Pharmacopoeia

I’ll proceed to infodump all the relevant substances in the sphere. Read the wikipedia articles, some studies, and spend a bit of time reading anecdotes, and you’ll essentially be pretty caught up with the ‘canon’.

I’ve put personal ratings next to most of the noots I’ve personally taken, but bear in mind subjectivity yields ± a star or 2; no brain/organism is exactly alike and I won’t bother trying to be context-invariant. It’s also on a bit of a relative scale: by all means, I can’t wait for the day all the five-star things I’ve listed pale in comparison to certain future therapies.

I’ve also left out a fair bit of ‘supplements’; I want to focus on compounds with more brain-selective MOAs rather than improving general metabolism/health with cognition being downstream (not that that isn’t perfectly legitimate) as well as whatever pharmeceuticals such as antidepressants where incurring a net benefit is rather far from universal (the lack of side effects is a requirement for being a proper nootropic)

9-Me-BC

Controversy around potential toxicity.

ABT-089

Dose: ~2mg intranasal may be the best. It is orally bioavailable, but there are multiple anecdotes of similar oral doses not yielding comparable effects, instead needing ~8-20mg.

Random α4β2 notes

Structure

Subtypes

Desensitization

Expression

α4β2α5

  • The α4β2α5 nicotinic cholinergic receptor in rat brain is resistant to up‐regulation by nicotine in vivo #Read

    • Suggests a regulatory role for α5 nAChR?
    • Subunit Composition and Pharmacology of Two Classes of Striatal Presynaptic Nicotinic Acetylcholine Receptors Mediating Dopamine Release in Mice
      • α5 nAChR knockout: diminished nicotine-sitmulated dopamine release
      • The β2 subunit is an absolute requirement for both classes. In contrast, deletion of β4 or α7 subunits had no effect
    • Virtually all of the α5-containing nAChRs in the rat hippocampus, striatum, cerebral cortex, and thalamus are α4β2α5 nAChRs.
    • The α5 subunit is associated in ~37% of the nAChRs in the hippocampus, ~24% of the nAChRs in striatum, and 11–16% of the receptors in the cerebral cortex, thalamus, and superior colliculus.
      • The fact that this resistance to up-regulation was seen in four different brain regions, suggests that it is the presence of the a5 subunit, rather than factors such as specific brain region or cell type that confers this property on a4b2a5 receptors in vivo.
      • Density is not even increased by chronic administration of nicotine.
    • Nicotine-induced increases in nAChRs in brain or neuronal cell lines are not accompanied by changes in subunit mRNAs, nor is de-novo protein synthesis of nAChR subunits required (Penget al.1994; Wanget al.1998).
      • Therefore, studies of the mechanisms underlying nicotine-induced up-regulation of nAChRs have focused on post-translational changes, including:
        • Increased assembly of the subunits intoreceptors (Wanget al.1998; Nashmiet al.2003)
          • The much higher level of nicotine-induced up-regulation in most transfected cells may result from the constant driving force of their constitutively active promoter leading to over-expression of nAChR subunits. Thus, the large nicotine-induced increase in nAChRs seen in most transfected celllines may reflect, to a large extent, enhanced assembly and/orincreased maturation of nascent nAChR oligomers formedfrom excess subunits and, to a lesser extent, decreased receptor degradation.
        • Decreased degradation of the receptors (Peng et al.1994;Wang et al.1998)
          • In brain, where a large excess of subunits is less likely to be the norm, this may be a more important mechanism.
            • α4β2 is perhaps rapidly regraded, while nicotine slows this, leading to upregulation (demonstrated in Peng et al.1994; Kuryatov et al.2005), and α5 may slow this down.
        • Increased maturation of nascent receptors (Kuryatovet al.2005;Salletteet al.2005)
        • Conversion of receptors from alow affinity to a high affinity conformation (Buisson andBertrand 2001; Vallejoet al.2005).

  • α5 lacks a Y190 residue found in all other a subunits (Karlin and Akabas 1995), and without this residue it probably cannot contribute to an agonist binding site.

    • In fact, although α5 has the two cysteine residues at approximately positions 192 and 193 that are common to all nAChR α subunits, it has highest sequence homology with the b3 subunit (Boulter et al. 1990). Thus, the a5 and b3 subunits may represent a branch point at which these two classes of subunits diverged.
      • Interestingly, the presence of β3 in α6β2β3 provides resistance to downregulation by nicotine.

  • Ca2+ Permeability of the (α4)3(β2)2 Stoichiometry Greatly Exceeds That of (α4)2(β2)3 Human Acetylcholine Receptors

    • Increased Ca2+ conductance several fold vs. regular α4β2.
      • α4, α5, and β3 subunits all have a homologous glutamate in M2 that contributes to high Ca2+ permeability, whereas β2 has a lysine at this position.
    • We show that Ca2+ permeability is determined by charged amino acids at the extracellular end of the M2 transmembrane domain

Agmatine

Rating: ★★. Helps misophonia, probably from antagonizing eNMDAR (due to being a polyamine site antagonist). eNOS giving you better pumps while antagonizing iNOS and nNOS is really unique as well. I can attest to it being somehow vaguely therapeutic for depression. It’s not too bad of a general supplement, but it’s not all good either (CB1 agonism, nAChR antagonism, PPAR, β-oxidation, etc.)

ALCAR

I personally never bothered with it due to the anti-thyroid/pro-FAO and pro-cortisol effects of carnitine.

Amphetamine

Rating: ★★★. I’m scared it destroys your brain and that I would become addicted, but with the few times in my life I’ve tried it, it made studying advanced topics as effortless as reading the morning paper and yet more engaging than they’ve ever been (this is not news to anyone who knows the slightest thing about adderall) so one simply cannot dock too many points. In fact I think stacking it with (afaik yet-to-exist) compounds that abolish neurotoxicity (such was the dream with antioxidants like Deferoxamine, SkQ1, and Selegiline) is a possible route to ’nootropic escape velocity’. (Related is the study of MDMA by QRI, et al. which is a whole different monster)

Dextroamphetamine

Stick with this. More dopaminergic and mental without the peripheral side effects.

Methamphetamine

Long-Term Treatment with Low Doses of Methamphetamine Promotes Neuronal Differentiation and Strengthens Long-Term Potentiation of Glutamatergic Synapses onto Dentate Granule Neurons

The neuroprotective potential of low-dose methamphetamine in preclinical models of stroke and traumatic brain injury HED = 0.08 mg/kg = ~5.5mg.

Ashwagandha

Like most herbals, it does way too many things. I wouldn’t fuck with it.

ASP2905

KCHN3 inhibitor, which is concentrated in the frontal lobe. This potentiates the recurrent excitation of delay neurons via preventing K+ efflux out of the dendritic spine in the PFC, a central component of working memory (cf. Amy Arnsten’s research on the dlPFC, guanfacine, etc.):

Anecdote: methylphendate-like headspace.

ASP4345

D1 PAM.

Atomoxetine

Bacopa

  • AChEi, ChAT activation, monoamine potentiation, lowers blood pressure.

Brilliant Blue G

P2x7 antagonist.

