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Brain stimulants

The document discusses various brain stimulants and cognitive enhancers, including their mechanisms of action, uses, and effects on conditions such as ADHD, depression, and Alzheimer's disease. It covers a range of substances including racetams, cholinergics, AMPA-kines, and more, detailing their roles in enhancing cognitive functions. Additionally, it elaborates on the clinical applications of these substances, particularly for individuals in high-stress professions and those with cognitive impairments.

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Amr Hassan MD,FEBN Professor of Neurology - Cairo University Brain Stimulants
A Ch
6 Neurobiology of sleep
7 Hypothalamic and brainstem sleep-wake regulation system
8 Arousal pathways maintaining cortical activation in the waking state
Neurobiology of sleep
SCOPE OF COGNITIVE ENHANCERS IN HEALTH & DISEASE Exam going students stressful jobs which need complete focus: physicians, pilots, military personnel Artists Athletes Alzheimer's Dementia (senile/vascular) TIA, CVA MR and ADHD in children Head injury Schizophrenia OCD Phobias Depression
RACETAMS • Piracetam • Aniracetam • Oxiracetam • Pramiracetam • Phenylpiracet • Nefiracetam • Coluracetam
PIRACETAM • ↑ ACh activity in the brain • ↑ glutamate activity via AMPA and NMDA receptors • Improve membrane permeability of neurons → enhances overall neuronal function MECHANISM OF ACTION USE • off-label ADHD treatment
Aniracetam MECHANISM OF ACTION • derivative of Piracetam • 5x more potent • also stimulates AMPA receptor: learning & memory encoding processes • activate D2 and D3 Dopamine receptors & 5-HT(2a) receptor involved in Serotonin processing USE • effective as an anti- anxiety and anti- depression treatment
Pramiracetam MECHAAISM OF ACTION • Piracetam analogue (30x) • influences both Glutamate and ACh receptors • ↑ reuptake at ACh receptor sites as well as increasing the efficiency of nerve impulse channels in the hippocampus → central role in memory formation as well as recall USE • mental clarity and concentration • speed of information processing
Noopept MECHANISM OF ACTION • Not racetam, but similar MoA • 1000 X • high affinity for ACh, AMPA and NDMA receptors: relate to short- term and long-term memory • also activates D2 and D3 receptors & selective Serotonin receptors • ↑ Nerve Growth Factor - maintenance and repair of healthy brain cells USE • investigated as a possible treatment for Alzheimer’s disease, Age-Related Memory Loss • Depression & anxiety
Nefiracetam MECHANISM OF ACTION • Potentiates excitatory neurotransmission → prolonging the opening of calcium channels • binds to N-ACh r: ↑ communication in GABAergc, Cholinergic, monoaminergic and glutamatergic neuronal systems • highly cytoprotective USE • treat apathy and improve motivation in post-stroke patients • Anti-amnesia effects • powerful anxiolytic
CHOLINERGICS Choline Alpha-GPC Citicoline Centrophenoxine Choline citrate/bitartarate DMAE Lecithin Phosphatidylcholine AChE inhibitors Galantamine Huperzine A
GENERAL PRINCIPLES • ACh is an excitatory NT • ↑ attention, synaptic plasticity, wakefulness and the reward system • ↑ cholinergic activity: improve focus, working memory, alertness, mental clarity and performance
Choline MECHANISM OF ACTION USE • water-soluble essential nutrient • structural integrity and signaling roles for cell membranes • ↑ cholinergic neurotransmission (ACh synthesis) • treat apathy and improve motivation in post-stroke patients • Anti-amnesia • anxiolytic • Anti depression
Alpha - GPC (Alpha Glycerylphosphorylcholine) MECHANISM OF ACTION • occurs naturally in the brain, human breast milk (associated with ↑IQ in breast fed babies) • highest bio-availability of Choline • readily crosses the blood-brain barrier
