There are many potentially new drugs that actually improve cognitive performance, and they are not herbs. DARPA and has a program called "Advanced Molecular Discovery" to find therapeutics that stimulate neurogenesis and improve arousal, cognition, and memory.

1. Nootropic Drugs and the Regulatory
Genome
Gerald A. Higgins, Ph.D.

2. ”We are very interested in computational and
experimental approaches that leverage novel findings
from genomics, epigenomics, neuroscience, and
psychiatry to advance treatment and resilience in
neurological health, transformative neural processing,
and optimization of human performance.”
- Dr. Kerrie Dugan, Acting Director, BTO, DARPA

3. Binding studies of modafinil and cocaine
• Modafinil to dopamine transporter (DAT): Ki of 2-5 mM;
• Cocaine to DAT (SLC6A3): Ki of 10 nM;
• Modafinil to HCRTR2* receptor: Ki of 0.1 nM;
• Modafinil to HCRTR1 receptor: Ki of 10 nM.
*Protein product is often called the orexin receptor. Genome biologists call it the
hypocretin receptor.

4. Cloning of brain-specific genes found that the product of clone
1B235 caused arousal and increased cognition [1, 2]
Hypocretin (orexin) – containing
neurons in the lateral hypothalamus
[1] Higgins, G. A., Schmale, H., Bloom, F. E., Wilson, M. C., & Milner, R. J. (1989). Cellular localization of
1B236/myelin-associated glycoprotein mRNA during rat brain development. Proceedings of the National
Academy of Sciences, 86(6), 2074-2078.
[2] Peyron, C., Tighe, D. K., Van Den Pol, A. N., De Lecea, L., Heller, H. C., Sutcliffe, J. G., & Kilduff, T. S. (1998).
Neurons containing hypocretin (orexin) project to multiple neuronal systems. Journal of Neuroscience, 18(23),
9996-10015.

5. Modafinil and related drugs: Provigil, Nuvigil (armodafinil) and –
adrafinil (OTC in Canada and most countries except the U.S.)
• Modafinil was originally developed by French neurophysiologist
Michel Jouvet who started Lafon Laboratories. Lafon was acquired by
Cephalon in 2001. TEVA acquired Cephalon in 2010 following the
death of Frank Baldino, founder of Cephalon;
• Modafinil, armodafinil, and adrafinil bind are high affinity agonists at
the hypocretin (orexin) receptor 2 in the lateral hypothalamus.

6. Adverse drug events associated with modafinil and related drugs
Adverse Drug Event
Incidenc
e
Comments
Headache 34% Adult
Insomnia 30% Adult
Severe anxiety and psychotomimetic effects 21%
Drug-induced, found in healthy
controls
Heart palpitations 20% Adult
Nausea, GI problems 20% Adult, children
Skin rash 15% Adult
Stevens Johnson Syndrome and TEN 0.01%* Pediatric only
*This percentage is quite high for any medication and has led to discontinued use of
these drugs in children with ADHD in most countries. It should be noted that another
drug, allopurinol, binds with affinity to the HCRT1 and HCRT2 receptors, but not in
brain. This antibiotic also exhibits rare adverse events such as SJS and TEN.

7. Suvorexant (Balsomra®) exerts its therapeutic
effect as an anti-insomnia drug acting as an
antagonist at HCRTR1 (0.55 nM) and HCRTR2
(0.35 nm) receptors.
• Suvorexant, considered the first successful drug developed by the NIH (with Merck) to provide an
alternative to the controlled substances (schedule IV) currently for treatment of insomnia;
• Balsomra® proved to be ineffective because the steric hindrance at the receptors was too high, and thus
the dosing was too low to provide adequate relief from insomnia.