P2X7

Extracellular ATP

Neurogenesis

  • immature neurons fire much more quickly and are more disinhibited and have a much higher p2x7 receptor expression than should mature neurons. Increased p2x7 activity should disinhibit young neurons and that would be responsible for increased plasticity in young neurons but it also contributes to cell death

Bromantane

Rating: ★★★. Never noticed much besides an increase in verbal fluency, especially since the benefits are long-lasting.

Its primary action is upregulation of Tyrosine Hydroxylase, AADC, and increasing GDNF (possibly via HDAC1 inhibition, extrabolating from the other adamantane-containing drugs like amantadine and memantine). PDE10 inhibitor. GAT-3 inhibitor in high doses. Possible inhibitor of Kir2.1.

Bupropion

Some bad some good.

  • Atypical antidepressant. NET/DAT (in high doses) inhibitor and non-competitive antagonist of α4β2, α3β4, and α1β1γδ.
  • Bupropion metabolites pharmacology
    • Compare to dl-Methylphenidate’s DAT/NET IC50 of 20 and 51 respectively (.35 vs .39 ratio). The difference is in the metabolites as you can see.
  • Bupropion metabolism
  • Associated with a high risk of release of mediators from mast cells. I don’t think it activates H1 though.
  • Psychopharmacology of bupropion in normal volunteers.
    • α3β4 nAChR antagonism isn’t cognitively impairing.
  • [Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects]
    • Dwoskin (2006) can exacerbate depression and increase suicidal thoughts.
    • Should be administered early in the morning as it exacerbates insomnia.
    • Vivid dreams, hallucinations, unusual thoughts/behavior, confusion, tremors, agitation, anxiety, swollen glands, joint pain, increased blood pressure
  • Inhibits CYP2D6 (58 mM IC50?)
  • [Seizures after overdoses of bupropion intake]
    • Pronounced increase in catecholamines is the main factor, I believe. QT prolongation can be seen.
  • [Alcohol significantly lowers the seizure threshold in mice when co-administered with bupropion hydrochloride]
    • In mice, 116mg/kg (660 HED) without, or 89.4 for ethanol/bupropion.
  • Bupropion increases striatal vesicular monoamine transport
    • Rapidly, reversibly, and dose-dependently increased vesicular DA uptake; an effect also associated with VMAT2 protein redistribution.

Caffeine/Coffee (Coffeine)

Rating: ★★★★. Pure Wakefulness is capable of eliciting divine euphoria and connection to the universe, and I thrive on the noradrenergic drive it gives, BUT I think the long-term effects on the brain are questionable. I am currently taking a break until further notice.

Cerebrolysin/Cortexin

As a vegan I haven’t exactly bothered into looking into it too much, but there’s a lot of info and anecdotes on the NooTopics discord server. (This goes for most things).

It’s pretty infamous for a certain Longecity thread where he was convinced prions were giving him strange autoimmune reactions. There have been absolutely zero reports of this in the literature. The presence of prions is impossible: prions are ≥25 kDa, whereas peptides are filtered such that they don’t contain peptides >5 kDa. This single user did quite a number on cerebrolysin’s whole reputation; something truly surreal.

Citicoline

Rating: ★★. I’m super sensitive to this stuff and get existential depression from taking any dose worth its salt. It does increase concentration before that kicks in though.

One of the better choline sources.

Choline

Made primarily in the liver via phosphatidylethanolamine methylation.

  • https://chrismasterjohnphd.com/blog/2010/12/04/meeting-choline-requirement-eggs-organs/

    • The Sweet Truth About Liver and Egg Yolks — Choline Matters More to Fatty Liver Than Sugar, Alcohol, or Fat
      • Lab rats are choline deficient. It is capable of completely protecting lab rats against NAFLD induced by sugar+fat+alcohol.
        • So, pregnant rats fed 3x their normal amount had their progeny see a lifelong 30% increase in visuospatial and auditory memory.
      • Effect of different dietary fats on choline requirement of rats (1957)
        • Saturated fats require more choline than PUFAs to prevent liver steatosis.
      • This is rather remarkable, because much lower concentrations of sucrose started spontaneously producing fatty liver disease in lab rats in the late 1970s and early 1980s once the American Institute of Nutrition set standards for purified rodent diets that relied exclusively on isolated vitamins and minerals rather than whole-food supplements like cod liver oil, yeast, and wheat germ.

  • Choline Redistribution during Adaptation to Choline Deprivation

    • Deprivation is achieved by feeding PEMT-/- mice a choline-deficient diet. Lethal due to liver failure. Apparently lacking MDR2 (multiple drug-resistant protein 2) allows hepatic choline recycling!
      • The mice lacking PEMT still initiated choline redistribution.
    • Normal levels of choline-containing metabolites were maintained in the brains of choline-deficient Mdr2–/–/Pemt–/– mice for 90 days despite continued choline consumption via oxidation. Choline oxidase activity had not been previously detected in the brain. Plasma levels of choline were also maintained for 90 days, whereas plasma phosphatidylcholine levels decreased by >60%.

  • By weight, the more common forms:

    • PC increases choline stores and is ~13%.
    • Alpha-GPC is more for enhancing its release in the brain, and is 40% choline by weight.
    • ‘Lecithin’ is 10-20% PC, thus like 1-2% choline.
    • Phosphatidylcholine = 15%.
    • Citicoline is ~18.5% by weight.
    • Betaine is worth something like 25% its does in choline?
      • CMJ recommends to have it be ≤50% of choline intake if you choose to supplement with it.

  • I think supplementation-induced depression is possibly from excessive methylation via conversion into Trimethylglycine and onwards to DMG → sarcosine. Longecity. Another explanation is maybe overencoding of negative experience due to excessive brain ACh R

  • Water-soluble choline bompounds (PChol/GPC) can enter the portal circulation of the liver intact. Lipid-soluble (PC/SPM (sphingomyelin) are either hyrdrolysed by phospholipases or enter the lymph incorporated into chylomicrons. R

Requirements

  • CMJ - Meeting the Choline Requirement — Eggs, Organs, and the Wheat Paradox
    • Bear in mind only methionine can actually be used to make choline, while B6/8/12 and TMG merely spare it.
    • PEMT ctually creates homocysteine in the process of creating choline! So, if your PEMT is running smoothly, you can make your own choline, but you still need more betaine and B vitamins to neutralize the homocysteine that’s generated in the process. If your PEMT engine is working like this, however… well, then, you’ve got another problem: If PEMT isn’t using up your methionine to make choline, the methionine is just going to go further on down that pathway shown above and make more homocysteine anyway! Thus, although having a PEMT gene that Uncle Buck would surely envy might lower our choline requirement, consuming lots of methionine won’t help us at all. In fact, extra methionine just gives us more homocysteine and thereby increases our need for choline, betaine, folate, B12, and B6.
  • The Chris Masterjohn calculator says I need 1124 mg Choline daily. WTF!
    • The calculator uses SNPs in the folate transporter (SLC19a1, rs1051266, G80A), the enzyme that helps make the precursor to methylfolate (MTHFD1, rs2236225, G1958A), and the enzyme that helps make methylfolate itself (MTHFR, rs1801131, A1298C and rs1801133, C677T) to develop a “methylfolate score.” This is used to calculate how much choline you should aim for.
    • It then uses a polymorphism in the enzyme that helps make phosphatidylcholine, a specific form of choline that protects against fatty liver disease, promotes gall bladder health, and facilitates healthy digestion of dietary fats and absorption of fat-soluble vitamins (PEMT, rs7946, 5465G>A). This is used to tell you the likelihood that missing your choline requirement will hurt these functions in your body.