Citicoline MECHANISM OF ACTION • intermediary in the conversion of choline into phosphatidylcholine in the liver • ↑ availability of choline in the brain by freeing up quantities of choline • preservation of cardiolipin and sphingomyelin • Citicoline decreases phospholipase stimulation → less hydroxyl radicals USE • approved for treatment in cases of head trauma, stroke, neurodegenerative diseases
Centrally acting anticholinesterases tacrine approvedforthetreatment ofAlzheimer's disease galantamine mildtomoderatevasculardementiaandAlzheimer's rivastigmine mildtomoderatedementiaoftheAlzheimer’stype anddementiaduetoParkinson'sdisease donepezil approvedforthetreatmentofAlzheimer'sdisease HuperzineA
AMPA-KINES • Sunifiram • Unifiram • Ampalex (CX-516)
AMPA-KINES GENERAL PRINCIPLES • activate glutamatergic AMPA r: promote alertness, ↑ attention span and memory • ↑ synaptic communication: promote growth of neurons and the formation of long term memories • potential treatment: Alzheimer's disease, Parkinson's disease, schizophrenia, treatment-resistant depression, neurological disorders such as Attention Deficit Hyperactivity Disorder (ADHD)
Sunifiram MECHANISM OF ACTION • Sunifiram activates AMPA- mediated neurotransmission • It enhances LTP • improves cognitive deficits via CaM kinase II and protein kinase C activation • ↑ release of ACh in the cerebral cortex USE • alleviate symptoms of ADHD
SMART DRUGS • Adarafinil • Modafinil • Armodafinil • Methylphenidate
31 Eurogenics
32 Armodafinil FDA approval 1. Obstructive Sleep Apnea/Hypopnea Syndrome (OSAHS) 2. Narcolepsy 3. Shift Work Sleep Disorder (SWSD)
How Armodafinil and Modafinil Are Similar 33 Structurally, two enantiomers make up modafinil: the R-enantiomer and the S-enantiomer The two compounds are flip-copies of each other, just like your right hand and your left. Armodafinil consists of only the R-enantiomer of modafinil (in medical jargon, it’s an enantiopure version of it). It turned out the R-enantiomer gives much stronger psychoactive effects. This discovery is ultimately what drove scientists to isolate and produce it as a stand-alone drug. .((Claus J. Loland, et al. R-Modafinil (Armodafinil): A Unique Dopamine Uptake Inhibitor and Potential Medication for Psychostimulant Abuse. Biol Psychiatry. (2012) Sep 1; 72(5): 405–413.)) .((Wisor JP, et al. Armodafinil, the R-enantiomer of modafinil: wake-promoting effects and pharmacokinetic profile in the rat. Pharmacol Biochem Behav. (2006) Nov;85(3):492-9.))
34 Modafinil/Armodafinil mechanism of action
Methylphenidate MECHANISM OF ACTION • Prevents re-uptake of dopamine & NE • Also a 5HT1A receptor agonist • Enhances the function of neurons in the prefrontal cortex: impulse control, motivation, and mental clarity USE • ADHD • Off-label: treatment- resistant lethargy, BPAD, major depressive disorder
DOPAMINERGICS • L-Dopa • Theanine • Suntheanine • Piribedil • Sulbutiamine • Rasagiline • Selegiline
DOPAMINERGICS MECHANISM OF ACTION • Regulate metabolism and synthesis of dopamine • are often direct pre-cursors to dopamine • used to treat severe dopamine deficiency disorders like Parkinson’s disease • May also be effective treatments against symptoms of ADHD, anxiety, and depression
Piribedil MECHANISM OF ACTION • piperazine derivative which acts as a D2 and D3 receptor agonist. It also has α2-adrenergic antagonist properties USE • PD
Sulbutiamine MECHANISM OF ACTION • Synthetic derivative of thiamine • Crosses BBB > thiamine • increases the levels of thiamine and thiamine phosphate esters in the brain • improves memory: potentiation of cholinergic, dopaminergic, and glutamatergic transmission USE • Asthenia: chronic fatigue of cerebral origin • improves memory in schizophrenics and AD