8. Can we use the results from GWAS to predict other druggable targets for
arousal and wakefulness?
The top SNPs are within genes controlled by the same enhancer: HCRTR2, GFRAL, and
FAM83B:Variant P-value Type Mapped gene Reported trait PubMed ID Location
rs2653349-A 3 x 10-48 Missense, TAD boundary HCRTR2 Morning person 30696823 6:55277539
rs2653349-A 3 x 10-48 Missense, TAD boundary HCRTR2 Chronotype 30696823 6:55277539
rs2653349-A 1 x 10-32 Missense, TAD boundary HCRTR2 Morningness 30804565 6:55277539
rs35833281-C 2 x 10-31 Intragenic enhancer HCRTR2 Morning person 30696823 6:55156763
rs2653343 4 x 10-30 Intragenic enhancer HCRTR2 Morning person 30595370 6:55268528
rs2653349-A 8 x 10-29 Missense, TAD boundary HCRTR2 Ease of getting up in the morning 30804565 6:55277539
rs13208701-A 6 x 10-19 Intergenic enhancer HCRTR2, FAM83B Morning person 30696823 6:55015670
rs76899638-A 8 x 10-13 Intergenic enhancer HCRTR2, GFRAL Chronotype 27494321 6:55282711
rs9382445-A 6 x 10-11 Distal promoter HCRTR2, FAM83B Sleep duration 30846698 6:55073176
rs3122163-A 4 x 10-10 Intergenic enhancer HCRTR2 Sleep traits (multi-trait analysis) 27992416 6:55191570
rs35833281-A 4 x 10-9 Intergenic enhancer HCRTR2 Morning vs. evening chronotype 26835600 6:55156763
rs9382484-G 1 x 10-8 Distal promoter, GFRAL GFRAL, HCRTR2 Ease of getting up in the morning 28604731 6:55318062
rs2653344-T 1 x 10-8 Intragenic enhancer HCRTR2 Daytime nap 30804565 6:55268788
rs144870624-T 2 x 10-8 Enhancer HCRTR2 Morningness 30804565 6:55170886
rs13208701-A 6 x 10-19 Intergenic enhancer HCRTR2, FAM83B Morning person 30696823 6:55015670
rs4715491-G 2 x 10-14 Intragenic enhancer FAM83B Morning person 30696823 6:54899522
rs9382445-T 6 x 10-11 Intergenic enhancer HCRTR2, FAM83B Sleep duration 30846698 6:55073176
rs11969918-A 2 x 10-9 Intragenic enhancer FAM83B Morningness 30804565 6:54883421
rs13208701-A 6 x 10-19 Intergenic enhancer HCRTR2, FAM83B Morning person 30696823 6:55015670
rs4715491-G 2 x 10-14 Intragenic enhancer FAM83B Morning person 30696823 6:54899522
rs9382445-T 6 x 10-11 Intergenic enhancer HCRTR2, FAM83B Sleep duration 30846698 6:55073176
rs11969918-A 2 x 10-9 Intragenic enhancer FAM83B Morningness 30804565 6:54883421

9. Can we use the results from GWAS to predict druggable targets for cognition?
Several SNPs in the HRCTR1 gene are significantly associated with decreased or increased
cognition:
Variant P-value Mapped gene Reported trait Trait(s) PubMed ID Location
rs10798879-T 6 x 10-15 PEF1, HCRTR1 General cognitive ability Intelligence 29844566 1:31631214
rs10798880-T 9 x 10-13 HCRTR1, PEF1 Cognitive performance (MTAG)Cognitive function measurement 30038396 1:31631487
rs10798880 8 x 10-10 HCRTR1, PEF1 Cognitive ability (MTAG)
Intelligence, self reported
educational attainment
29186694 1:31631487
rs7518151-T 1 x 10-9 TINAGL1, General cognitive ability Intelligence 29844566 1:31596250
rs7518151-T 1 x 10-8 TINAGL1, Intelligence Intelligence 29942086 1:31596250
rs4949448-T 1 x 10-8 TINAGL1, Intelligence Intelligence 29942086 1:31596465
rs10914457-A 2 x 10-8 HCRTR1 General cognitive ability Intelligence 29844566 1:31628660
rs10798880 5 x 10-8 HCRTR1, PEF1 Cognitive ability Intelligence 29186694 1:31631487

10. Can we use the results from GWAS to predict other druggable targets for
cognitive enhancement?
• Intelligence
• Mathematical ability (self-reported)
• Educational attainment (self-reported)
• Cognitive performance
• Cognitive ability
• Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)
• Highest math class taken
• Household income
• Automobile speeding propensity
• Automobile driving skill
Many of the top 258 SNPs are within a single RNA gene (ENS00000271860;
Chromosome 6: 97,283,303-98,400,869) that produces 51 transcripts with significant
associations:

11. Super-enhancer
Enhancer
HLA and related
genes TADs
HCRTR2
GFRAL
FAM83B
Gene that encodes
Modafinil target
Stevens Johnson Syndrome, TEN
RNA Genes: ENS00000271860 and related
Cognitive performanceWakefulness
Chromosome 6, Human build 38
Long non-coding RNAs
SNPs are significantly
associated with cognition
SNP rs2734583,
Noncoding super-enhancer variant:
Significant association with SJS/TEN;
Large effect size, OR=66, CI=[19.8-225.0]

13. • In a bygone era of neuroscience (before 2015), it was thought that the HLA complex on chromosome 6
controlled the orexin receptor 2 (hypocretin receptor 2 – HCRTR2).
• We know know that SJS and serious adverse events related to modafinil are caused by mutations in a
common super-enhancer that also controls the HLA genes in some cells

14. Modafinil – THE END