Clausenamide

  • The anti-dementia drug candidate, (−)-clausenamide, improves memory impairment through its multi-target effect (2016)
    • Mild elevation of intracellular Ca2+ concentrations -> neuron survival + outgrowth & antagonism of neural apoptosis induced by growht factor deprivation.
      • Intracellular Ca2+ levels are mainly regulated by the following factors: (1) extracellular Ca2+ influx into the cytoplasm, (2) Ca2+ release from intracellular stores, (3) Ca2+ clearance via either outflow from the cytoplasm to the extracellular space or accumulation into internal Ca2+ stores, and (4) cytoplasmic Ca2+ buffering.
    • Modulation of the cholinergic system
      • In vitro promotion of ChAT in frontal cortex neurons -> suppored cholinergic neuron survival + neurite outgrowth & synaptosomal ACh release.
      • In vivo: Increased ChAT in the neocortex, hippicampus, and sitratum: [Effects of (-), (+)clausenamide on anisodine-induced acetylcholine decrease and associated memory deficits in the mouse brain (1998)]. reversibly inhibited ACE with much lower potency than inhibitors like galantamine.
    • Upregulation of synaptic plasticity
      • There are two forms of LTP in the hippocampus: N-Methyl-D-aspartate-(NMDA-) or VGCC-dependent LTP. Clau induced the latter. LTP is not inhibited by nimodipine, indicating VGCC (potentiation) is only necessary for induction but not maintenaince.
      • Did not bind to NMDAR, indicating it is NMDAR independent: [Effects of (-), (+) clausenamide on central N-methyl-D-asparate receptors in rodents (1997)].
      • APV, an NMDAR blocker, had no effect on clau-induced LTP: [Two forms of long-term potentiation induced by different compounds (Xu et al 2007)]
      • However, chronic administration of clau promoted the expression of synaptic NMDA receptors:
        • (1) increasing NMDA receptor density in synaptic membranes,
        • (2) increasing NMDA receptor affinity to their endogenous ligands as indicated by the (-)-clau-increased Bmax values of NMDA receptors in the synaptic membrane, and
        • (3) ameliorating oxidative stress-induced synaptic membrane fluidity, which facilitates NMDA receptor turnover in synaptic membrane.
      • Increased mossy fiber sprouting and expression of GAP43
    • Activation of cellular and molecular signaling pathways involved in learning and memory.
    • Inhibits Tau hyperphorsphorylation and Amyloid β-induced intracellular Ca2+ overload.
      • APP mice are generated by overexpression of the mutant APP gene and are characterized by senile plaque overload and related apoptosis in the central nervous system.
      • There’s a Chinese study out there where it improved symptoms in human Alzheimer’s patients - 400mg/week, once a week.
      • Anti-apoptotic in five regards:
        • (1) low potassium in cerebellar granule cells, (2) growth factor deprivation in cortical neurons,
        • (3) 6-OHDA in high BAXα-expressing PC12 cells,
          • Inhibited BAX-α-induced cytochrome C release, possibly by increasing glutathione content?
        • (4) ischemia/reperfusion in rats, and (5) Aβ1-40 infusion- and natural aging in rat brain
        • Inhibits expression of p53, c-Myc, etc.
        • PKC-MEK negatively regulates GSK-3β (-> Tau hyperphosphorylation.) Akt and mitogen-activated protein kinase enhance C-type lectin-like receptor 2-mediated platelet activation by inhibition of glycogen synthase kinase 3α/β (CLEC-2 and GPVI (potentiated by AKT/MAPK:) activate platelets through Src, Syk, and PLCγ-2)
        • And Clau surely increases PKC, which was shown in Xu 2005. Clau-induced microtubule protection was at least in part mediated by PP1, responsible for tau dephosphorylation.
    • They go relatively in-depth regarding its chemistry. Its nootropic effects are chirality-dependent. Clau was more potent than piracetam (5-10mg/kg vs. 500mg/kg respectively) for improving performance in memory-impaired animals.
  • Previously, Recent advances in the study of (–)clausenamide: chemistry, biological activities and mechanism of action (Oct 2014)
    • NGF & BDNF induce small elevations of Ca2+ in neurons
    • Shown to be a potassium channel antagonist (preventing efflux) and inducing membrane depolarization.
  • (−)Clausenamide facilitates synaptic transmission at hippocampal Schaffer collateral-CA1 synapses (2012)
    • Calcium release from endoplasmic reticulum is mediated by two main types of receptors: RyRs and IP3-Rs. Ryanodine blockage of RyR suppressed synaptic facilitation, whereas IP3 blockage showed no effect, suggesting even PLC might not even be involved.
    • CAMKII dependent.
    • PKA inhibitor: no effect.
    • So it’s turning out to be a slightly exotic cascade, I guess. VGCC -> RyR -> CAMKII -> CREB -> Egr1, BDNF, etc. - CAMKII -> p-ERK peaked 5 and 30 minutes in hippocampus and cortex respectively. p-nCREB 9 minutes after.
  • Study on the Nootropic Mechanism of (-)Clausenamide - Influence on the Formation of Synapses in Mouse Brain (Jiang & Zhang (1998/2006)
  • ()-Clausenamide Potentiates Synaptic Transmission in the Dentate Gyrus of Rats (Xu et al 2005)
  • Physiological signature of a novel potentiator of AMPA receptor signalling (Szulc et al., 2018) not even chinese
    • We have synthesized a novel small molecule based on the pyrrolidinone–containing core structure of Clausenamide.: BRS-015
    • Overall quite similar to clausenamide; no NMDAR effects, chirality, etc. They hypothesize AMPA potentiation is via CAMKII -> γ-8.
    • Potentiated inward currents evoked by local application of l–glutamate onto CA3. It facilitated the induction of mossy fibre LTP, but the magnitude of potentiation was smaller than that observed in untreated slices.
    • Asymmetrical synapses between large mossy fibre terminals and thorny excrescences in CA3 pyramidal neurons contain an average number of AMPA receptors exceeding 4 times the number reported for C/A synapses.
    • C/A (not CA) synapses can be void of AMPAR, while mossy fibre synapses have smaller variability.
    • High-resolution immunogold localization of AMPA type glutamate receptor subunits at synaptic and non-synaptic sites in rat hippocampus
      • Higher GluR1 expression at A/C (associational/commissural synapses) synapses, compared to mossy fibre synapses which have subtypes more equally.
        • Well that’s a whole other rabbithole.
  • [Activation of ERK1/2-CREB pathway during potentiating synaptic transmission of (-)clausenamide in rat dentate gyrus. (2012)]
  • Increases Choline Acetyltransferase.
  • Gintrux: The cortex begins to thin after the age of five or six as part of the normal aging process. This study is the first to show the association between cortical thickness and development in full scale IQ, and has potentially wide-ranging implications for the pedagogical world and for judicial cases in which the defendant’s IQ score could play a role in determining the severity of the sentence
    • Could this be a correlate for the cut-off point for development intelligence in early life?

