Wakefulness: nootropics and compounds | sci-wiki

Adrafinil

Adrafinil (CRL-40028) is a prodrug of modafinil and one of the most accessible routes to clean, sustained wakefulness and focus. Once converted by the liver into modafinil, it delivers the same eugeroic, alertness-promoting effect that made modafinil famous, without requiring a prescription in many countries. Marketed originally in Europe as Olmifon, it remains a favorite among those seeking long-lasting, jitter-light energy and mental stamina.

1 outlet

Nootropic

Fladrafinil

Fladrafinil (CRL-40,941) is a synthetic wakefulness drug from the same French research programme of the 1970s and 1980s that produced modafinil and adrafinil; chemically it is adrafinil with a fluorine atom added to each of its two rings. It was never approved or marketed as a medicine anywhere, and it now circulates online as a research chemical and turns up in products sold as nootropic supplements. The body converts it into flmodafinil, which is what actually produces the effect; that conversion has been demonstrated directly in people, but almost nothing else about the drug has been tested in humans. There are no efficacy trials, no safety studies and no published measurement of what it binds to, so claims that it sharpens focus or that it is several times stronger than adrafinil rest on marketing and a 1984 patent rather than on evidence.

3 outlets

Nootropic

Flmodafinil

Flmodafinil, also written FL-Modafinil and originally coded CRL-40,940, is a fluorinated analogue of modafinil in which both phenyl rings carry a fluorine. It is a genuinely different molecule from modafinil and not a brand of it, which is worth stating plainly because the two names are routinely sold as though interchangeable. Fladrafinil (CRL-40,941) is its prodrug, standing to flmodafinil roughly as adrafinil stands to modafinil. Vendors commonly claim greater potency and better solubility than modafinil; those claims come from early rodent work and from sellers rather than from human trials.

1 outlet

Nootropic

Modafiendz

Modafiendz is a fluorinated, N-methylated analog of the wakefulness agent modafinil, marketed online as a next-generation nootropic alternative. It is built around the same eugeroic blueprint that made modafinil a favorite for focus and sustained alertness, with structural tweaks intended to modify its activity. Because the analog itself has not been formally studied, it is best understood as an experimental research chemical riding on the well-mapped pharmacology of its parent.

1 outlet

Nootropic

Paraxanthine

Paraxanthine is what caffeine mostly becomes. Around 70 to 80 percent of a caffeine dose is converted by the liver enzyme CYP1A2 into paraxanthine, so for most of the time a coffee is working, the compound doing the work is this one [14]. Selling it directly is an attempt to skip a step that varies enormously between people: CYP1A2 activity differs several-fold across individuals, which is a large part of why the same espresso is pleasant for one person and unpleasant for another. Human trials are small but real, and they point at improved cognition at modest doses with less of the sleep disruption caffeine causes [4][6]. It is the most credible caffeine alternative on this site, and the evidence base behind it is still thin and largely tied to the company selling it.

1 outlet

Nootropic

Modafinil

Modafinil is a prescription wakefulness-promoting drug, approved in the United States in 1998 for excessive sleepiness caused by narcolepsy, obstructive sleep apnea, and shift work disorder. It works mainly by blocking the dopamine transporter, the protein that clears dopamine out of the synapse; human brain imaging confirms it occupies roughly half of those transporters at ordinary doses, although it binds them far more weakly than classic stimulants do. The evidence that it reduces sleepiness in the three approved sleep disorders is strong and rests on large placebo-controlled trials, but the evidence that it improves thinking in healthy, well-rested people is much weaker; the best meta-analysis found only a small overall effect confined to one narrow memory task. It is a Schedule IV controlled substance in the United States, banned in competition by WADA, and carries warnings for rare but serious skin reactions and for making hormonal birth control less reliable.

2 outlets

Nootropic

Armodafinil

Armodafinil is the prescription wakefulness drug sold as Nuvigil; it is one of the two mirror-image halves of modafinil, the longer-lasting half, so it does much the same job at a somewhat lower dose. In the United States it is approved only to reduce excessive sleepiness in adults with narcolepsy, obstructive sleep apnea, or shift work disorder, and the evidence for those three uses is genuinely solid; several 12-week placebo-controlled trials show people stay awake longer, though the benefit is measured in a few extra minutes of resisting sleep rather than a cure. Its one well-supported molecular action is weak blockade of the dopamine transporter, which brain scans confirm happens at ordinary doses; the histamine and orexin explanations that circulate online come from studies of modafinil, not of armodafinil itself. Outside the sleep indications the record thins out fast and is often negative, including a clean phase 3 failure for cancer-related fatigue, and this is a Schedule IV controlled drug carrying a pregnancy registry signal for birth defects.

