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Mood Beyond SSRIs: GB-115, ACD856 & Tianeptine

By Nootopics July 3, 2026

Research and education, not medical advice.

The thesis

SSRIs are becoming objectively obsolete for broad treatment, with both ends of the neurotic spectrum (anxiety, depression) now more than sated by just two substances while simultaneously showing promise for cognitive gains, with trials showing no/ very minimal side effects. This is something I’ve always wanted to pull off at scale, and it seems things have consolidated a lot from where they were.

GB-115 covers anxiety. ACD856 plus Usmarapride cover depression, and both potentiate the BDNF-mediated nootropics we already use. Stop talking to LLMs for your pharma research because they keep saying nonsense. Below is the actual pharmacology.

For the cognition side of this same machinery (TrkB, AMPA, BDNF), see Raising IQ.

GB-115

Benzodiazepines are up there with the most barbaric drugs in circulation, complete with a well documented risk profile ranging from cognitive impairment, abuse potential, and one of the most dangerous withdrawal syndromes known to date. This, among other things, make anxiety treatment a necessary target for innovation.

GB-115 is a dipeptide, which has only just recently been approved in Russia under the brand name of “Ranquilon”. The clinical data with this is of particular interest to our sect of biohacking, as it not only improved anxiety in people suffering from Generalized Anxiety Disorder (GAD), but it also enhanced attention, information processing and reaction speed. Contrasting with prior treatments, these effects only grew better with time, making for a lasting therapeutic effect. In addition to these compounding benefits, GB-115 lacks the side effects, abuse potential and toxicity that is present in so many of these drugs. While the jury is out on whether or not GB-115 has the capacity to enhance intelligence in non-anxious people, it is certain that it does in those with GAD, and has among the highest rates of remission I’ve personally seen for anxiety. GB-115 also aides mental fatigue, and has been characterized as possessing pseudo-stimulatory properties.

Mechanism

Three primary receptor targets (CCK1, KOR and BRS3 receptors) were determined for GB-115 which is in accordance with data obtained in behavioral studies demonstrated three dome-shaped curve “dose-effect”. Low doses of GB-115 blocked central CCK1 receptors despite the low affinity, making this the central mechanism, and a secondary role goes towards BRS3 antagonism due to its nature of disinhibiting GABAergic systems under emotional stress and reversing orexinergic hyperactivation. KOR, on the other hand, would be otherwise understood as an anxiogenic mechanism, however in the literature isn’t, as it only became relevant at exceedingly high doses orders of magnitude higher than those targeting CCK1, wherein it relieved pain. But at no point did GB-115 ever become anxiogenic meaning it was likely overpowered by the other two mechanisms. [2]

Initially this effect of GB-115 was attributed to antagonism at CCK2, but this isn’t likely to be the case, due to the high selectivity of GB-115 to CCK1 over CCK2, a shocking revelation, and likely why CCK2 ligands developed by western pharmaceutical companies were unsuccessful in treating anxiety. [2] [3] However, it all makes sense, because CCK2 modulates acute anxiety, whereas CCK1 modulates chronic anxiety, neatly tying together the results observed with GB-115 in clinical trials. [4] Indeed it would also seem that blocking CCK prevents fear from becoming chronic, suggesting a strong synaptogenic shift. [5] Another possible mechanism by GB-115 would be a reduction in cortisol, wherein it was shown to do this in nonhuman primates, with therapeutic strength comparable to a benzodiazepine. [6]

Intranasal

GB-115 has a half life of 0.6 - 1 h, and was detectable for up to 6 hours depending on dose. The drug is quickly absorbed into the systemic bloodstream, but has an oral bioavailability of only 4.65 %, hence why Everychem has formulated it as a spray, as intranasal regularly achieves 90%+ absorption for many compounds and is less invasive than injection. [7] [8] I’ve read dozens of studies where compounds with low oral bioavailability were almost completely absorbed via intranasal and I believe that to be the case here as well.

It’s nothing like phenibut. Doesn’t bind at GABA or at calcium channels.