Cordyceps Militaris

Rating: ★★. Noticeable increase in endurance, but I think its long-term effects on D2, adenosine, and lovastatin content are questinoable.

D21

aka TAT-D21.

Calcium

  • Perhaps it’s been known well that D1 activates phospholipase C? D2 agonists potently enhance AA release, initiated by increasing intracellular Ca2+ or stimulating constitutive purinergic receptors - which trigger Ca2+. Naturally, all this stimulates phospholipase A2. R.
  • Calcium signaling cascade links dopamine D1-D2 receptor heteromer to striatal BDNF production and neuronal growth
    • CAMK IIα increases BDNF expression.
  • Rats have a lower prescence and importance of the heteromer in their brains than humans. The further up in intelligence you go across species, the more prevalent. It implies that the heteromer counteracts brain power/force in some way, and it does play the role of a negative dopamine regulator (it lowers dopamine transmission in general by lowering dopa release). In theory, society is like a Swiss army knife in making the d1/d2 heteromer appear. (wtf? lol stoner.)
  • Dopamine D1 and D2 Receptor Co-activation Generates a Novel Phospholipase C-mediated Calcium Signal (Lee et al. 2004)
    • Coexpression barely changes adenylyl cyclase activity in these cells compared to D1 alone. PKA, PKC, or PI3K inhibition did not change calcium levels, but PLC inhibiton shut it down >90% (and blocked Gq-coupled P2Y receptors along the way).
    • Gi/o is not directly involevd in the calcium signal. Gi and Gq crosstalk does not appear to underlie, since neither couple to Gq to begin with. Good reasoning?
    • Virtually all Medium Spiny Neurons that express D1 also technically express D2.
    • Coexpression did not affect the ligand binding pocket of either receptor.
    • In the rat frontal cortex, interneurons only expressed D2, unlike pyramidal neurons.
    • Heteromers of the CCR2 and CCR5 chemokine receptors and heteromers of the μ- and δ-opioid receptor may couple to G proteins distinct from those associated with homogeneous populations of their constituent receptors, but interestingly the cellular responses is not different from that of the individual receptors.
  • Dopamine receptor-mediated Ca(2+) signaling in striatal medium spiny neurons (Tang et al. 2004)
    • ~40% MSN elicit robust repetitive Ca2+ oscillations following application of dopamine - PLC-dependent.

Deferoxamine

Rating: ★. Didn’t notice anything. See: Scattered Notes: Deferoxamine

Dihexa

High affinity to hepatocyte growth factor and potentiates c-Met, the protein it encodes.

Pretty controversial. It’s supposedly 7x more potent than BDNF for improvint alzheimer’s-like cognitive impairment. This sounds awesome to a lot of people but it really dosen’t help.

  • Dihexa is not bdnf
    • Bam says Dihexa mainly works in the sensory systems, but notes it’s weird how the cortical systems increase autistic symptoms from being given different sensory information?

Donepezil

  • Developed under the ‘cholinergic hypothesis’ of Alzheimer’s, i.e. over-activation of ACE, which isn’t always the truth let alone the whole story.
  • Acetylcholinesterase inhibitor and σ1 agonist (14.6 nM).
    • Non-competitive inhibitor, unlike galantamine
  • Inhibits voltage-activated Sodium Channel currents and delays Kir currents and fast transient potassium currents.
  • [Mechanisms of alpha7-nicotinic receptor up-regulation and sensitization to donepezil induced by chronic donepezil treatment.]
    • Upregulates α7 nAChR in the hippocampus. This was prevented by coadministration with PI3K inhibitor.
  • Donepezil impairs memory in healthy older subjects: behavioural, EEG and simultaneous EEG/fMRI biomarkers
  • Donepezil modulates nicotinic receptors of substantia nigra dopaminergic neurones
  • Modulates α4β2, I think.
    • Depressed Nicotine currents that were in vitro “induced by brief puffer pulses, through a glass micropipette positioned above the slice”.

D-Serine

Obsoleted by Neboglamine. Sarcosine is also a safer option.

Erythropoietin

There’s demonstrated proof that engaging in cognitive work increases the long term potentiation or the “connections between neurons” through a variety of mechanisms and models that test this are called “environmental enrichment” within the literature. Increasing the load or demand that we place on our neurons when we learn strengthens the connections between neurons as well as neuronal morphology through induction of functional hypoxia.

Neurogenesis

Epobis

Galantamine

I don’t believe it has tolerance, but it and other rapidly irreversible AChEis upregulate AChE with long-term use: Acetylcholinesterase and its inhibition in Alzheimer disease

Ginkgo Bilboa

Rating: ★★. I don’t really notice anything (Swanson brand. Maybe I’ll try Ginkgold one day).

The anecdotes: improves focus and (long-term) memory.

Guanfacine

Rating: ★★. It’s not for me—but I can see it being very helpful for some. When you read about people being prescribed Intuitiv (guanfacine XR), etc. they’ll describe it as removing an element of anxiety, and that removing sudden drives to action makes it easier to focus. But I’m on the other side of the coin; having that ‘push’ is totally how I’ve learned to work.

  • Effects of acute and sub-chronic administrations of guanfacine on catecholaminergic transmissions in the orbitofrontal cortex
    • Sub-chronic (7 days iirc) systemic administration:
      • Reduced norephinephrine release in OFC, LC, and thalamic reticulra nucleus.
      • Reduced GABA release in Medial Dorsal Nucleus
      • Enhanced AMPA-induced glutamate, NE, and DA release in OFC.
    • Obviously subchronic is the name of the game, but checking what the acute effects are could be relevant for learning how long benefits take to kick in.
    • **Attenuation of direct noradrenergic LC-OFC transmission at the resting stage and enhancement of direct co-releasing catecholaminergic LC-OFC transmission via GABAergic disinhibition in the intermediate LC-OFC pathway. **
    • Inhibiting HCN (via (guanfacine) inhibiting cAMP or blocking HCN directly) (which colocalizes with α2A) activates limbic-frontal cortex network connectivity, enhancing signal-to-noise ratio and improving focus on a particular stimulus:
      • Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex (Wang, Arnsten et al. 2007)
        • Commentary: Molecules to remember
        • Guanfacine, But Not Clonidine, Improves Planning and Working Memory Performance in Humans
          • The 29 μg/kg dose of guanfacine improved spatial working memory and planning… had no effect on attentional set-shifting.
            • An attentional set is formed when a subject learns that a set of rules can be applied to complex stimuli in order to differentiate relevant from irrelevant cues. Two stages within the AST protocol measure aspects of cognitive flexibility: reversal and the extra-dimensional shift. At the reversal stage, the previously negative stimuli within one dimension (medium in this example) is now positive. At the extra-dimensional shift stage, when the irrelevant dimension (odor in this example, perhaps as opposed to visual) becomes the relevant dimension. R
              • *The neural circuits underlying behavior during the AST are highly conserved across humans, nonhuman primates and rodents..
          • Clonidine is nonselective for α2 Adrenergic Receptor.
        • α2A blockade profoundly impairs spatial Working Memory. R (using yohimbine)
        • Recent studies indicate that elevated cAMP signaling in PFC impairs behavioral measures of WM. In contrast to LTM obviously.
  • Chronic Administrations of Guanfacine on Mesocortical Catecholaminergic and Thalamocortical Glutamatergic Transmissions
    • chronic guanfacine administration did not affect intrathalamic GABAergic transmission, but it phasically enhanced thalamocortical glutamatergic transmission
    • Acutely: postsynapic LC→OFC/VTA efferents reduces noradrenergic neurotransmission.
    • Proposed downregulation of α2A in the LC

dlPFC

https://beta.nootropicswiki.org/article/dlpfc-modulation

Human Studies

IDRA-21

Obsoleted by TAK-653, and arguably retroactively obsoleted by (pi)racetam. Read this for some ampakine lore.

