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Nootropics Guide for Beginners

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In this nootropic guide presentation learn the complete history behind the discovery of these brain enhancing smart drugs used by Dave Asprey, The Bulletproof Exec.

http://ilovebuttercoffee.com/nootropics-guide/

Things you will learn:
# Origins of the word nootropic: Greek root noos for mind and trepein for toward
# Drugs along this line aim selectively at the noetic functions (relating to neocortical mental activity, cognition or the intellect)
# Discovered in 1964 by Dr Corneliu Giurgea at UCB
# Famous quote: “Man is not going to wait passively for millions of years before evolution offers him a better brain.”
# Was experimenting with GABA pathways in the brain & discovered Piracetam, also called Nootropil®
# He wrote the 1983 paper “The nootropic concept and its prospective implications“
# Discovered cognitive benefits to patients with epilepsy and post-concussion patients
# Caffeine, Modafinil and L-Theanine are considered smart drugs
# Piracetam, aniracetam, and Levitiracetam are considered nootropics

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Nootropics Guide for Beginners

  1. 1. The Discovery of Nootropics: A History of the Inadvertent Synthesis of Noetic-Enhancing Drugs
  2. 2. The Discovery of Nootropics: A History of the Inadvertent Synthesis of Noetic-Enhancing Drugs
  3. 3. _ hilt‘! _ _ ‘J. ’ ,1. F) ‘_“. __ «'4 ‘I. /I L‘; ",v"”. y:‘, r—“'/ ’“JrV‘[ E‘ _J_ _ _ __c ; ‘_y _; _w_ _i_ 7 _. _s 7 V1,. The history of an atypical neuropharmacological concept, Nootropics, was studied in my research. It is argued below that this recent, publicly unfamiliar, and yet widely studied paradigm originated by accident; a consequence of the investigation of unexpected noetic and cognitive-enhancing properties in one of many compounds synthesized by chief neuropharmacologist Dr. Corneliu Giurgea and his team at UCB in 1963. 77 again: 1 :1 ‘I ‘L’ I, . q'. " '4 u. . u id}: ries of lit l | d . vs (UCB iiredaugnfiron mental functioning.
  4. 4. Ixloetic: relating to neocortical mental activity, cognition, or the intellect Greek roots vooc noos-, mind and tponéu) trepein—, towards / noo. a'tropiks/ pronounced, noh—a—trop—iks v—*—-T--A
  5. 5. "Man is not going to wait passively for millions of years before evolution offers him a better brain. " - Dr. Corneliu Giurgea . .«“Y"-r, C: J Prezi "“au| “‘
  6. 6. In 1928, Emmanuel Jannsen founded the Union Chimique Belge, U. C.B. in Brussels, Belgium. s, “I'If, ‘E I : : PTCZI '1 5‘ ‘Iut| ‘
  7. 7. i ’ i' Emmanuel Janssen established Union Chimique Belge iUCBi in Brussels Belgium in 1928 primarily focusing on industrial chemicals it was one of the first companies in the world to distil ammonia from coal - UCB also had a small pharmaceutical division based around the l. leuiice Laboratories During the First World War the scientists at l. leLirice pioneered a method to isolate and purify insulin ll‘ >: i' i‘ ' ‘: ."li'ii - UCB expanded into industrial films notably cellophane _ with the acquisition of Sidac isociete lndustrielle de la - - - Came, Union Chimique Belge l ‘l i l - Entered the United States in 1938 with the purchase of the l. ‘ l packaging business Silvannia ‘ii 7 l ' ‘ ‘ - Manufactured pharmaceutical products during World War ll including calcium phosphorus vitamins insulin and l i sulphamides l l - Reinforced its film business and international presence l with the creation of Cellophane Espanola in 194.3 DI. Giurgea is ‘ hired
  8. 8. - Established a pharmaceutical research center in 1952 and soon made a string of breakthroughs including the discovery of one of the world's first tranquilizers Ataraxé ihydroxysiiieji a non-benzodiapenic tranqulizer Ataraxiii lent its name to a new class of therapeutic products — ataraxics — and provided the resources for the company to expand its R&D - Awarded the US distribution licence for Ataraxéi to a at this time small young company Pfizer — helping the US company evolve into a maior pharma UCB's partnership with Pfizer continues to this day , i “l‘, ‘l""*: '," - Started to research the potential of biotechnology in 19-35 - Consolidated its position in chemical and films moving into new value-added‘ fields ~-r i ll '2» i L ‘ - Launched Flootropiliii ijpiracetam) in 1972 for the treatment of memor_y and balance disorders providing the resources to create a new state-of-the-art pharmaceutical R&D centre in Braine-I Alleud Belgium - Still focused on three core areas — chemicals films and pharmaceuticals the company expanded its network of European subsidiaries
