CNS Stimulants

• CNS Stimulants


  • Psychomotor Stimulants
  • Hallucinogens
• Psychomotor Stimulants


  • Promotors of DA and NA release
  • Histamine receptor modulators
  • Methylxanthines (e.g. caffeine)
• Psychoactive Drugs


  Broadly described drugs that act on the brain to produce changes in perception, mood, consciousness and behaviours
• Psychoactive Drugs


  • Anaesthetic
  • Anxiolytic
  • Antipsychotic
  • Antidepressant
• Psychoactive Drugs


  • Useful in treating behavioural disorder
  • Attention deficit/hyperactive disorder (ADHD)
  • Narcolepsy (sleep disorder with disrupt sleep-wake processes)
• Lisdexamphetamine


  • An inactive form of dextroamphetamine (i.e. prodrug)
  • Dextroamphetamine covalently linked to L-lysine (natural amino acid)
  • Rapidly absorbed from gastrointestinal tract
  • Break down into dextroamphetamine (1.5 hours after oral administration)
  • Slow release (13 hours): less likely to get abused
  • Short-acting drugs: effective for only a few hours
  • Treatment of ADHD
• Mechanism of Action


  1. Increase the availability of noradrenaline, dopamine, and 5-HT (to a lesser extent) at the synaptic clefts

  2. Inhibit and reverse the functions of dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT )

  3. Inhibit the reuptake of dopamine, noradrenaline and 5- HT from presynaptic terminal

  4. Active release of endogenous dopamine, noradrenaline, and 5-HT

  5. Activate trace amine-associated receptor 1 (TAAR1 )

  6. Phosphorylation of DAT

  7. Internalisation of DAT into presynaptic neurons

  8. Reduced surface expression: decrease DA removal

  9. Enter the presynaptic monoamine vesicles

  10. Release of DA and NA towards the synapses

  11. Inhibit monoamine oxidase (MAO)

  12. Prevent the degradation of DA and NA
• Methylphenidate


  • Inhibit the transporters of both DA and NA on neuronal plasma membrane
  • Block DAT and NET, and weak agonist for 5-HT1A receptors
  • Increase DA and NA levels at the synaptic cleft of the prefrontal cortex
  • Control hyperactivity and deficits in inhibitory behaviours
  • NOT a substrate for DAT and NET
  • Lisdexamphetamine is a substrate for DAT and NET
  • Do NOT enter the nerve terminal to facilitate DA and NA release
  • Profound and elevated extracellular DA and NA
  • Less potential for drug abuse
  • Treatment of ADHD
• Atomoxetine


  • Selective, presynaptic, norepinephrine reuptake inhibitor (NET inhibitor)
  • Bind to NET, inhibit the reuptake of NA
  • Increase NA level in prefrontal cortex
  • NET also facilitate the reuptake of DA
  • Increase DA level in prefrontal cortex, but NOT in other reward circuits
  • Treatment of ADHD
  • Cognitive enhancer to improve alertness, attention and memory
• Guanfacine


  • Agonist of α2A adrenoceptors at post-synaptic terminals of dendrite spines within the pyramidal neurons of prefrontal cortex
  • α2A adrenoceptors: neuronal inhibition via Gi-mediated inhibition of adenylyl cyclase and PKA
  • Inhibit opening of HCN and KCNQ (Kv7) channels (potassium)
  • Strengthen the synaptic strength, and enhance neuronal firing
  • Improve working memory in prefrontal cortex
  • Treatment of ADHD
• Histaminergic System


  • Tuberomamillary (TM) nucleus is the only brain region where histaminergic neurons are found
  • Project to cerebral cortex, amygdala, substantia nigra, striatum, hippocampus, thalamus and spinal cord
  • Histaminergic neurons show high activity during waking and attention
  • Low or even absent activity during sleep
  • Their activity is inhibited by GABAergic neurons in ventrolateral preoptic area (located in anterior hypothalamus; sleep-promoting area)
  • Arousal (activation of brain regions involving wakefulness via H1R)
  • Cognition, learning and memory (via H3R activation)
  • Sleep (inhibition of sleep-promoting region)
  • Sensory and motor systems (depletion of histamine decreases locomotion)
  • Energy balance and endocrine functions
• Histamine Receptors


  • Histamine H1, H2 and H3 receptors are expressed in brain
  • All are G protein-coupled receptors
  • Use different second messengers
  • H1 receptors (localised postsynaptically) - Induce neuronal excitation via PKC and InsP3 in thalamus, striatum, cerebral cortex and brainstem
  • H2 receptors (localised postsynaptically) - Induce neuronal excitation via Gs-coupled activation of AC and PKA in hippocampus and cortical neurons
  • H3 receptors (localised presynaptically, cell soma, dendrites) - autoreceptors that cause autoinhibition of TM neurons via Gi coupled inactivation of AC and PKA & Inhibit the release of histamine
• Pitolisant


  • Antagonist and inverse agonist targeting histamine H3 receptors
  • Promote the histamine synthesis and release
  • Increase wakefulness without psychostimulation
  • Narcolepsy with or without cataplexy (temporary loss of muscle control resulting in weakness and possible collapse)
• Modafinil


  • Weak inhibitor of DAT in the brain
  • Increase DA bioavailability
  • Decrease cortical GABA, increase orexin, leading to an increase in histamine release (wake-promoting neurotransmitter)
  • Increase daytime sleep latency and reduce excessive daytime sleepiness
  • Low propensity for causing euphoric effects associated with traditional psychostimulants (cocaine, amphetamine)
  • Narcolepsy with or without cataplexy
  • Sleep work shift disorder
• Solriamfetol


  • Full mechanisms of action remains unclear
  • DAT and NET inhibitors - low affinity
  • Block the reuptake of DA and NA with low potency
  • Increase DA and NA activity
  • NO binding affinity to serotonin transporters
  • NO binding affinity to GABA/histamine/orexin/ACh receptors
  • Narcolepsy with or without cataplexy
• Caffeine


  • Commonly found in tea, coffee (account for 90% of caffeine consumption) and cocoa
  • Belongs to the class of Methylxanthines, which includes theophylline
  • Antagonist of adenosine receptors
  • Adenosine production increases during daytime: promote sleep
  • Caffeine reduces GABA transmission (disinhibition) in TMN: increase histamine release
  • Reduce the experience of fatigue, improve concentration and clear flow of thoughts
  • Less locomotor stimulation and do NOT induce euphoria compared with amphetamines
  • Co-ingredient with analgesic preparations (e.g. with aspirin or ergotamine for migraine headaches)
  • Used as a respiratory stimulant in the treatment of apnoea of prematurity: developmental disorder caused by immaturity of central respiratory control
• Psilocybin (Magic Mushrooms)


  • Agonist at 5-HT2A receptors
  • Naturally occurring psychedelic prodrug found in more than 200 species of fungi
  • Metabolize into psilocin: structurally similar to serotonin
  • Alternation of perception: sight and sound appear distorted and fantastic
  • Activate 5-HT2A receptors in thalamus (processing sensory input): reduce thalamic activity, sensory alternations
  • Deactivate the hyperactivity of medial prefrontal cortex: anti-depressant
  • Induce significant alternation of brain connectivity: general cortical activation, increase DA and 5-HT in mesocortical pathways; increased density and size of dendritic spines
  • No current clinical use
  • May have potential for the treatment of depression and some forms of anxiety