Summary:
Caffeine consumption 30-60mg it’s prior to Sabroxy is the best way to capture its stimulatory effects (Dopamine transport inhibition and KOR antagonism) at the expense of its pro neurogenesis and BDNF. If the goal is to increase focus and attention we want to avoid the A2A agonist properties, preloading with a competitive antagonist at A2A (like caffeine) prevents this A2A agonism by blocking the orthosteric site on the receptor. This increase arousal by preventing inhibition of key nuclei involved in the release of norepinephrine, acetylcholine, serotonin, and histamine all of which collectively contribute to concentration and focus by maintaining the conditions for wakefulness.

Sabroxy® is a premium standardized extract derived from the bark of Oroxylum indicum, delivering exactly 10% oroxylin-A (ND product overview)

In vitro studies showed that oroxylin A inhibited DA uptake similar to methylphenidate, a dopamine transporter blocker, but did not influence norepinephrine uptake unlike atomoxetine, a selective NE reuptake inhibitor.

Citation:
Yoon, S.Y., dela Peña, I., Kim, S.M. et al. Oroxylin A improves attention deficit hyperactivity disorder-like behaviors in the spontaneously hypertensive rat and inhibits reuptake of dopamine in vitro. Arch. Pharm. Res. 36, 134–140 (2013). https://doi.org/10.1007/s12272-013-0009-6

Overall, oroxylin A might regulate BDNF production in cortical neuron through A2A receptor stimulation
[…A2A agonist] which promotes cellular survival, synapse formation and neurite extension

Citation:
January 2012Biomolecules and Therapeutics 20(1):27-35
DOI:10.4062/biomolther.2012.20.1.027

A2A receptors are inhibitory G of i/o leading to decreased activity.

A2A receptors are expressed in key brain regions associated with arousal (energy and wakefulness NOT sexual arousal) and attention, specially the Tuberomammilary nucleus (TMN) responsible for histamine release a key neurotransmitter associated with consciousness/wakefulness and is generally precognitive, locus coeruleus (LC) the primary source of Norepinephrine (NE) in the brain which is probably equally if not more important for arousal and sustained attention and is one of the three foundational neurotransmitters/neuromodulatory involved in sustained attention and concentration, as well as the Dorsal Raphe Nucleus (DRG) the primary source of serotonin/5-hydroxytryptamine (5-HT) Brain also invoked in modulating the excitability and sensitivity of neuronal circuits throughout the brain.

Lastly, we have the Lateral Dorsal Tegmental Nucleus (LDT) and the pedunctopontine tegmental nucleus (PPT) these are big sources of acetylcholine.

NE+DA+ACh are the core neurotransmitter needed for focus and attention. Sabroxy blocking this receptor leads to reduced levels of arousal

A lesser known fact is Baicalein is a KOR antagonist. Kappa opioid receptors function like brakes on the dopamine system so reliving this inhibition would increase DAergic activity

In the study, we found that the isolated compound baicalein (3) has shown the most potent and competitive antagonistic activity at 20 mg/kg dose in vivo experiments. The acute dose of 3 (20 mg/kg) and pan opioid receptor antagonist naloxone (20 mg/kg) block the morphine-induced antinociception and the paw withdrawal latency decreases up to 8.3 s and 9.6 s, respectively. The in silico studies also support our in vitro data that compound 3 binds with MOR and KOR.

Citation:
Singh, K., Yadav, A., Khan, S., Shukla, A., Alam, M., Verma, A. K., … Dev, K. (2025). Baicalein isolated from Oroxylum indicum acts as a potent µ- and κ-opioid receptor antagonist agent via the reversal of agonist-mediated cAMP inhibition. Natural Product Research, 39(23), 6837–6845. https://doi.org/10.1080/14786419.2024.2396452

DRI+KOR antagonism+GABA-A NAM work together to increase focus and now with the A2A agonism blocked you can fully harness the stimulatory benefits. I also like to take a cold shower with Sabroxy to promote NE+DA release and with the DRI effect they work synergistically.

Also, my guess is that the MOR antagonism may be partially responsible for the increase anxiety reported and if you’re actively taking opioids this may intervene with the analgesia due to reduced cAMP suppression from Baicalein.

This article examines the ideological and institutional forces that led to the marginalization of homeopathy in American medicine, despite its popularity among prominent figures, including John D. Rockefeller.

>Even though John D. Rockefeller Sr., America’s richest man and first billionaire, provided substantial financial support to conventional medical schools and institutions, his personal medical care was supervised by doctors specializing in homeopathic medicine, a completely different type and style of treatment.