  9. 9. Emmanuel Jannsen of UCB hired professor of neurophysiology Dr. Corneliu Giurgea from the University of Bucharest. Giurgea left Romania and traveled to Belgium where he assumed a position as Head of the Department of Neuropharmacology at UCB . .vi“Y"ir, Prezi ‘Iu| |“
  10. 10. Born in 1923 in Romania, Giurgea was a Jewish-born atheist, holding an M. D. from the University of Bucharest, and a Ph. D from the Pavlovian Laboratory in St. Petersburg (at the time ‘Leningrad'). Giurgea taught a lively course in psychopharmacology, the scientific study of the effects that drugs have on mood, perception, thinking, and behavior.
  11. 11. Shortly thereafter, Corneliu Giurgea and his small team of chemists, neuroscientists, and psychologists were commissioned by UCB to synthesize artificial chemical sedatives. Giurgea and his team of specialized scientists in Belgium set to work for two years assigned the psychopharmacology of creating man-made and purely synthetic sleep-inducers in 1963. Given the recent discoveries of chemically-based neurotransmitters in the years of the 1950's, scientific consensus demonstrated that gamma- amino-butyric acid (GABA) acts as a major inhibitory neurotransmitter in the brain.
  12. 12. UCB’s efforts towards innovative and industrial production of new and undiscovered drugs was at the epicenter of a culture of high scientific interest in GABA—related experiments in pharmacology. In 1964, the scientists under Dr. Giurgea came together to synthesize a calming ‘inhibitory’ drug with sedative effects that was at once a cyclic derivative of the neurotransmitter GABA. What they found they could never have predicted. “QIVIQ Prezi r, ‘ “s
  13. 13. In one of his landmark publications on the research of nootropics, Giurgea wrote in a peer—reviewed academic article called The Nootropic Concept and Its Prospective Implications explaining the failure, “It all started with a wrong hypothesis, namely, that by working with cyclic GABA derivatives we should find new sedative hypnotics because, we thought, we would provide an “extra amount” of inhibition to the brain. ”
  14. 14. éqtvn, Prezi ‘Iu| |‘ Unfortunately, each of their new compounds did not inhibit nor provide ‘extra inhibition’ to the brain. Giurgea and the UCB team of scientists N‘ realized they had relied on a wrong de hypothesis, unwittingly producing GABA- ex ineffective compounds by synthesizing cyclic, disubstituted GABA derivatives. 38 cc Hi pl NI
  15. 15. Nevertheless, Dr. Giurgea and his team at UCB were determined to not give up, eager to turn the expensive failure into an unexpected success. Carrying forward with animal trials, tests of their compounds in 1965 with rats and rabbits proved again that no sedative effects were present in their compounds. However, one compound stood out for its unusual pharmacology. One specific synthesis, UCB 6215: Nootropyl®, was observed to inhibit vestibular nystagmus in successive animal trials on rabbits [Giurgea et al. , 1965]. Nystagmus is a condition that causes involuntary eye movement and is known as a neurological disorder. . .vi“Y"ir, Prezi ‘Iu| |“
  16. 16. Ch/ mlqul Belg _ Prezi Working from the clues they discovered in animal experiments, chief neuropharmacologist Dr. Giurgea and his team of scientists had learned: i. Compound 6215 inhibited nystagmus ii. Compound 6215 inhibited vertigo iii. Compound 6215 had no traces of chemical toxicity in rabbits and rats While all other compounds failed to elicit results. these neurological findings authorized compound 6215 for clinical human trials. Giurgea and Oosterveld, 1965: Human trials on healthy, average individuals. Tested with 6215 for sedative effects. Jabro and Hillbom, 1966: Human trials on post- concussion patients. Tested with 6215 for sedative effects. FWIW. Giurgea and Oosterveld, 1965: No results, no sedative or sleep-inducing inhibitory effects. Jabrci and Hillbom, 1966: No sedative effects. However, just after one month of exposure to 6215 the scientists observed surprising feedback. Astonishingly, post-concussion patients demonstrated a statistically significant difference in the recovery and improvement of memory than control groups of post- concussion patients not given compound 6215.