2 outlets

Nootropic

Guarana

Guarana is a climbing plant native to the Amazon basin, classified as Paullinia cupana in the soapberry family Sapindaceae, whose seeds are prized for an unusually high caffeine content. Indigenous peoples of the region, including the Sateré-Mawé, have long processed the seeds into a dried paste used to brew a stimulating beverage. Today the seed powder and its extracts are used chiefly as a caffeine source in soft drinks, energy drinks, and dietary supplements.

1 outlet

Nootropic

Hydrafinil

Hydrafinil, also called 9-fluorenol or 9-hydroxyfluorene, is a simple laboratory chemical that Cephalon tested around 2012 while looking for a successor to the wakefulness drug modafinil; despite the similar sounding name it is not chemically related to modafinil and belongs to a different chemical family. In the single rat experiment that exists it kept animals awake longer than modafinil did at the same injected dose, after which the programme was dropped with no published reason and never reached a human trial. The entire human record is one anti-doping study in which three healthy men each swallowed a single 50 mg dose so that laboratories could learn to detect it in urine; nothing at all has been published on whether it improves alertness, attention or fatigue in people, and nothing has been published on its safety. It is banned in competition by the World Anti-Doping Agency and is not an approved medicine in any country.

1 outlet

Nootropic

Orexin-A

Orexin-A, also known as hypocretin-1, is a 33-amino-acid neuropeptide produced by a small population of neurons in the lateral hypothalamus that is central to promoting wakefulness and arousal. It is one of two orexin peptides cut from a single precursor and signals through two G-protein-coupled receptors. Narcolepsy type 1 is essentially an orexin-deficiency disease, in which the roughly 70,000 orexin-producing neurons are selectively destroyed and cerebrospinal-fluid orexin becomes undetectable; this is the rationale for orexin-2 receptor agonists now in clinical trials as the first mechanism-based, replacement-style treatment rather than a symptomatic stimulant. Since its discovery in 1998 the orexin system has become a major target in sleep medicine.

1 outlet

Nootropic

Orexin-A Fragment 17-33

Orexin-A fragment 17-33 is a shortened, C-terminal portion of the neuropeptide orexin-A, comprising the last seventeen of its thirty-three amino acids. It belongs to a group of truncated orexin peptides studied to map which parts of the parent molecule are needed to activate orexin receptors. Research on such fragments showed that the activity of orexin-A resides mainly in its C-terminal end, and the fragment is used chiefly as a laboratory tool for probing the orexin system rather than as a medicine.

1 outlet

Nootropic

Orexin-B

Orexin-B, also known as hypocretin-2, is a 28-amino-acid neuropeptide made in the hypothalamus that, together with orexin-A, promotes wakefulness, arousal, and appetite. It is cut from the same precursor as orexin-A but lacks internal disulfide bonds and preferentially activates the orexin type 2 receptor. That receptor is the target of the dual orexin receptor antagonists suvorexant, lemborexant, and daridorexant, which treat insomnia by blocking the same signaling whose loss causes narcolepsy, making the two conditions pharmacological mirror images; one of these drugs was also reported to acutely lower tau and amyloid-beta in human cerebrospinal fluid. The orexin system was discovered in 1998.

1 outlet

Nootropic

Theacrine

Theacrine is a naturally occurring purine alkaloid, chemically 1,3,7,9-tetramethyluric acid, that is closely related to caffeine and found in the leaves of kucha tea (Camellia assamica var. kucha) and in the cupuacu fruit. It has stimulant-like properties and, like caffeine, acts on adenosine and dopamine signaling to influence energy, alertness, and locomotor activity [1]. Sold as a dietary supplement, often under the trade name TeaCrine, it has drawn attention as a longer-acting alternative to caffeine that appears less prone to tolerance with repeated use [2].

1 outlet

Nootropic

Amphetamine

Amphetamine is a potent central nervous system stimulant and the parent compound of a broad family of related drugs. In medicine it is used chiefly to treat attention-deficit hyperactivity disorder (ADHD) and narcolepsy, where it improves attention, wakefulness, and impulse control by raising the brain's levels of the neurotransmitters dopamine and norepinephrine [1]. It also has a long history of recreational misuse and a potential for dependence, and it is tightly regulated as a controlled substance in most countries [1].