Insulin (Intranasal)

Rating: ★★. More stable postprandial energy levels, and appetite suppression is alright when cutting. But it’s not very prominent to a young lad such as myself.

Intranasal

Istradefylline

Rating: ★★★★. I thrive on the kind of ‘impulsivity’ it gives you (i.e. even on the level of micro-behaviors like googling 3 things that show up in my head to find the answer for something instead of lazily paying attention to one laconic query), but it’s too bad it’ll reliably give you insomnia if you take too much.

Adenosine A2A

Heteromers

CB1

BDNF

Isoxazole-9

https://old.reddit.com/r/NootropicsFrontline/comments/muak0e/the_role_of_isoxazole9_on_invitro_invivo/

J147

Inhibitor of ATP synthase (sounds fucked up). Upregulates NGF, Egr, and AMPK.

Whitens skin via suppressing α-MSH induced melanogenesis.

Kanna

Rating: ★★★★. Puts a smile on my face. But it often just doesn’t work, though that could be a failure to dose properly or poor quality extract.

Kanna

Lion’s Mane

Rating: ★★. I’d be lying if I said I didn’t enjoy the headspace and weird dreams (enough to take it for like a year straight under the premise, which may have been successful for all I know) but I think it’s mostly overhyped/marketed trash (at least for healthy people) at this point.

Downregulates D2, 5-AR inhibitor, and κ-opioid agonist.

L-Histidine

Rating: ★★★. Inconsistent, but it can be pretty fun sometimes.

  • Tadaho Nakamura has interesting articles on histamine and cognition:

    • [Oral histidine intake improves working memory through the activation of histaminergic nervous system in mice.]

  • Role of dietary histidine in the prevention of obesity and metabolic syndrome

    • Obese middle-aged chinese women received 2g 2x/day for 12 weeks. Average fat loss in the histidine group was 2.71 kg and TNF-α, IL-6 decreased.

LSD

Rating: ★★★★★

L-Theanine

Say hello to the laughing stock (?). You might enjoy adding it to coffee/stimulants to attenuate certain side effects but I don’t think it’s exactly anything pro-cognitive.

L-theanine and Caffeine Improve Sustained Attention, Impulsivity and Cognition in Children with Attention Deficit Hyperactivity Disorders by Decreasing Mind Wandering (OR29-04-19)

Memantine

Modafinil

Rating: ★★★★★. It’s one of the most effective nootropics I’ve ever taken. See the post on Modafinil

NAC

More of a therapeutic (HPPD, tinnitus, OCD) than a nootropic for most people. Don’t expect it to be pro-cognitive.

Neboglamine

Rating: ★★★★. A scarily lucid potentiation of executive function and ‘motivation’ that feels purely rational and nothing to do with dopamine or anything. So many people get into nootropics for ‘getting things done’ and doing the things the better part of themselves wants to do without geting sidetracked on unimportant things, and I find negoblamine to be oddly effective at this.

Nicotine

Rating: ★★

Tolerance

Noopept

Rating: ★★. Crazy laser focus. So crazy that I swear it bleeds into negatively affecting other cognitive faculties like short-term memory. It just felt weird sometimes. There are plenty of weird ass anecdotes out there, like it giving long-lasting 2D vision. So proceed at your own risk. There are better compounds out there for most of the things it does.

  • AKA (N-Phenylacetyl-L-prolylglycine ethyl ester) Converted into phenylacetic acid, prolylglycine, and Cycloprolylglycine, a naturally-produced neurodipeptide which I think is how noopept exerts its effects.
  • I believe it is much more glutamatergic than the other racetams; its vasodilatory effects can cause headaches which seem to be not uncommon. It can be used to kill NMDA antagonist trips (like Ketamine).
    • The drug action is based on the Antioxidant effect, the antiinflammatory action, and the ability to inhibit the neurotoxicity of excess calcium and glutamate, and to improve the blood rheology.
  • Piracetam (400mg/kg (=~4.6g HED)) increased Alpha waves/Beta waves EEG activity in the left frontal cortex, and Alpha waves activity in both the right cortex and Hippocampus. Noopept (0.2mg/kg (=~2.27g HED)) increased Alpha waves/Beta waves activity… in all brain areas. The effect of Noopept in the alpha/beta1 ranges was replaced by increased beta2 activity after the eighth injection, while no effects were observed after the ninth one. R
  • AMPA agonist: Studying specific effects of nootropic drugs on glutamate receptors in the rat brain

NSI-189

Rating: ★★. It felt pretty awesome but I think it gave me chronic fatigue. Perhaps a shift from beta wave to alpha wave dominance increasing propensity for dissociation into more sedated states.

Its mechanism is pretty much unknown but it’s speculated to be adrenergic somehow.

Octreotide

Potent somatostatin mimetic.

Somatostatin

2-Oxazolidinones

Discussed pretty extensively on /r/researchchimicals

Cyclazodone

TAAR1 agonist

N-Methyl-Cyclazodone

Possible serotonergic effects.

Fenozolone

Pemoline

Probably the only sustainable one in terms of safety, but also the most difficult to obrain. Unknown MOA but likely has dopaminergic actions and is a possible AADC inhibitor (Pemoline and urinary excretion of catecholamines and indoleamines in children with attention deficit disorder)

It faded into obscurity after cases of liver failure in kids being prescribed pemoline for ADHD. But it would seem hepatotoxicity is overblown.

Pitolisant

Phenidates

Methylphenidate

Dexmethylphenidate (Focalin)

Probably the most sustainable of the DRIs prescribed for ADHD.

IPPH (Isopropylphenidate)

Has a much greater affinity for DAT than NET.

Pinealon

https://unyieldingvigor.com/resources/b/pinealon-glu-asp-arg & https://old.reddit.com/r/NooTopics/comments/12lvvjq/pinealon_improves_cognition_and_performance_in/

https://penchant.bio/products/pinealon-spray

Pregnenolone

Rating: ★★. Good stuff, but I’m too young to get much out of it.

“A couple of times I saw men who were not quite suicidal, but extremely depressed, talking about quitting their job and just giving up, and they both happened to be sitting in a dark corner of the room with a glass of wine, wanting to retreat, even within the room as well as from life in general. And, thinking about the old bayonet studies and such, I put a pinch of pregnenolone in their wine; and within about 15 minutes, in both cases, they were grinning and talking about projects and went back to work and were just as happy as they could ever be.”