  17. 17. Working from the clues they discovered in animal experiments, chief neuropharmacologist Dr. Giurgea and his team of scientists had learned: i. Compound 6215 inhibited nystagmus ii. Compound 6215 inhibited vertigo iii. Compound 6215 had no traces of chemical toxicity in rabbits and rats Wl net clin Giu ave effe Jab con effe
  18. 18. “qIVl I ‘it Prezi 4, . .‘ [_r-. ' i Li . . , _i P r - . I r_ at . p l '—l llilJr. r:lr {Till lli‘ ‘J l _l _l_i 7’ 7i _i 7l 7,_l_i _i‘ _ f. }._l _. i‘ r. :'; _e ‘L [L ‘I. _ fi, "l_i '7” i‘ While all other compounds failed to elicit results, these neurological findings authorized compound 6215 for clinical human trials. Giurgea and Oosterveld, 1965: Human trials on healthy, average individuals. Tested with 6215 for sedative effects. Jabro and Hillbom, 1966: Human trials on post- concussion patients. Tested with 6215 for sedative effects.
  19. 19. Giurgea and Oosterveld, 1965: No results, no sedative or sleep—inducing inhibitory effects. Jabro and Hillbom, 1966: No sedative effects. However, just after one month of exposure to 6215 the scientists observed surprising feedback. Astonishingly, post-concussion patients demonstrated a statistically significant difference in the recovery and improvement of memory than control groups of post- concussion patients not given compound 6215. v ¢§“_"' . ° 5 ‘In Prezi I
  20. 20. Carrying the inadvertent investigation into Nootropyl's cognitive- activating rather than inhibiting properties further, another scientist at UCB. Dr. Sorel, conducted a longitudinal study of Nootropyl®’s unexpected properties in epileptic children. Surprisingly, patients or their parents claimed that consistent and prolonged dosage of the drug not only alleviated symptoms but actually caused. “. ..some kind of improvement in their overall mental efficiency. " R. PIK nan : - Dr. Jabro and Hillbom reported that patients seemed to actually ‘think better’ after a consistent and noticeably prolonged exposure to the drug while also confirming an absence of pm. .. chemical toxicity in humans. I, ‘an, ’ Amen. .- Nu- I! v At this time Giurgea and scientists studying the compound suspected that this new drug must therefore selectively activate Rapidly, new experiments at UCB responded to M" . , transcallosal evoked potentials as well as facilitate higher cognitive Dr. Jabro and Hillbom‘s hypothesis that the €X€CUtiVE menial f1nCfi0I15» synthesis of GABA sedative sleep inducers had accidentally generated a cognitive activating, Bu 1 , , The dl-lemma h0W€V€| ’i W33 that the drug W35 3 CYCHC GAB-“chased rather than inhibiting drug derivative and yet didn't interfere or inhibit any GABA-related structures of the brain. Instead of inhibition or any sedative effect. the scientists of UCB had confirmed that this drug did the reverse; activating and facilitating the communication between many of the frontal higher spheres of cognition and executive control.