>According to Kirschmann in A Vital Force, not only did Rockefeller use homeopathic physicians, but all of the Standard Oil families sought homeopathic care, primarily with Dr. Merrick. Merrick was highly respected by both homeopathic and conventional physicians, and it was rumored that various conventional obstetricians secretly consulted with her on their more complex cases.

>Small-molecule natural products (NPs) have a long and successful track record of providing first-in-class drugs and pharmacophore (scaffolds) in all therapeutic areas, serving as a bridge between modern and traditional medicine. This trajectory has been remarkably successful in three key areas of modern therapeutics: cancers, infections, and CNS diseases. Beginning with the discovery of morphine 200 years ago, natural products have remained the primary source of new drugs/scaffolds for CNS diseases.

>In this perspective, we address the question: why are the majority of active compounds in the CNS domain natural products? Our analysis indicates that ∼84% approved drugs for CNS diseases are NPs or NP-inspired, and interestingly, 20 natural products provided more than 400 clinically approved CNS drugs. We have discussed unique physicochemical properties of NPs and NP-inspired vis-à-vis synthetic drugs, isoform selectivity, and evolutionary relationship, providing a rationale for increasing focus on natural product driven discovery for next-generation drugs for neurodegenerative diseases.

>In this study, we designed and synthesized novel 5-HT2A partial agonists based on the structures of the antipsychotic drug aripiprazole and our previously reported lead compound IHCH-7086. Two series of new compounds were synthesized, a number of which exhibited potent 5-HT2A partial agonist activity in G protein coupling and β-arrestin2 recruitment assays.

They "rediscovered" a desmethylene-type LSD analog (see 23m) similar to compound 11 from this patent.

This is a spicy meatball (but a fresh preprint so proceed with caution)

Coming from the Roth lab, is a challenge to decades of work coming from Javier Gonzalez Maeso's lab (oooh drama) - while there is still an established functional relationship between 5HT2A/mGlu2 - the Roth lab, using cutting edge technology, was unable to discern a physical interaction between the two in vitro/vivo. A good read for the mechanistic psychedelic enthusiast 🌝

Abstract:

is well established that activating the mGluR2 metabotropic glutamate receptor (mGluR2), which is the main presynaptic autoreceptor for glutamate in the brain, attenuates the behavioral and electrophysiological actions of LSD and other psychedelics. However, the mechanisms responsible for these actions are controversial. The two competing mechanistic hypotheses have been proposed to explain this phenomenon are: (1) direct actions mediated by mGluR2/5-HT2A heterodimers, and (2) inhibition of 5-HT2A-mediated excitation of pyramidal neurons via presynaptic inhibition of glutamate release by mGluR2 receptors. Consistent with prior reports, we show mGluR2 agonist pretreatment attenuates the head twitch response induced by the psychedelic drug 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in these mice. We next employed multiple orthogonal in vivo and in vitro approaches to explore the potential for direct physical interactions between mGluR2 and 5-HT2A receptors. We next engineered mice to express mGluR2-mCherry-CT and 5-HT2A-eGFP-CT tagged receptors and found no evidence for receptor colocalization or oligomerization under basal or 5-HT2A agonist-exposed conditions in vitro or in vivo. Radioligand binding and kinetic analyses revealed no evidence for mGluR2-mediated modulation of 5-HT2A ligand binding in vitro or in vivo. Collectively, our findings support models in which mGluR2 signaling modulates the activity of Gq-coupled 5-HT2A receptors in layer V pyramidal neurons, rather than models positing the requirement of mGluR2/5-HT2A multimers.  

Abstract

Ketamine offers rapid relief for treatment-resistant depression and severe pain in the clinic, providing immediate benefits that traditional medications often fail to deliver. While its antagonistic action at the N-methyl-D-aspartate receptor (NMDAR) is a key mechanism, ketamine’s dual nature as both a promising treatment and a drug with abuse potential suggests its therapeutic effects extend beyond NMDAR inhibition. Here we provide structural evidence of human opioid receptors bound to ketamine and its parent analog phencyclidine (PCP), supporting that both ligands can directly bind and activate opioid receptors. The structures, together with site-directed mutagenesis and structure–activity relationship studies, identify key motifs involved in ketamine and PCP recognition and efficacy modulation. Furthermore, we determine the structure of the ligand-free state of human κ opioid receptor, revealing molecular details before ligand engagement. Compared to PCP, ketamine displays more notable binding dynamics in the orthosteric site that may contribute to its unique pharmacology at opioid receptors. Our findings highlight the importance of including opioid receptors to fully understand ketamine’s versatility in clinical settings.