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Pharmacological Advances in Cognitive Enhancement

Pills, pixels, and personal genomes: how new smart drug directions and precision pharmacology are changing cognitive enhancement

From university libraries smelling of modafinil tablets to AI engines offering you the optimal caffeine and L-theanine ratio – the desire to sharpen attention and memory only grows stronger. In 2025, this acceleration is driven by two converging trends: a new wave of purpose-designed "smart drugs" (nootropics) and a precision medicine toolkit that allows matching molecules to genomes, microbiomes – even individual human neural rhythms every hour. This article reviews the most advanced cognitive enhancement drugs, analyzes the ethical tensions related to their use, and explains how pharmacogenomics and AI are turning "one-size-fits-all" drugs into individualized neuroenhancement protocols.

Contents

  1. 1. Why now – a new pharmacological wave?
  2. 2. New directions in smart drugs
    1. 2.1 GlyT‑1 inhibitors | Iclepertin
    2. 2.2 GABAB modulators | TAK‑041
    3. 2.3 Triple reuptake agents | Centanafadine
    4. 2.4 Next-generation ampakines | GT‑032
    5. 2.5 Microdosed psychedelics and "wild cards"
  3. 3. Ethical and social discussions on smart drug use
  4. 4. Personalized medicine: individualized cognitive pharmacology
    1. 4.1 Pharmacogenomics and drug-gene tests
    2. 4.2 AI-driven dosing and digital biomarkers
    3. 4.3 Combined profiles: microbiome, sex, chronotype
  5. 5. Regulatory, clinical, and equity guidelines
  6. 6. Conclusion
  7. 7. References

1. Why now – a new pharmacological wave?

Three forces combined:

  • Deeper chain understanding. Single-cell RNA atlases reveal hundreds of new receptor types in the human cortex – not just dopamine or acetylcholine.
  • Risk and public funding. Cognitive enhancement startups raised $1.2 billion in 2024, and the US NIMH launched the "Cognitive Therapeutics for All" program.
  • Precision platforms. Affordable whole genome sequencing and wearable devices enable real-time monitoring of pharmacodynamic effects and "closed-loop" nootropic titration.
Summary: The appetite of science and business for a sharper mind has never been greater, yet public concern about justice, safety, and coercion is also growing.

2. New directions in smart drugs

2.1 GlyT‑1 inhibitors | Iclepertin (BI 425809)

Iclepertin blocks glycine transporter-1, enhancing NMDA-induced plasticity. In phase III trials in 2024, it met the primary MCCB (MATRICS Consensus Cognitive Battery) endpoint in schizophrenia; preliminary data show generalized effects on verbal learning domains, potentially extending benefits to other cognitive issues1. Boehringer Ingelheim submitted an FDA "Breakthrough" status application in early 2025. Unlike stimulants, iclepertin did not cause heart rate or sleep disturbances during 52 weeks of monitoring2.

2.2 GABAB modulators | TAK‑041

TAK‑041 is a positive allosteric modulator of GABAB receptors designed to precisely regulate prefrontal excitation/inhibition balance. A 2024 phase II trial with 160 participants showed a 2-point improvement in the NIH Fluid Cognition composite score without causing dependence or drowsiness. This has sparked interest as a physician-prescribed alternative to "benzodiazepine microdoses" used by some students3.

2.3 Triple reuptake agents | Centanafadine

Unlike methylphenidate or modafinil, centanafadine acts on dopamine, norepinephrine, and serotonin transporters almost equally. Post-hoc analyses of two ADHD studies (n = 1,022) showed significant working memory improvement, promising broader cognitive enhancement potential. Manufacturer Otsuka submitted an application in February 2025 for an "executive function disorder" indication – ethicists warn this may blur the line between treatment and enhancement.4.

2.4 Next-generation ampakines | GT‑032

Classical ampakines failed due to seizures and tachyphylaxis. GT‑032, developed by Cal-Tech startup GliaTune, features a transient covalent binding motif that enhances AMPA currents only during high-frequency impulses. A primate study published in Nature 2024 showed 28% faster maze learning without EEG hyperactivity; first human trials are planned for Q3 20255.

2.5 Microdosed psychedelics and "wild cards"

A placebo-controlled RCT conducted in the United Kingdom showed that a 10 μg LSD microdose for four weeks increased divergent thinking scores by 7%, but did not affect sustained attention6. Meanwhile, the biotech startup Tactogen is developing "empathogen-lite" analogs (e.g., MDMA-0x) aimed at enhancing social cognition with minimal cardiotoxicity. Regulators remain cautious: the UK Home Office rejected an application in 2024 to market low-dose psilocybin gummies as over-the-counter "wellness" products.