  21. 21. Inadvertent Investigation Dr. Jabro and I-Iillbom reported that patients seemed to actually ‘think better’ after a consistent and noticeably prolonged exposure to the drug while also confirming an absence of chemical toxicity in humans. Rapidly, new experiments at UCB responded to Dr. J abro and Hi11bom’s hypothesis that the synthesis of GABA sedative sleep inducers had accidentally generated a cognitive activating, rather than inhibiting drug
  22. 22. Carrying the inadvertent investigation into Nootropyl’s cognitive- activating rather than inhibiting properties further, another scientist at UCB, Dr. Sorel, conducted a longitudinal study of Nootropy1®’s unexpected properties in epileptic children. Surprisingly, patients or their parents claimed that consistent and prolonged dosage of the drug not only alleviated symptoms but actually caused, “. ..some kind of improvement in their overall mental efficiency. ” "'00-: drugs
  23. 23. I Iurolqpnn uni" "w", Afoucti 1 I At this time Giurgea and scientists studying the compound suspected that this new drug must therefore selectively activate R". .. transcallosal evoked potentials as well as facilitate higher cognitive executive mental functions. , The dilemma however, was that the drug was a cyclic GABA—based derivative and yet didn’t interfere or inhibit any GABA-related 1 structures of the brain. Instead of inhibition or any sedative effect, the scientists of UCB had confirmed that this drug did the reverse; activating and facilitating the communication between many of the frontal higher spheres of cognition and executive control.
  24. 24. The Discovery of Nootropics: A History of the Inadvertent Synthesis of Noetic-Enhancing Drugs
  25. 25. In a historical experiment, Dimond [1976] and Dimond and Brouwers [1976] gave Piracetam to healthy, average, college—age student volunteers at Braine l'Aleud. Coupled with a placebo, the experimental results observed a distinct and significant increase in verbal and working memory in the experimental group. I-lowever, Dimond and Brouwers confirmed a paradoxical finding also observed in the first human trials by Dr. Sorel, labor, and Hillbom. When ingested, Nootropyl® did not immediately produce an observable change in the constitution or intelligence of the subject such as traditional ‘smart drugs’ might (modafinil, adderall, coffee). Instead, the consistent administration of piracetam only revealed a statistically significant and measurable effect when sustained with long—term administration. Piracetam's mechanism of action seemed to function in an aggregational and culmulative way, unlike many other drugs. Indeed, the threshold of distinguishable effects of Piracetam only manifested when it was administered every single day during a three week or longer period. Just as Dr. Jabro and I-Iillbom's concussion patients did not improve immediately in experimental trials when given Piracetam, so too did Dr. Sorel's epileptic patients fail to improve in any observable way immediately when first given compound 6215. Nevertheless, when Piracetam was administered daily for a month- long period in Dr. Jabro and Hillbom [1965], Dr. Sorel [1967], and Dr. Dimond and Brouwers’ [1976] experiments, the drug had observably improved the cognition, mental efficiency, and overall intelligence of the patient. Zahkl. Mean number nf w averaged over [hire rzplications Control IN — 8) session: I 2 3 H; 1 l~Zn'ccu of l»’ur: u.~:1am ll. ‘
  26. 26. Psychoanaleptics CNS SHMULANIS llgfluv Al ywu. Vamphuamuus Ycauemu ANvIoEvRz_~, Illfibll ALII» I TEN llncyclucs Vlrlhmrn NOOVROPICS INUEHC At, ‘ . - '| )IIa(. olnm 'tlna(. eMm 1-. Unexpected Success Psychodyslepucs PSVCHOTOMIMFIICS IMAL—Ur I~()l'. lN§ V0D'iIcs VL$D imuunnc V unr-. w.no. m Dr. Giurgea and his specialized team at UCB had converted numerous failed attempts at synthetic sedative, sleep-inducing compounds into an accidentally and surprisingly atypical interhemispheric cognitive enhancer and protectant. Nootropyl® became one of UCB’s first critical commercial successes alongside the early distillation of ammonia from coal and the purification of insulin. Asserting the company’s enduring pharmaceutical legacy in Europe, the continued academic and research interest in Piracetam’s inadvertent success enabled the company’s expansion to a brand new research center in Braine—l’Aleud in South Belgium. concussion patients did when given Piracetam. improve in any observa 6215. Nevertheless. Wht long period in Dr. Jabro Dimond and Brouwers’ improved the cognition patient.