Trials

GB-115 displays procognitive effects that build over time: In 25 GAD patients, cognitive evaluations done on day 3, 7, 14 & 21 found increased reaction speed on days 7, 14, & 21 compared to baseline. Attention was found to be improved on the day 3 and day 21 of treatment compared to baseline. Decrease of time in performance of tables of Shulte-Platonov was found on day 7, day 14 and day 21 compared to baseline. [9]

6mg GB-115 caused improvement to GAD in 92% of patients: In another phase 2 clinical trial for GAD (n=31), 6mg was determined to be the superior dose. A therapeutic benefit manifested by day 3, again at day 7, and reaching very high significance by day 21 (92% of patients had moderate to very strong improvement to their GAD symptoms). Additionally, unlike benzodiazepines, GB-115 does not relax muscles, reducing the danger one would otherwise experience with similarly focused drugs. [10]

In a phase III clinical trial totaling 220 patients, they continued with the 6 mg dose. 70.0% of GB-115 patients achieved ≥50% reduction in Hamilton Anxiety Rating Scale (HARS) score at day 29, vs. 24.5% for placebo. All secondary efficacy criteria showed statistically significant improvement with GB-115 compared to placebo across HARS, Clinical Global Impression, Multidimensional Fatigue Inventory & Spielberger-Hanin scales, and 100% of the GB-115 group reached below moderate anxiety at day 29 vs 62.7% for the placebo group. [11] 25.5% of the GB-115 group vs. 14.6% of the placebo group reported adverse effects, however the authors report the difference as non significant, with all adverse events being classified as mild, and no one dropping out of the trial due to them. [11] This is consistent with the phase 1, and phase 2 trials as well, all of which indicate a very high level of safety, and near imperceivable side effect profile comparable to placebo.

It’s only designed for chronic use, doesn’t achieve as great remission in the early phases. No sleep impairment. Improvement to daytime sleepiness. It doesn’t interact with GABA, its use case regarding a benzo taper would be counteracting anxiety.

ACD856 + Usmarapride

ACD856, TrkB Positive Allosteric Modulator (BDNF PAM)

ACD856 is a neurotrophic growth factor-enhancing nootropic with antidepressant, and neuroprotective properties. It is currently being researched for Alzheimer’s. The mechanism is thought to underlie current antidepressant medications, while it is yet to be tested for nootropic potential despite the high likelihood. ACD856 is a pan positive allosteric modulator of Trk-type receptors, increasing the binding at TrkA, TrkB and TrkC. BDNF (TrkB ligand) and NGF (TrkA ligand) are quite famous in the biohacking nootropics community, as they’re known to mediate the activity of many drugs and/ or supplements we’re fond of. This makes ACD856 an interesting auxiliary compound, as by enhancing binding to these receptors it will potentiate actions mediated by neurotrophic growth factors released by other drugs.

Most antidepressants are direct TrkB PAMs

Last year I posted a bombshell study, showing that most antidepressant compounds are direct TrkB PAMs. [1] From this study, the following were found to bind to the allosteric site as a PAM: Ketamine (via its metabolite 2R,6R hydroxynorketamine), Shrooms (via Psilocin), LSD, Fluoxetine, Imipramine. The authors conclude the following: These data suggest the remarkable hypothesis that most (if not all) antidepressant compounds act by directly binding to TrkB’s TMD, allosterically potentiating the effects of BDNF and thereby promoting plasticity. [1] This is hugely significant, as a long understood theory is connected to a centralized mechanism, that being TrkB allosteric modulation, down to a molecular level.

The ketamine theory of depression is that antagonizing synaptic NMDA receptors leads to a release of glutamate, which then binds to extrasynaptic AMPA receptors, which releases BDNF, which then binds to TrkB to promote mTOR in the hippocampus, signaling a survival state to the organism. [2] TAK-653 has also recently passed Phase 2 trials for depression, working as an AMPA PAM and following a similar cascade but averting the anticognitive effects of NMDA antagonism. ACD856 is one of the only selective TrkB PAMs. In relation to TAK-653, which has most consistently elevated IQ in our experiments, ACD856 shows promise for either accomplishing this alone or as a complement to TAK-653. (More on this AMPA/TrkB overlap in Raising IQ.)

ACD856 has passed phase 0, and phase 1 clinical trials wherein administration of the compound to volunteers did not produce side effects. Importantly, the half life of this compound is 20 hours.

ACD856 TL;DR: ACD856 is a TrkB PAM, which is a nootropic and antidepressant mechanism. ACD856 can either be used as an auxiliary compound concomitantly with nootropics that have their effect mediated by BDNF, such as TAK-653 and others, or, it can be used alone.