3. Ethical and social discussions on smart drug use

3.1 Fairness and coercion

In surveys of 11 US universities, 27% of students admitted to using prescription stimulants without a prescription in the past year; 58% felt pressure to keep up with others using “brain enhancers.”7. This may spread to the workplace: a 2024 Deloitte survey showed 19% of tech sector employees would use nootropics if offered by their employer.

3.2 Regulatory gray areas

Iclepertin and TAK‑041 are developed for mental illnesses, but their use in healthy individuals may rise, repeating the modafinil example from the 2000s. Some ethicists propose a “cognitive doping passport” modeled on sports biological passports – critics argue such tracking would violate autonomy.

3.3 Safety and long-term unknowns

Animal data show chronic GlyT-1 inhibition may reduce NMDA receptor levels, causing cognitive “declines.” Ampakines may increase seizure risk. Long-term microdosing and its effects on the serotonin system remain unstudied.

4. Personalized medicine: individualized cognitive pharmacology

4.1 Pharmacogenomics and drug-gene tests

Commercially offered kits like GeneSight™ were pioneers in psychotropic drug PGx, but in 2023–24 a new player, IDgenetix®, added drug-drug and lifestyle interactions to a 22-gene panel. A real-world study presented at Psych Congress 2023 reduced “wrong drug recommendations” by 30% in moderate-severe depression8. However, regulators warned several labs about overly optimistic IQ predictions. The FDA’s proposed LDT rule (2024) would require analytic validity data for PGx tests before commercialization.

4.2 AI-driven dosing and digital biomarkers

Startups like Noot AI collect HRV, sleep phases, and reaction time from wearables, feeding Bayesian algorithms that adjust centanafadine dose daily – essentially an individualized “neuro-thermostat.” The European Digital Medicine Society guidelines (2025 draft) require AI dosing engines to be approved by physicians and explained to users.

4.3 Combined profiles: microbiome, sex, chronotype

Important gut-brain connection: germ-free mice did not experience the cognitive effects of iclepertino seen after Bifidobacterium transplantation in the Boehringer study. Sex hormones alter pharmacokinetics: TAK‑041 clearance is 40% faster in women, so sex-based dosing is planned for phase III. Chronopharmacology studies with L-ornithine show that dosing before sleep enhances nocturnal consolidation. Personalized cognitive medicine is rapidly becoming multifactorial.

5. Regulatory, clinical, and equity guidelines

Stage Expected date Challenges
Iclepertino FDA/EMA approval for cognitive impairments in schizophrenia End of 2025 Spread into healthy market without indication
Centanafadine approval for executive function disorder 2026–27 Definition of diagnostic criteria; risk of misdirection
First AI-driven adaptive dosing approval (Class II SaMD) 2027 Explainability, data protection (GDPR/CCPA)
WHO global cognitive enhancement ethics document 2028 project Cultural consensus; implementation
Equality question: if paid AI nootropic subscriptions cost $300/month, will only wealthy early adopters remain “mentally accelerated,” further increasing social divide?

6. Conclusion

A decade ago, “smart drugs” meant off-label Adderall or a dusty bottle of piracetam. Today’s portfolio includes receptor-selective compounds like iclepertin, allosteric modulators like TAK‑041, multifunctional agents like centanafadine, and even psychedelic microdoses. At the top is an emerging layer of precision pharmacology: DNA panels, digital biomarkers, AI dosing engines – all potentially turning cognitive enhancement from a blunt stick into a fine lever. Whether this lever becomes a public good or a private race depends on transparent regulation, long-term safety, and ethics. Human brains may soon run on “beta software”; let’s ensure the terms of use serve everyone.

Disclaimer: This article is for educational purposes and does not replace professional medical or legal advice. Drugs promoting cognitive enhancement – whether approved or experimental – may carry risks that should be discussed with a qualified physician.

7. References

  1. Iclepertin Phase III trial results, FierceBioTech (November 2024).
  2. Boehringer safety continuation study press release (January 2025).
  3. TAK‑041 Phase II cognition data, PharmaTimes (March 2024).
  4. Centanafadine NDA submission article, EndpointNews (February 2025).
  5. Ampakine GT‑032 primate study, Nature (August 2024).
  6. LSD microdoses RCT, Psychopharmacology (December 2024).
  7. Student stimulant use survey, JACC (2024).
  8. IDgenetix pharmacogenomics poster (Psych Congress 2023).

 

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