LTP

Supplementation

Peat has said that literally every source on the market today is unsafe for one reason or another.

  • 70-80% oral bioavailability.

  • Men/women age 30 produce ~30-50mg/day. A dose of 300mg acts for a week. Dosing actually improves the body’s ability to produce its own pregnenolone. But high doses such as >100 inhibit androgens/DHT?

  • We produce 5% as much in old age than we do in our youth - as is the case with DHEA and progesterone.

  • 30-50 for DHEA+progesterone pthway, while 100-150 is more like mainly in the way of progesterone.

Intranasal

PRL-8-53

Rating: ★★★. 5mg sublingually definitely enhances both working and long-term memory (I’ll never forget how one time I photographically recalled the image of a wikipedia article I had been reading earlier because I wanted to read the rest of it) but it also feels kind of dirty. I don’t feel comfortable taking compounds with unknown MOAs.

Hypermnesic, spasmolytic. Only two studies done on it, in ‘74 and ‘78.

Derived from benzoic acid and Phenylmethylamine.

  • Increased learning of words by 87.5-105% in poor performers, and 7.9-14% in high performers - but that’s just due to a ceiling effect. Was #1 by a decent margin in the /r/nootropics survey for memory.

  • Displays Cholinergic properties (probably ACh uptake/synthesis). potentiates Dopamine and partially inhibits Serotonin signaling, and maybe synthesis.

    • I’ve heard people say it doesn’t really work without choline. Especially when stacked with TAK-653, for whatever reason.
    • It may inhibit the reuptake of dopamine, which depending on the mechanism such as DAT, may not be good long term. Also may be a direct agonist, though no stimulant-like symptoms have been shown even up to 200mg/kg.
    • Possibly a M2 AChR agonist.
    • Sirsadalot suspects it’s a DAAO inhibitor

  • Possibly a HDAC inhibitor. Very contentious. https://old.reddit.com/r/Nootropics/comments/5bqrpm/i_figured_out_prl853s_mechanism_of_action/

Dose: ~5-10mg or so sublingually. Caustic to the teeth though. Can also do 1-5mg intanasally in water; easily dissolves.

Psychoplastogens

Iso-DMT, Tabernanthalog, etc.

Racetams

Many would argue their AMPA PAM properties have been obsoleted by TAK-653. But they still have other actions (and some racetams have nothing to do with AMPA)

Aniracetam

Activates 5-HT2A, D2, D3.

Coluracetam

  • Increases HACU. Mild AMPA PAM.

Fasoracetam

  • Upregulates GABA-B.

Oxiracetam

Rating: ★★★. My 3rd favorite racetam. Feels really clean and was relatively consistent.

Phenylpiracetam

Rating: ★★★★★. Higher doses with no tolerance feel very dopaminergic. Eugeroic too; amazing preworkout if timed correctly.

Apparently it was originally invented to be taken at ~100mg daily and that its stimulating properties (which are amazing and sustainable) are treated as a temporary side effect (indeed, unfortunately, it only lasts 1-3 days before a break of ~1-2 weeks is necessary), but I refuse to believe you don’t just slap a phenyl group on perfectly good piracetam and act like dopaminergic properties were an accident.

Methylphenylpiracetam

σ1 PAM. Nothing like regular phenylpiracetam.

Phenylpiracetam Hydrazide (RGPU-95)

Piracetam

Rating: ★★★★. Inconsistent, but the way it increases fluidity of thought is fantastic. I had an amazing honeymoon period with it at the very least. Everyone should try a cycle of piracetam.

  • Decreases the destabilizing effects Amyloid β, which causes lipid disorganization within cell membranes. Other racetams do this as well.
    • Increases (synthesis of) cytochrome B5
    • Inhibits stress-induced Prolactin increase
  • Reduces Erythrocyte adhesion to vascular endothelium, hinders vasospasm, and facilitates microcirculation. R
  • Influences Membrane fluidity in the whole body; protecting the cell against Hypoxia.
  • Increases brain O2 consumption, in connection to ATP metabolism.
  • Aldosterone receptors are involved in the mediation of the memory-enhancing effects of piracetam
    • Adrenalectomy blocks memory-enhancing effects of piracetam. This is abolished with administration of corticosterone or aldosterone so long as aldosterone receptors (Type I mineralcorticoid receptor) are not blocked.
  • Piracetam Defines a New Binding Site for Allosteric Modulators of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors (Ahmed & Oswald 2010)
    • GluR2/GluR3.
    • Along with Aniracetam, Both drugs bind to GluA2 and GluA3 in a very similar manner, suggesting little subunit specificity.
    • Piracetam binds to multiple sites along the dimer interface with low occupation, one of which is a unique binding site for potential allosteric modulators.
    • However, the binding sites for piracetam and Aniracetam differ considerably.
  • Increases Dopamine in cerebral cortex and striatum, and Serotonin in the cortex, while reducing serotonin in the Striatum, Brain Stem and Hypothalamus. R
  • Increases Noradrenaline by increasing Locus Coeruleus firing. R
  • Increases Noradrenaline and Serotonin turnover in Hippocampus.
  • Acetylcholinesterase inhibitor, in contrast to some other racetams that increase its synthesis.
  • Increases hippocampal acetylcholine, and in aged mice, increases population of mAChR in frontal cortex by up to 40%.
    • Carbachol-induced accumulation of Inositol Monophosphates was elevated, suggesting piracetam can normalize functional deficits associated with aging
  • Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats
    • 200mg/kg increased Choline content in Hippocampus by 88%, and decreased Acetylcholine levels by 19%.
    • Choline administration raised choline content about 50% in the Striatum and Cerebral Cortex, and 6-10% increase in ACh levels. None in hippocampus.
      • The combination of choline and piracetam did not potentiate these effects seen with either drug alone, and in some cases, were worse.
    • Rats given 100mg/kg of piracetam+choline exhibited retention scores several times better than piracetam alone. 200mg/kg of choline or piracetam alone was still inferior.

Glutamate

  • Enhances efficacy of AMPA-induced calcium influx and maximal density of AMPARs in synaptic membranes, due to the recruitment of a subset of AMPA receptors which normally don’t contribute to synaptic transmission.
    • Normalized the age-related elevated affinity of L-glutamate for NMDAR
  • Binds to AMPARs with much lower affinity than ampakines or Aniracetam, but it can bind to multiple sites on the AMPA receptor, potentiating what binds to it, including piracetam itself.
  • Larger doses can potentiate potassium-induced release of glutamate from hippocampal nerves.
  • Significantly increases NMDAR density by 20% after 14 days of treatment.
  • Allosteric modulator of certain CNS glutaminergic receptors. I wanna know how this prevents overactivation, because it does.

Pramiracetam

RAP-103

Long-lasting inhibitor of CCR5 (also CCR2/CCR8). Downstream inhibition of GSK-3β reactivates myelinating cells in the brain, improving LTP/cognition. This also enhances opioid analgesia and reduces anxiety.

Rapamycin

The basic premise as a nootropic is intranasal adminitration to facilitate synaptic pruning.

Was originally discovered in the soil of Easter Island in 1975 from Streptomyces tsukubensis. Wtf. And that molecule: a macrolide.

