to green tea catechins in terms of effect.
- Catechins. Green tea catechins have extremely low bioavailability, and have shown to be a second-order PAM, which means it is a PAM of PAM, theoretically hinting that co-administration of green tea and xanax may enhance the effects of xanax.
- Triethylene glycol, as found in Ashwaghanda. Unclear GABAA profile, is reported to be sedative, pass.
- Withaferin-A from Ashwaghanda. GABAA binding profile unclear. Shows anxiolytic efficacy without tolerance in rats following subchronic administration.
- Miltirone, https://sci-hub.tw/10.1016/0304-3940(91)90802-z, a partial agonsit of benzodiazepine receptors. No GABAA binding profile. Miltirone showed promising anxiolytic effects and was neither sedative nor addictive in mice even after chronic repeated administration. Miltirone also showed lower tolerance just as expected.
- Kava’s bioactive compounds, several kava compounds seem to have unique properties at the GABAA receptor. Chronic heavy users of Kava appear to be perfectly fine in terms of dependence and cognitive function. Caution, Kava contain amounts of liver toxins that vary by strain, this has caused unlucky users to suffer liver failure.
- Magnolol from Magnolia officinalis have shown to have efficacy to be an anti-convulsant in animal models just like diazepam, at 40 times the diazepam’s dosage. GABAA binding profile unknown. It is also an anxiolytic in animal models.
- Euphorbia hirta’s bioactive compounds, confirmed to contain bioactive compounds that produces relaxing effects through GABAA benzodiazepine receptors. However, sedative effects were also noted.
below this line is another post I reposted to make this post more thorough
(Up-)Regulating GABAergic Function: Underutilized Potential Compounds
GABA obviously is incredibly important for overall health and has direct impacts on sleep and anxiety. While we have seen some supplements with the potential to upregulate GABAb, GABAa upregulation is much more rare and hard to establish leaving those with insomnia, anxiety, and post-substance abuse with a long road ahead of them.
I have done a very cursory** analysis of some often overlooked compounds with potential for upregulation of either GABAa or GABAb with sources. Those with less data or unclear information will be collected on the bottom.
Main Upregulators
Gabapentin
- https://www.thelancet.com/article/S2352-3964(19)30148-3/fulltext
- Gabapentin enhanced expression of δGABAA receptors and increased a tonic inhibitory conductance in neurons.
Agmatine
- https://link.springer.com/article/10.1007/s00210-020-01910-5
- …may involve an activation of GABAAreceptors dependent on NMDA receptor inhibition, similar to ketamine, as well as modulation of GABAB receptors.
Nigella Sativa (GABAa)
- https://pubmed.ncbi.nlm.nih.gov/27849392/
- N. sativa treatment ameliorated the PTZ induced neurodegeneration in the cerebral cortex as reflected by neuronal apoptosis and neuronal GABAA receptor frequency.
Bacopa (GABAa)
- https://pmc.ncbi.nlm.nih.gov/articles/PMC3306740/
- Bacopa monnieri and Bacoside-A treatment reverses epilepsy associated changes to near control
- https://www.sciencedirect.com/science/article/pii/S0753332218383914
- Bacopa monnieri abrogates alcohol abstinence-induced anxiety-like behavior by regulating biochemical and Gabra1, Gabra4, Gabra5 gene expression of GABAAreceptor signaling pathway
Rhodiola Rosea (GABAa)
- https://pubmed.ncbi.nlm.nih.gov/34585202/
- Third, ELLISA results showed that the concentrations of GABA, 5-HT, norepinephrine (NA), PGD2, and IL-1β in plasma were significantly increased after HJT-I and HJT-II administration, while IL-6 was decreased. HJT-I and HJT-II also exhibited differential modulation of the receptors of 5-HT, GABA, PGD2, and IL-1β expression. In hypothalamus, HJT-II was more powerful than HJT-I in regulation of the GABAARα2, GABAARα3, and glutamic acid decarboxylase (GAD) 65/67 expression, as well as 5-HT2A and IL-1β. As for DPR and PGD2, HJT-II was more effective in the hippocampus. The efficacy of HJT-I was better than HJT-II at stimulating GABAARα2, GAD 65/67, 5-HT1A, and IL-1β expression in the hippocampus.
Garum Armocium (Stabilium)/Gabolysat/Magzen \[Hard to decipher the data but *seems* to be effective\]
Schisandra (GABAa)
- https://pubmed.ncbi.nlm.nih.gov/29677536/
- In conclusion, SchB is the active component in Schisandra chinensis Baill responsible for the sedative and hypnotic function through up-regulating the expression of GABAAreceptors and modulating the content of GABA and Glu in the peripheral blood and brain tissues.
Fasoracetam (GABAb) \[Well documented\]
BPC-157
- https://pmc.ncbi.nlm.nih.gov/articles/PMC8504390/
- Hence, it is interesting that BPC 157 counteracts GABA system disturbances, such as diazepam-induced tolerance/withdrawal (Jelovac et al., 1999b). Perrault et al. (1992) examined physical dependence, which is commonly studied in similar models as increased sensitivity to convulsant challenge, in mice that were chronically treated with diazepam for different times. After discontinuation of diazepam conditioning, the authors examined the latency to convulse induced by the convulsant challenge (Perrault et al., 1992). The development of tolerance and physical dependence are among the most serious side effects of benzodiazepine therapy. Importantly, BPC 157 has anticonvulsant activity against several challenges (Sikiric et al., 2013; Lozic et al., 2020).
Homotaurine (GABAb)
NS-105 (GABAb)
- https://pubmed.ncbi.nlm.nih.gov/9424016/
- Biochemical data showed that repeated administration of NS-105 increased the number of GABA(B) receptors in rat cerebral cortex
Protective/Potentiation:
Afobazole / fabomotizole (GABAa)
- https://pmc.ncbi.nlm.nih.gov/articles/PMC10253922/
- First, fabomotizole prevents stress-induced decrease in binding ability of the GABAA receptor’s benzodiazepine site. Second, fabomotizole is a Sigma1R chaperone agonist, and exposure to Sigma1R antagonists blocks its anxiolytic effect.
American Ginsing
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779932/
- GABA-ergic mechanism could be involved in the neuroprotective effect of P.quinquefolius against sleep deprivation induced anxiety-like behavior, oxidative stress, mitochondrial dysfunction, HPA axis activation and neuroinflammation.
Oleamide
- https://pubmed.ncbi.nlm.nih.gov/9620523/
- Oleamide potentiates benzodiazepine-sensitive gamma-aminobutyric acid receptor activity
- https://www.nature.com/articles/1395784
- GABA Phosphorylator
Unsure:
Menthol/Peppermint Oil
- Like Inhaled Propofol?
Kava
Caffeine
Berberine
- https://pubmed.ncbi.nlm.nih.gov/16516421/
- Binds GABAa Benzo Site
Silexin
Muscimol
Emoxypine Succinate / Mexidol
- https://pmc.ncbi.nlm.nih.gov/articles/PMC9389226/
- Mexidol has been shown to increase binding interaction at GABA-benzodiazepine receptor complex (Iasnetsov et al., 2012). As an anxiolytic agent, Mexidol exerts a GABA-modulating action and may be used in the treatment of acute strokes
Archived into the Nootopics wiki from r/NooTopics — originally posted by u/makefriends420 on 2026-02-01. Curated, not authored by the community.
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