  27. 27. Smart Drugs i. Caffeine ii. Adderall iii. Modafinil iv. L—theanine Nootropic Drugs i. Piracetam ii. Levitiracetam iii. Choline iv. Aniracetam Whereas psychotropics like coffee and stimulants such as modafinil and adderall are characterized by their temporary enhancement of the activity within the central nervous system, compound 6215's properties discovered unintentionally by UCB was unlike any other preexisting traditionally cognitive enhancing drug. Stimulants produce a variety of useful effects and are still considered ‘smart drugs’, because they enhancing alertness, arousal, locomotion, heart rate, and blood pressure. Nootropyl® did none of these when administered for the first time, having no observable effects in the patient who had ingested Nootropyl. Yet, after one entire month of consistent administration. statistically significant effects were observable in the patient, lending to the unanticipated conclusion that the culmulative effects of Piracetam warranted an entirely new category of ‘smart drug’; cognitive—enhancing, without side effects, without toxicity, cumulative and non—immediate, solely noetic, and lacking its own classification.
  28. 28. Giurgea and the scientists at UCB knew that piracetam's properties did not fit into any known categories of pharmacology. Uncertain of the direction of this line of research despite ongoing studies, new data at UCB and from neighboring institutions demonstrated an undeniable and direct impact on mental functioning. Confirming Giurgea and UCB’s hypotheses, studies revealed a selectivity in Piracetam’s distinct mechanism of action. Unlike any other preexisting drug and drug classification, Nootropyl® interacted solely and purely with the higher executive cognitive functions. Compound 6215 did not act immediately, but instead worked on the brain culmulatively. Further, Nootropyl was completely non-toxic in both animal and human clinical trials. In his landmark and first peer reviewed publication of the findings surrounding Nootropyl®, Dr. Giurgea presented his famous and unprecedented claim that piracetam should consequently be a distinct category of pharmacological drug, incomparable to all other existing classifications in pharmacology [Delay-Deniker classification system]. In his paper, The Nootropic Concept and Its Prospective Implications, Giurgea wrote, "Because drugs along this line ‘aim’ selectively at the noetic functions, we suggest that they should be called nootropics (noos-, mind and trepein-, turn/ towards). " Consequently, Giurgea concluded that the paradigm of neuropharmacology and traditionally cognitive enhancing drugs had met a classic kuhnian anomaly. This anomaly was the accidental discovery of the culmulative properties of Piracetam in the 1960's, the first ever nootropic drug.
  29. 29. .. «“Y"-r, Prezi ‘Iu| |“ As a result of the accidental discovery of cognitive-activating properties instead of sedative, cognitive-inhibiting effects in Piracetam in the late 1960's, Giurgea created and advocated for the acceptance of a distinct category of noetic cognitive enhancing drugs. He coined the term nootropics in 1964, labeling compound 6215 and the discovery of its effects, the first nootropic
  30. 30. Ii! 9* "1 If rt II. I'«. ‘‘ ‘ W’ 4:16-21’? 3‘ ‘C _ I _ I Giurgea and UCB continued to pursue the psychoanaleptic line of research, subtly altering Nootropyl’s chemistry. In the late 1980's, Dr. Giurgea and his team would go on to synthesize another Nootropic drug similar to the composition of Piracetam. Fast tracked by UCB in the 80's and 90's to market distribution, Levetiracetam, also known as Keppra®, would go onto become a billion-dollar blockbuster anti—epileptic drug. Currently a standard treatment for the symptoms of Epilepsy throughout the U. S. and the globe since 1999, the accidental discovery of the nootropics paradigm and its continued investigation provided UCB the resources to become a multi—national pharmaceutical company. “IV! ” Prezi ‘Iu| |‘
  31. 31. ° 0 40 j/ CH, N H 0 , N _’ IN Hit N 0 N 0 Z | c'ctimCct: nm Cu, N/ ( 0 Cu, T HIC4 CH3 pciminncclzrm OH N 43 13/ K —. o ‘(T 0 N N S, NH; 0 - wunifiram N I O NH: 0 F / 0 V un; {,, ,,, ,, )_ pimccmm oxiracctarn . -nirucclam 0 Y fiisorncctam m ,4“: 0 0 N 4 OCH, n: bmccLxm
  32. 32. f 3»: I. I:I«: :IL. .!; :.'‘ »:1,’": I - Becoming known as a ‘drug in search of a disease’, hundreds of scientific papers were published on compound 6215's surprising properties and inadvertent origins. Increasing the cognition, memory, and learning of healthy individuals, Piracetam was discovered to simultaneously protect against amnesic agents, chemical toxicity, and hypoxia. Also completely non-toxic to both humans and animals, Nootropyl’s continued research interest and success enabled the multi—national expansion of the pharmaceutical company UCB. - Advocating for the establishment of an entirely new system of classification around the discovery of Piracetam’s atypical properties, Dr. Giurgea pioneered the paradigm-shifting historical concept in the 1960’s that changes can be induced in the higher mechanisms of the brain by chemical compounds and substances. Enjoying lasting research interest, Piracetam has become the most widely studied, safest, mass-produced cognitive enhancing nootropic drug in the world. Catalyzing the paradigm of nootropics and the pharmaceutical industry for the brain, Piracetam’s inadvertent discovery opened up new and undiscovered avenues of research for the future of intelligence- enhancing drugs in the field of pharmacology.