reference

Nootropic

Dexmethylphenidate

Dexmethylphenidate is a central nervous system stimulant used to treat attention deficit hyperactivity disorder (ADHD). It is the more active of the two mirror-image forms of methylphenidate, specifically the d-threo enantiomer, and is sold under the brand name Focalin in immediate-release and extended-release forms. By blocking the reuptake of dopamine and norepinephrine, it raises the availability of these neurotransmitters in the brain. In the United States it is a Schedule II controlled substance available only by prescription.

reference

Nootropic

Dextroamphetamine

Dextroamphetamine is a central nervous system stimulant and the more active of the two mirror-image forms of amphetamine. It is used mainly to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy, and it forms the active component of several widely prescribed medicines, including Dexedrine, the mixed-salt product Adderall, and the prodrug lisdexamfetamine. The drug works by increasing the release and availability of the neurotransmitters dopamine and norepinephrine in the brain. Because it carries a risk of dependence and misuse, it is a Schedule II controlled substance in the United States.

reference

Nootropic

Lisdexamfetamine

Lisdexamfetamine is a central nervous system stimulant used to treat attention-deficit hyperactivity disorder (ADHD) and moderate-to-severe binge eating disorder. It is a prodrug of dextroamphetamine, meaning it is inactive until the body converts it into the active stimulant, which gives it a smooth, long-lasting effect. Sold mainly under the brand name Vyvanse, it is a once-daily oral medicine and a controlled substance.

reference

ADHD

Methamphetamine

Methamphetamine is a potent central nervous system stimulant of the substituted amphetamine class. Although it has a limited approved medical role in treating attention-deficit hyperactivity disorder and obesity, it is far better known as an illicitly manufactured drug of abuse, sold in crystalline form and taken for its intense euphoria and stimulation. Methamphetamine raises levels of the neurotransmitters dopamine, norepinephrine, and serotonin in the brain, and heavy use is strongly addictive and can damage dopamine-releasing nerve cells.

reference

Nootropic

Methylphenidate

Methylphenidate is a central nervous system stimulant widely used to treat attention-deficit hyperactivity disorder (ADHD) and narcolepsy. Sold under brand names such as Ritalin and Concerta, it works by blocking the reuptake of the neurotransmitters dopamine and norepinephrine, raising their levels in the brain and improving attention and impulse control. First synthesized in the 1940s, it is one of the most commonly prescribed medications for ADHD and is a controlled substance because of its potential for misuse.

reference

Nootropic

Serdexmethylphenidate

Serdexmethylphenidate is a prodrug of the stimulant dexmethylphenidate, created by attaching the amino acid serine to the active drug so that it is only slowly converted to its active form in the gastrointestinal tract. It is used to treat attention-deficit/hyperactivity disorder (ADHD) and is marketed in the United States as part of the combination capsule Azstarys, which pairs it with a small amount of immediate-release dexmethylphenidate. The prodrug design gives a rapid onset with an extended duration of effect and is intended to reduce the potential for misuse.

reference

Dopaminergic

4-PMPD

4-PMPD is an obscure research chemical that vendor and reference sources identify with 4-benzylpiperidine, also named 4-(phenylmethyl)piperidine [1]. 4-Benzylpiperidine is a documented monoamine releasing agent that preferentially releases dopamine over serotonin and has been studied as a candidate agonist medication for cocaine dependence [1]. Because the mapping of the trade name 4-PMPD to 4-benzylpiperidine rests on vendor and encyclopedic identification rather than peer-reviewed confirmation of this exact product, the identity should be treated as probable but not definitively verified.

reference

Nootropic

ABT-239

Abbott Laboratories built ABT-239 as a drug-like, orally active histamine H3 antagonist with real human-development ambitions behind it, unlike most H3 tool compounds; it was investigated as a candidate for ADHD, Alzheimer's disease, and schizophrenia-related cognitive deficits. It bound the human H3 receptor with subnanomolar potency and more than 1000-fold selectivity over the other histamine receptor subtypes, and it worked in rodent cognition and stress models. Abbott dropped it from human trials after it showed QT interval prolongation, a cardiac liability serious enough to end clinical plans outright, and ABT-239 has since lived on purely as a widely used preclinical benchmark for newer H3 antagonists.

reference

Dopaminergic

Amfonelic Acid

Amfonelic acid (AFA, WIN 25978) is a synthetic 1,8-naphthyridine carboxylic acid structurally derived from the antibacterial scaffold of nalidixic acid, and it functions as a potent and highly selective dopamine reuptake inhibitor with minimal action on the norepinephrine or serotonin transporters [1][2]. Unlike amphetamine, which reverses the dopamine transporter to force efflux, amfonelic acid raises extracellular dopamine by blocking reuptake, and it has been used experimentally as a pharmacological probe of dopamine transporter function and vesicular dopamine storage [1]. It is a long-acting central stimulant and is sold today only as a research chemical, not as an approved medicine [3].