Disease

Roxadustat

Rating: ★★★. Increase in both physical and mental endurance. It gives an enjoyable headspace, though it’s all pretty subtle. 100 mg taken 4x/week (workout days).

- See also FG-4497.

Selegiline

Rating: ★★. This is partially a longevity/health supplement, but acute effects are to be expected, and I didn’t notice too much besides increased ADHD-like symptoms, probably from an acute tyrosine hydroxylase inhibition that’s seen. It’s controversial whether it’s worth taking especially now that we know MAO-B isn’t selective for dopamine like originally thought, and instead is part of GABA biosynthesis (Glial GABA, synthesized by monoamine oxidase B, mediates tonic inhibition). It’s an interesting one though.

Semax

Rating: ★. Felt nothing.

Reverse tolerance!

Other Forms

  • N-Acetyl-Semax: Possibly anxiogenic.

  • N-Acetyl-Semax Amidate: ~33% longer half life. Anxiolytic.

  • Adamax: 2x the half life of NAS, and better absorption.

SkQ1

Rating: ★★. I don’t notice anything.

  • Part of SkQ (which includes -R1, 2, 2M, 3,4,5, -berb, -palm, C12TPP, and MitoQ) which are mitochondrial Antioxidants. They’re lipophilic cations so they penetrate through membranes. They inhibit ROS directly due to plastoquinone oxidation, or reducing ΔΨ.

  • I suppose they’re pretty popular for Longevity. Mice in a study lived 335 days vs. 290.

  • Behavioral Effects Induced by Mitochondria-Targeted Antioxidant SkQ1 in Wistar and Senescence-Accelerated OXYS Rats

    • SkQ1-treated rats of both strains displayed significantly higher locomotor and exploratory activity in the open field (OF) and less anxiety in the elevated plus-maze (EPM)
    • SkQ1-treated Wistar rats exhibited slower learning in the Morris water maze (MWM) task comparison to the control group… may be associated with differences in redox homeostasis.

  • Mitochondria-targeted antioxidant SkQ1 improves impaired dermal wound healing in old mice

    • SkQ1 treatment resulted in accelerated resolution of the inflammatory phase, formation of granulation tissue, vascularization and epithelization of the wounds. Wounds contained increased amount of myofibroblasts which produce extracellular matrix proteins and growth factors mediating granulation tissue formation.
    • Earlier we have found that SkQ1 stimulated production of active TGFβ by fibroblasts
    • The TGF-β produced by SkQ1-treated fibroblasts was found to stimulate motility (and tubulogenesis) of endothelial cells in vitro, an effect which may underlie pro-angiogenic action of SkQ1 in the wounds. Movement of the epitheliocytes into the in vitro “wound” was directly stimulated by SkQ1
    • Prevention of excessive reaction of endothelium to the pro-inflammatory cytokine(s) might account for anti-inflammatory effect of SkQ1.

  • Important to support Electron Transport Chain complex IV to prevent peroxide buildup.

Store in the fridge. Can be injected or administered intranasal (~33 μg/spray)

SR9009

Rating: ★★★. My first cycle of 10mg daily, it reduced my sleep drive/need by a whole REM cycle. But I don’t get this anymore. The benefits seem endless and I can’t think of any negatives besides the fact it is untested in humans and we don’t know if something bad could crop up.

  • According to tyw’s citiation that is 404, it peaks around 10 PM - noon? ZT0 (zeitgeber time) = midnight to the system being studied, which is the opposite between mice and humans I suppose.
    • (This post is a fantastic writeup on SR9009 though)

Metabolism

SR9011

  • There are ohter rev-erb-α ligands. For one thing, this has better bioavailability. Sonething like 5x? Idk if this matters when intranasal, though aerin has recommended intranasal for all of them.
  • (α IC50 = 970 nM and αβ IC50 = 790)
  • Far less studied. Idk, I’ll check it out some other time maybe? It’s hard to say what the differences are without going deep asf. I guess I’ll see what’s different between α and β.

SR10067 (1380548-06-2)

Also has strong Rev-Erb-β affinity. And something like 6-8x more potent in general. IIRC, this is orally available.

Dose

  • 6-20mg intranasal. 4 hour half-life. Very poor oral bioavailability.

Nasal spray in caprylic acid (it’s lipophilic) is what you won’t see a lot of people discussing on the internet.

Rev-Erb

Rev-Erbα (NR1D) and Rev-Erbβ (NR1D2) (aka αβ). The latter was originally thought to be redundant, but it does have some more novel research into distinct actions.

Nuclear receptor transcription factors for the circadian clock.

(S)unifiram

Stimulates CAMK II and PKCα.

  • Antagonizes barbituate-induced inhibition of glucose transport (as do racetams)
  • [Pharmacological characterization of DM232 (unifiram) and DM235 (sunifiram), new potent cognition enhancers.]
    • Increase Acetylcholine release in rat cerebral cortex.
    • Unifiram increases fEPSP amplitude in rat hippocampal slices.

TAK-653

Rating: ★★★★. The impressionistic subjective report would be something like it makes everything slightly simpler, obvious, lubricated. Neboglamine can be described as quite similar except on the more behavioral side of things rather than cognitive. You can pretty much think of it like if observing the connections between things as nodes overlapping venn diagrams. TAK makes the overlapping bigger/more obvious. And realistically this corresponds nicely to what it’s doing physiologically. But for the first few days, it’s kind of a mess and can induce sensory overload and a dissociative feeling, because the context of those nodes is also part of the overlap. I.e., it’s hard to consciously parse these things into a more generalizable form if you know what I mean. (This might be mediated by A dentate gyrus-CA3 inhibitory circuit promotes evolution of hippocampal-cortical ensembles during memory consolidation) Whereas without TAK things feel more context/‘scale’-invariant, but as one might assume, that’s ultimately at the cost of nuance no? But after a few days though you just magically get used to it.