  33. 33. Giurgea. CE. "Psychophannacology Tomorrow: 1984 or the Little Prince? " Psychological Medicine. 14.3 (1984): 491-6. Print. Quote discovered in this paper from Romanian scientist Corneliu E. Giurgea, first credited with proposing in the 1960s that smart pills should be developed to increase the intelligence of the general population in the paper above. Emmanuel. Janssen. Union Chimique Belge, "UCB Pharmaceutical History. " Accessed November 11. 2013. on the UCB websites pharmaceutical history page of notable successes and half-century long development of the business. Marginineanu. Dr. Doru Georg. "A Weird Concept with Unusual Fate: Nootropic Drug. " Department of Neuroscience, University of Mons. Belgium, Revue des Questions Scientifiques, no. I (2011): 33-52. Little is known about Dr. Comeliu Giurgea. While Giurgea left behind a large body of work with his death, there are no encyclopedic. historiographic, or known sources of knowledge about his early life, motivations, heritage, or even his dates of birth and death. The most that is known about Dr. Giurgea’s life and biography was recorded in an interview with Giurgea by his last living colleague. Dr. Doru Georg Margineanu, who studied Giurgea's contributions to neurophan-nacology and transcribed his primary source interview into footnote #1 of his publication, A Weird Concept with Unusual Fate: Nootropic Drug. Giurgea. Corneliu. ‘The Nootropic Concept and Its Prospective Implications. " Drug Development Research. (1982): 441446. The first record of Dr. Giurgea and his team's ongoing curiosity with the atypical pharmacology of compound 6215 is documented here, in which Giurgea et al. . discover a higher cognitive neurochemical correlation between 6215 and the brain during the years 1963-1967. after which the first human trials begin at UCB. Dimond, Stuart 1., and E. Y. M. Brouwers. "Increase in the power of human memory in normal man through the use of dmgs. " Psychopharmacology 49, no. 3 (1976): 307-309. Some of the first human trials are recorded by pioneering scientists Dimond and Brouwers from within UCB, drawn to the recent academia emerging from UCB’s compound 6215. Not only did Dimond and Browuers observe experiments with medical patients. but observed cognitive enhancement in healthy. normal individuals. Chatterjee A. 2004. "Cosmetic neurology: the controversy over enhancing movement. mentation. and mood". Neurology. 63 (6): 96874. Article on ‘brain boosting’ by the large public and the culture of self-medicated ‘smart drug‘ use. Safety and ethical concerns. the concern of ‘academic doping’. college blackmarkets for ‘smart drugs’. the development of ‘nootropic stacks’ and the propensity of patients to frame neurologists or clinicians as ‘gatekeepers’ of medicine. Buccafusco J}, T Weiser, K Winter, K Klinder, and AV Terry. 2004. "The effects of IDRA 21, a positive modulator of the AMPA receptor, on delayed matching performance by young and aged rhesus monkeys". Neuropharmacology. 46 (1): 10-22. p.11. Employed in Prospective Implications. analyzing the effects of promising new nootropics such as IDRA 21.
  34. 34. The Discovery of Nootropics: A History of the Inadvertent Synthesis of Noetic-Enhancing

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