reference

Nootropic

Bavisant

Bavisant started life at Johnson & Johnson as JNJ-31001074, a potent, brain-penetrant histamine H3 antagonist aimed at adult ADHD; a controlled dose-ranging trial found it did not produce a clinically meaningful benefit over placebo, and J&J's ADHD program quietly closed. The molecule's story did not end there. BenevolentAI, an AI-driven drug discovery company, later licensed the same compound, renamed it bavisant, and repositioned it around a side effect noted in the original data, dose-dependent insomnia, betting that the same wake-promoting H3 blockade could help excessive daytime sleepiness in Parkinson's disease instead. That reran the drug through a Phase IIb trial testing three doses against placebo in roughly 230 Parkinson's patients, an unusually direct case of an abandoned CNS candidate getting a second clinical life through indication-hopping rather than fresh chemistry.

reference

Nootropic

Ciproxifan

Ciproxifan never had a pharma sponsor chasing an indication; it exists almost entirely as an academic tool compound, and it became the reference histamine H3 antagonist that an entire generation of sleep, attention, and Alzheimer's-related rodent studies were built around. Its defining quirk is species selectivity: it binds rodent H3 receptors in the subnanomolar range but only moderately at the human receptor, which is exactly why it stayed a lab reagent instead of becoming a clinical candidate. Later work found it also reversibly inhibits monoamine oxidase A and B, an unplanned second mechanism that complicates interpreting some of the older behavioral data attributed purely to H3 blockade.

reference

Nootropic

CX-1739

CX-1739 is a second-generation, low-impact ampakine developed by RespireRx Pharmaceuticals (formerly Cortex) as a positive allosteric modulator of AMPA receptors. Unlike early high-impact ampakines, it is designed to enhance excitatory transmission without producing excitotoxicity, and it crosses the blood-brain barrier rapidly. Its most striking property is the ability to reverse opioid- and sedative-induced respiratory depression without blocking analgesia, and it also improves social behavior and cognition in preclinical models. It has been examined in early human respiratory studies.

reference

Nootropic

Declozindol

A dechlorinated mazindol analogue tuned to be a clean noradrenaline reuptake blocker plus a partial orexin-2 agonist; an orexin-forward wake drug aimed at narcolepsy.

reference

Nootropic

Fluorene Myristate

Fluorene myristate is an obscure research compound marketed as a nootropic; based on its name and vendor descriptions it appears to be a myristic-acid ester of a fluorene or fluorenol core, likely intended as a lipophilic prodrug or slow-release form of 9-fluorenol (hydrafinil), a weak dopamine reuptake inhibitor and modafinil metabolite. There is no primary peer-reviewed literature on fluorene myristate itself, and even its exact structure and CAS identity are inconsistently reported by suppliers. This entry is therefore deliberately cautious and does not assert mechanisms or effects that have not been demonstrated for this specific molecule.

reference

Nootropic

Irdabisant

Irdabisant (CEP-26401) is a potent, highly selective histamine H3 receptor antagonist and inverse agonist developed by Cephalon. Because the H3 receptor is largely an inhibitory autoreceptor and heteroreceptor that restrains release of histamine and other arousal-related neurotransmitters, blocking it disinhibits wake-promoting signaling; in preclinical models irdabisant showed robust wake-promoting activity and improved short-term memory at low doses, alongside favorable central nervous system drug-like properties and high selectivity over other histamine receptor subtypes. It was studied as a candidate cognition-enhancing and wakefulness-promoting agent for conditions such as cognitive impairment and schizophrenia. Early human studies characterized its pharmacokinetics and pharmacodynamics, including dose-dependent effects on sleep, but the compound advanced only into early clinical trials and was never brought to market.

reference

Nootropic

Istradefylline

Istradefylline is a selective adenosine A2A receptor antagonist used as an add-on to levodopa-based therapy in adults with Parkinson's disease. It is taken to reduce daily off episodes, the stretches of the day when dopaminergic medication wears off and motor symptoms return [1][2]. Structurally a xanthine derivative, it was the first drug of its class to reach the market and acts through a non-dopaminergic pathway distinct from conventional Parkinson's treatments [1].

reference

Amphetamine

Levoamphetamine

Levoamphetamine is the other half of Adderall. Mixed amphetamine salts are three parts dextroamphetamine to one part levoamphetamine, and this is the part almost nobody talks about, despite it being the main pharmacological difference between Adderall and plain dextroamphetamine. The two enantiomers are not equivalent: the levo form is markedly weaker at releasing dopamine and relatively stronger on noradrenaline, which shifts its profile toward peripheral and cardiovascular effects and away from the central reinforcement that makes the dextro form what it is [1]. It is not sold on its own; it is a component.