Rasagiline MECHANISM OF ACTION • Irreversible inhibitor of monoamine oxidase →↑Dopamine • neuro-protective and neuro- rescuing property: effect on the mitochondria → interferes with and blocks apoptosis in neurodegenerative disorders USE • Monotherapy in Early PD • Adjunct Therapy in Advanced PD • treatment of Restless Legs Syndrome, AD
COGNITIVE METABOLIC ENHANCER • Acetyl L-Carnitine • Alpha Lipoic Acid • Creatine • Pyritinol • Vincamine • Vinpocetine
Acetyl L-Carnitine MECHANISM OF ACTION • Crosses BBB • Converted into Acetyl-COA, which binds with choline = acetylcholine
Vincamine MECHANISM OF ACTION • Derived from the Vinca Minor • (Periwinkle) plant • ↑ blood flow to the brain • improve memory capability in Alzheimer’s disease
NATURAL NOOTROPIC Artichoke Extract Ashwagandha Bacopa Monnieri Forskolin Grape Seed Extract Ginseng Hordenine Kava Kava Kratom Pterostilbene Rhodiola Rosea St John’s Wort
GINKOBILOBA
NEURORMONES • DHEA (Dehydroepiandrosterone) • Vasopressin • Desmopressin • Melatonin • Pregnenolone
NEURORMONES • class of hormones manufactured by neuroendocrine cells • stimulation of cellular growth, stress responses, fight or flight responses, emotional balancing etc.
DHEA (Dehydro-epiandrosterone) • neurohormone produced in human adrenal glands • commonly used by athletes as a performance enhancer • reduce the visible signs of aging, and prevents neuronal dysfunction
Vasopressin • exerts several nootropic benefits: • better short term memory • heightened metal acuity • deeper memory imprinting • used as a treatment for memory issues relating to age, dementia or Alzheimer’s disease • popular with students
SCOPE OF COGNITIVE ENHANCERS IN HEALTH & DISEASE Exam going students stressful jobs which need complete focus: physicians, pilots, military personnel Artists Athletes Alzheimer's Dementia (senile/vascular) TIA, CVA MR and ADHD in children Head injury Schizophrenia OCD Phobias Depression
References Ingole, S. R., Rajput, S. K., & Sharma, S. S. (2008). Cognition enhancers: Current strategies and future perspectives. CRIPS, 9(3), 42-48. Bostrom, N., & Sandberg, A. (2009). Cognitive enhancement: methods, ethics, regulatory challenges. Science and Engineering Ethics, 15(3), 311-341. Lippincott., Cognitive Enhancers and Neuroprotectants. ln: Gualtieri,T., Brain Injury & Mental Retardation: Neuropsychiatry & psychopharmacology, 2004; 2nd ed. NY. Wolters Kluer. P: 1-37 Insel T.,Krystal J., Ehlers M. (2013a). New drug development for cognitive enhancement in mental health: challenges and opportunities. Neuropharmacology 64 2–7 Greely, H., Sahakian, B., Harris, J., Kessler, R. C., Gazzaniga, M., Campbell, P.,& Farah, M. J. (2008). Towards responsible use of cognitive-enhancing drugs by the healthy. Nature, 456(7223), P: 702-705.
References www.nootriment.com [last accessed on 25.02.2015] Swerdlow, N. R. (2012). Beyond antipsychotics: pharmacologically-augmented cognitive therapies (PACTs) for Schizophrenia Neuropsychopharmacology, 37(1), P: 310. Lanni, C., Lenzken, S. C., Pascale, A., Del Vecchio, I., Racchi, M., Pistoia, F., & Govoni, S. (2008). Cognition enhancers between treating and doping the mind. Pharmacological Research, 57(3), P: 196-213. Ressler, K. J., Rothbaum, B. O., Tannenbaum, L., Anderson, P.,Graap, K., Zimand, E & Davis, M. (2004). Cognitive enhancers as adjuncts to psychotherapy: Use of D-cycloserine in phobic individuals to facilitate extinctionof fear. Archives of general psychiatry, 61(11), P: 1136-1144. Stip, E., Chouinard, S., & Boulay, L. J. (2005). On the trail of a cognitive enhancer for the treatment of schizophrenia. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 29(2), P: 219-232.
THANK YOU amrhasanneuro@kasralainy.edu.eg