  • A more selective TAK-137. Finally a bona-fide ampakine, as it has basically no agonist activity.
  • Central nervous system effects of TAK-653, an investigational alpha-amino-3-hydroxy-5-methyl-4-isoxazole receptor (AMPAR) positive allosteric modulator in healthy volunteers (Sep 2022)
    • Improves Stroop test (proxy of Executive Function apparently): TAK-653 0.5 mg but not 6 mg decreased the number of correct responses in incongruent trials
    • demonstrated a psychostimulant-like pharmacodynamic profile on the NeuroCart consistent with previously reported increase of cortical excitability following Transcranial Magnetic Stimulation (TMS) of the human motor cortex.
  • [Pharmacokinetic and pharmacodynamic properties of the investigational AMPA receptor positive allosteric modulator TAK-653 after single and multiple rising doses in healthy volunteers]
    • Tried 0.3-18mg.
    • Maximum plasma concentrations were attained within 1.25 h to 5 h after dosing, the terminal half-life varied from 33.1 h to 47.8 h and cerebrospinal fluid concentrations were suggestive of rapid brain penetration
  • Strictly regulated agonist-dependent activation of AMPA-R is the key characteristic of TAK-653 for robust synaptic responses and cognitive improvement (Suzuki et al. 15 July 2021)
    • 3 and 10mg/kg in mice. The former had like a 20% greater effect on BDNF release after AMPA treatment.
    • Did not show prominent subunit selectivity for homomeric AMPA-R
    • In monkeys, the beneficial effect (~20%) on “delayed match-to-sample” task was maintained for 24 hours after administration. Its half life is 9.4 $\pm$ 3.8 hours at 0.03 mg/kg p.o in monkeys.
    • Enhanced sustained attention in poor-performing mice. Increased novel objection recognition test results by like 10%. 0.03-0.3 mg/kg were all pretty similar.
    • Ameliorated abnormal social interaction in models of schizophrenia (poly-I:C. No idea, but it made them complete antisocial and then back to near baseline)
    • 10 μM in prefrontal cortex had the best effect on AMPAR-mediated EPSPs in the PFC: tripling EPSP duration and 6x the number of spikes.
  • TAK-653, an AMPA receptor potentiator with minimal agonistic activity, produces an antidepressant-like effect with a favorable safety profile in rats (Dec 2021)
    • 0.1 or 1 mg/kg p.o. The time to reach peak plasma concentration after the oral administration of TAK-653 at 1 mg/kg was between 1 and 2 h
    • “Increased” phosphorylated and active forms of mTOR, P70S6, and AKT and ERK.
    • Stimulated mTOR and BDNF production.
    • Despite expectations, no relevant clinical effects have been demonstrated for the CX series.
    • In vitro for 10 minutes wih 1μM tripled ERK phosphorylation. Nothing tooo crazy otherwise
    • Virtually no agonist activity. Steric repulsion by GluR2 Ser750 of the closed AMPAR caused TAK-653 only to bind in the presence of a ligand.
      • Otherwise, there would be some kind of bell-shaped dose-response curve whereby excess glutamate release could get you in big trouble.
      • GluR2 Ser750 = GluR1 Ser743.
  • [Novel AMPA Receptor Potentiators TAK-137 and TAK-653 as Potential Rapid-Acting Antidepressants (2021)]

THC

Opioid

  • Cannabis-Induced Hypodopaminergic Anhedonia and Cognitive Decline in Humans: Embracing Putative Induction of Dopamine Homeostasis
    • it is possible to induce ‘dopamine homeostasis,’ that is, restore dopamine function with dopamine upregulation with the proposed compound and normalize behavior in chronic cannabis users with cannabis-induced hypodopaminergic anhedonia (depression) and cognitive decline
    • I believe they’re referring to ‘Pro-Dopamine Regulator’ (KB220(Z)), which is an Enkephalinase inhibitor. As well as screening for risk alleles, and balancing dysfunctional dopamine with pro-dopamine reward genes - and they actually cite DAT1, D2, D4, and COMT.
  • Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism (Tanda 1997)
    • Increased extracellular dopamine concentrations selectively in the shell of the nucleus accumbens; these effects were mimicked by the synthetic cannabinoid agonist WIN55212-2.
    • SR141716A, an antagonist of central cannabinoid receptors, prevented the effects of THC but not those of heroin. Systemic naloxone, or naloxonazine (selective μ-1 antagonist) infusion into the ventral tegmentum, prevented the action of cannabinoids and heroin on dopaine transmission.
  • [Cannabinoid receptor and WIN 55 212‐2‐stimulated [35S]‐GTPγS binding in the brain of mu‐, delta‐ and kappa‐opioid receptor knockout mice (Latimer 1987)]: The efficacy of CB1 receptor activation by the cannabinoid agonist WIN 55 212-2 was dramatically reduced in the caudate-putamen of MOR knockout animals
  • Cannabinoid withdrawal syndrome is reduced in double mu and delta opioid receptor knockout mice
    • Acute effects and physical dependence were not modified in single deletion of μ-opioid receptor, δ-opioid receptor, or κ-opioid receptor.
    • Antinociception and hypolocomotion induced by acute THC administration remained unaffected, whereas the hypothermic effect was slightly attenuated in these double knockout mice.
    • During chronic THC treatment, knockout mice developed slower tolerance to the hypothermic effect, but the development of tolerance to antinociceptive and hypolocomotor effects was unchanged.
    • The rewarding properties of THC, measured in the conditioned place preference paradigm, were reduced in knockout mice.
    • Interestingly, the somatic manifestations of THC withdrawal were also significantly attenuated in mutant mice, suggesting that a cooperative action of MOR and DOR is required for the entire expression of THC dependence.

Neurotransmitters

I’d say it’s contentious.

Prenatal

Tropisetron

Rating: ★★★★. Laser focus, and it delivers every time. Not to mention it seems to be healthy and neuroprotective.

Neuroprotection

Vinpocetine

  • Periwinkle

  • PDE1 inhibitor, improving peripheral Vasodilation.

  • Compare to Ginkgo or Reserpine.

  • Inhibits The NF-κB cascade via inhibiting IKK.

  • Potent antioxidant. Used as a treatment for tinnitus.

  • Reduces neuronal calcium influx without blocking presynaptic Ca2+ channels.

  • [Effects of several cerebroprotective drugs on NMDA channel function: evaluation using Xenopus oocytes and [3H]MK-801 binding]

    • These results suggest that the inhibition of NMDA channels by vinpocetine shows a similarity to the action of Zn2+ which closes the gate of the NMDA channel

  • [Vinpocetine preferentially antagonizes quisqualate/AMPA receptor responses: evidence from release and ligand binding studies.]

    • Reduced the efflux of dopamine and acetylcholine evoked by glutamate, quisqualate and NMDA, but not that evoked by kainate**

  • Vinpocetine reduces cisplatin-induced acute kidney injury through inhibition of NF–κB pathway and activation of Nrf2/ARE pathway in rats

    • Seems to increase HO-1 and NF-κB inthis injury model unless I’m reading this wrong.

  • Unique alterations to the rheological properties of Red Blood Cells. Reduced MDA and increased GSH levels in models of neurological damage

  • Characterization of vinpocetine effects on DA and DOPAC release in striatal isolated nerve endings

    • Does not modify baseline DA release or exocytotic release evoked by K+; it inhibits DA release evoked by veratridine reversal of DAT.
    • Increases DOPAC levels suggesting an augmentation of dopamine metabolism, likely indepdendent of VSSC blockage, via increasing availability of the cytoplasm extravesicular DA; Impairs vesicular storage of Dopamine.
      • Does not enhance MAO, rather it acts like reserpine (VMAT2 inhibitor (it’s over)) which decreases the monoaminergic tone.
    • Inhibits voltage-gated sodium channel permeability, selectively inhibiting the transporter-mediated release of all neurotransmitters.

  • [Vinpocetine and Ischemic Stroke]

    • Cerebral vasodilation enhances supply of oxygen & glucose, and ATP production.

  • [Psychopharmacological Effects of Vinpocetine in Normal Healthy Volunteers]

    • Reported a lasting increase of cerebral 5-HIAA levels after treatment and transitorily enhanced 5-HT levels 2 h following (i.p.) treatment. Catecholamine levels were similarly increased 4-6 h following administration of vinpocetine.
    • Twelve females age 25-40 had dose-dependent decrease in reaction time in this memory test thing. Placebo 600 and plumetted from 560 to 420 after 20=>40mg.