Usmarapride, 5-HT4 partial agonist

Usmarapride is a hippocampal nootropic with antidepressant, anxiolytic and neuroprotective properties. It is currently being researched for Alzheimer’s. Two studies have validated the mechanism as having nootropic effects in healthy people. A new drug, which ended up blowing away my expectations, and in my experience had an unexpected synergy with ACD856, is Usmarapride. At this time, I believe the pronounced effect to be mediated by a BDNF release into the hippocampus, which then gets enhanced by ACD856. [11]

But Usmarapride alone has a lot going for it, and that is due to Prucalopride having been shown to enhance cognition in healthy people. [12] [13] Usmarapride was designed to be more CNS-selective, and avoid peripheral cAMP promotion, which was especially problematic with Prucalopride and limited its dose viability. This mixed inhibitory potential could explain the anxiolytic activity of the drug, whereas the hippocampal neurogenesis would explain the potent antidepressant effects. [11] [15]

Usmarapride, in a phase 1 trial, was generally safe, but there was a relatively high occurrence of headaches, and rarer occurrence of nausea versus placebo. [16] This is my experience as well, no nausea, but headaches over a dose of 15mg. The subjectively good combination of Usmarapride and ACD856 cannot be understated.

Community feedback

Polling showed that out of ACD856, Neboglamine, TAK-653, and Tropisetron, 50% (60 people) preferred ACD856. This is surprising to me, because the love TAK-653 received was monumental when I first brought it to market. Sure ACD856 has a lot more use cases because so many drugs positively interact with it, and the attempted benefit is broad, but I still wasn’t expecting this level of success from a synthesis.

GB-115 I’ve wanted to make for years, literally since 2022 due to the cognition enhancement and high anxiety remission in GAD patients, but I couldn’t afford it until this year. Already people are saying it changed their lives and is a dead stop to their anxiety. Tons in the discord basically confirming the study.

This year has been way better than those to come before it. And now that these domains are conquered, everychem will have more freedom to tackle other aspects of biohacking. Thanks for believing in me, those who do, I know some of you have even been around since like 2021, I bet you like watching it all unfold as much as I do. Stay posted because it’s not over yet.

Tianeptine: just an opioid

In humans, a single dose of tianeptine (12.5 mg) results in 1 μM maximal concentration of the drug in the plasma. Therefore, the in vivo concentration range appears sufficient for the activation of MOR (EC500.2–1 μM), whereas activation of DOR (EC50~12–34 μM) may only become relevant with higher dosing. This dispels the rumors about Tianeptine being somehow unique in its mechanism. It’s just an opioid.

How does it have a unique mechanism when everything presented just suggests MOR agonism? And if it’s a MOR agonist how would this not lead to significant withdrawal and addiction? It clearly has withdrawal and I’m starting to believe the low doses would have addiction as well. I have to say my faith in tianeptine is a bit low at the moment. I’m not sure if evading respiratory depression is enough incentive to rationalize using an opioid drug. In theory you can just use a similar opioid at a lower dose to achieve its effects. I wonder how realistic it is for Tianeptine patients to stick to antidepressant doses when they are not in a clinical setting. It doesn’t make sense that it would be devoid of the same issues as other opioids.

I’d go for agmatine sulfate, bromantane, D serine and ALCAR before bothering with an opioid. But I no longer have depression, I cured it months ago with Agmatine Sulfate. D-Serine now just enhances my focus and provides an anti-anhedonic effect that I appreciate. ALCAR, endogenous acetylated amino acid, also shows similar efficacy to first line treatment. It is well tolerated in all trials and not linked to addiction or withdrawal. I cant think of a use for opioids outside of temporary moments of extreme pain.

A common narrative on Tianeptine is “it’s not an opioid in low doses”, whereas this source suggests otherwise. As for kratom: Kratom is still highly addictive, it’s just unlikely to cause fatality, which is perhaps its only aspect of rationalization. As someone who has been through it with Kratom, I strongly advise anyone considering it to stay far away. I would avoid completely. I’ve had far better results with nootropics. Even 8g/day was a nightmare. Also it’s funny they say it’s like coffee when coffee contains opioid receptor antagonists whereas kratom does the opposite. It shows how manipulative they are to get people hooked.

See What To Avoid for tianeptine and kratom.

Telmisartan

There was significant reduction in the immobility time in telmisartan group when compared to the control group and this time was comparable with the immobility time of standard drug fluoxetine. As evident from our study, telmisartan can be a newer target for antidepressant effect.

Sources

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