reference

Nootropic

PACAP

PACAP, short for pituitary adenylate cyclase-activating polypeptide, is a naturally occurring neuropeptide that acts as a hormone, neurotransmitter, and neuromodulator. Encoded by the ADCYAP1 gene and closely related to vasoactive intestinal peptide, it signals through G protein-coupled receptors to raise cellular cAMP and takes part in the stress response, circadian timing, and neuroprotection. It has become a prominent target in migraine research, since infusing PACAP can trigger migraine-like attacks in susceptible people.

reference

Nootropic

Pitolisant

Pitolisant is a histamine H3 receptor antagonist and inverse agonist used to treat excessive daytime sleepiness and cataplexy in adults with narcolepsy. By blocking the H3 autoreceptor it boosts the brain's own histamine signalling, which promotes wakefulness and places it among the wake-promoting agents sometimes called eugeroics. Marketed mainly as Wakix, it was approved in the European Union in 2016 and by the United States FDA in 2019, and it is unusual among narcolepsy drugs in not being classified as a controlled substance in the United States.

reference

Nootropic

Solriamfetol

Solriamfetol is an oral selective dopamine and norepinephrine reuptake inhibitor (a phenylalanine derivative) approved in the United States and European Union to improve wakefulness in adults with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea. It is marketed as Sunosi and is a US Schedule IV controlled substance.

reference

Eugeroic

TAK-861

Oveporexton (TAK-861), approved by the FDA on 5 August 2026 as Orzeyful; the first oral orexin receptor 2 selective agonist licensed for narcolepsy type 1, and the first approved treatment aimed at the cause of the disease rather than its symptoms.

reference

Nootropic

Theophylline

Theophylline is a naturally occurring methylxanthine (1,3-dimethylxanthine) that has been used as a bronchodilator and respiratory stimulant for more than 80 years. Structurally related to caffeine and theobromine and found in trace amounts in tea and cocoa, it relaxes airway smooth muscle and stimulates respiration through a combination of non-selective phosphodiesterase inhibition and adenosine receptor antagonism. At the low plasma concentrations achieved with modern sustained-release dosing, it also exerts anti-inflammatory effects by restoring histone deacetylase-2 (HDAC2) activity, a mechanism that can reverse corticosteroid resistance in severe asthma and chronic obstructive pulmonary disease (COPD). Because it has a narrow therapeutic window and numerous drug interactions, it is now generally reserved as an add-on therapy after inhaled agents.

reference

Nootropic

THN102

THN102 is an investigational drug combination that pairs the wakefulness-promoting agent modafinil with a low dose of flecainide, a compound that here acts on the brain's glial support cells. It was developed by the company Theranexus on the premise that inhibiting connexin gap junctions in astrocytes strengthens modafinil's effects. It has been studied chiefly for the excessive daytime sleepiness of narcolepsy and is not an approved medicine.

reference

Peptide

TRH

Thyrotropin-releasing hormone (TRH), whose pharmaceutical form is called protirelin, is a small peptide hormone made by neurons of the hypothalamus. Its best-known role is to signal the pituitary gland to release thyroid-stimulating hormone and prolactin, placing it at the top of the hormonal axis that controls the thyroid. TRH and its more stable analogues have also been studied for effects on mood, alertness, and the nervous system.

reference

Nootropic

Xelstrym

Xelstrym is dextroamphetamine delivered through the skin, and it is the first amphetamine patch approved for ADHD; the methylphenidate patch preceded it by fifteen years. The drug is not new and nothing about its pharmacology is: what is new is the delivery. A patch worn for about nine hours produces a gradual rise and then a controlled stop when it comes off, which solves two specific problems that oral stimulants handle badly, namely swallowing difficulty and the need to end the effect early rather than wait it out [2]. It was approved in 2022 on the strength of a pivotal study in children and adolescents [1].

reference

Stimulant

Zylofuramine

Zylofuramine (WIN 25873) is a mid-twentieth-century central nervous system stimulant belonging to the alpha-benzyltetrahydrofurfurylamine series, specifically the d-threo alpha-benzyl-N-ethyl tetrahydrofurfurylamine isomer [1]. It was investigated as a psychomotor stimulant and appetite suppressant during an era of intensive research into amphetamine alternatives. The published pharmacological record is sparse, consisting largely of the original characterization of the chemical series [1], and the compound is now encountered only as an obscure research chemical.

reference