1. Plant Drugs of the Central Nervous System

2. Central Nervous System • The brain and spinal column • The body’s control system…also responsible for sensory perception, thought, mood, memory, etc. • synapses within the CNS rely on a number of different neurotransmitters

3. CNS Neurotranmitters • Catecholamines (norepinephrine, epinephrine, dopamine) • Acetylcholine • Tryptamines (serotonin) • GABA (= ϒ-aminobutyric acid) • Endorphins • Cannabinoids • Histimine • Glutamate • Glycine

4. Norepinephrine • primary catecholamine, released from the adrenal medulla and postganglionic sympathetic neurons • removed from synapses through re-uptake • metabolized in the presynaptic terminal by endogenous monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT)

5. Norepinephrine • Drugs that increase norepinephrine concentrations in CNS synapses can be used to treat depression • Norepinephrine antagonists can be used to treat psychosis and mania

6. Norepinephrine Antagonist: Reserpine • from Rauvolfia serpentina • binds storage vesicles in membrane transport system, causing them to release their norepinephrine…this results in its destruction by MAO and the subsequent depletion of norepinephrine from andrenergic terminals

7. Norepinephrine Antagonist: Reserpine • in Ayurvedic medicine, root of Rauvolfia serpentina used to treat mania and as a sedative • in Western medicine, Reserpine is used as a treatment for hypertension and psychosis

8. Norepinephrine Enhancer: Cocaine • from Erythroxylum coca • blocks nerve terminal membrane transport system, preventing re-uptake of norepinephrine (and other catecholamines) • results in an accumulation of norepinephrine at receptors

9. Norepinephrine Enhancer: Hypericum perforatum • St. John’s wort • Originated in Eurasia, naturalized in North America • All plant parts taken to treat depression • Clinically demonstrated efficacy for treatment of mild to moderate depression

10. Norepinephrine Enhancer: Hypericum perforatum • mechanism of action is probably through inhibition of MAO, which results in accumulation of norepinephrine • may also inhibit re-uptake of serotonin

11. Norepinephrine Enhancer: Peganum harmala

12. Peganum harmala • Harmal • Native to eastern Mediterranean to India • Seeds traditionally used as an entheogen (sacred hallucinogen) and as a source of “Turkish Red” used in western Asia for dyeing carpets • Widely naturalized / weedy in southwestern US (very drought tolerant)

13. Peganum harmala • One of the active compounds in harmal is harmaline • Harmaline is used as a sedative and to treat depression • Mechanism of action: Harmaline inhibits MAO-A, which leads to an increased availability of neurotransmitters (norepinephrine, serotonin)

14. Dopamine • prominent neurotransmitter in midbrain neurons • released from hypothalamus • metabolized by MAO and COMT • D1 and D2 receptors use dopamine as signal • Parkinson’s disease is the result of degeneration of neurons that use D2 receptors

15. Dopamine Enhancers • Levodopa, derived from Mucuna spp. is the metabolic precursor to dopamine. In the body, levodopa is decarboxylated to dopamine, which is then available to the brain • Bromocriptine and pergolide, chemical derivatives of the ergot fungus, Clavaceps purpurea. Both are dopamine receptor agonists

16. Dopamine Enhancer: Mucuna spp. • in pea family, Fabaceae • in India, seeds taken orally to lessen irritability and leaves taken orally as a nerve tonic

17. Dopamine Enhancer: Mucuna spp. • active compound: L-dopa (levodopa), metabolic precursor to dopamine • in Western medicine, levodopa used in treatment of Parkinson’s disease • especially good for akinesia (immobility) and postural imbalance

18. Dopamine Enhancer: Claviceps purpurea • ergot fungus • origin: Europe • small parasitic fungus that attacks rye grain • historically, people would eat infected rye and have vivid hallucinations because of the similarity of some of the ergot alkaloids to LSD • “St. Anthony’s Fire”

19. Dopamine Enhancer: Claviceps purpurea • Chemical derivatives of ergot alkaloids: • bromocriptine • pergolide • In modern medicine, used to treat Parkinson’s disease

20. Serotonin • neurotransmitter with high concentrations in brain • formed from tryptophan • converted to melatonin in the pineal gland • compounds that inhibit the re-uptake of serotonin at receptors (and hence increase levels of serotonin in synaptic cleft) are used to treat depression • synthetic inhibitor: Prozac • putative plant serotonin uptake inhibitors: St. John’s wort, harmal

21. Hallucinogenic Compounds with Structure Similar to Serotonin • LSD (synthetic) • Harmine from Ayahuasca (Banisteriopsis caapi) • Mescaline from peyote (Lophophora williamsii) and San Pedro cactus (Echinopsis pachinoi) • Ergot alkaloids from Claviceps purpurea • Psilocin from various mushrooms (e.g., Psilocybe) • Morning glories (Turbina corymbosa and Ipomoea violaceae)

22. Hallucinogenic compound that blocks CNS muscarinic receptors in the brain • Scopolamine from various members of the Solanaceae • Atropa belladonna • Hyoscyamus niger • Datura spp. • Brugmansia spp.

23. GABA (γ-aminobutyric acid) • major inhibitory neurotransmitter in CNS • synthesized from glutamate • GABAa receptor protein is the site of action of benzodiazepines and barbituates (synthetic anti-seizure medications and sedatives)

24. GABA Antagonist: Anamirta cocculus • fish-berry or Indian berry in Indomalaysia • in Indomalaysia, fruit is used as a fish poison, insecticide, and treatment for head lice • active compound: Picrotoxin • stimulates CNS by inhibiting action of GABA • modern therapeutic uses: • treats barbituate poisoning • CNS stimulant • schizophrenia

25. GABA Enhancer: Areca catechu • nipecotic acid in Areca catechu is precursor of chemical derivative, gabitril • Gabitril blocks the re-uptake of GABA and increases its concentration at receptors

26. GABA Enhancer: Areca catechu • seizures occur when too many impulses generated in brain • since gabitril enhances GABA levels and GABA has an inhibitory effect on neurotransmitters, gabitril is used to treat seizures

27. GABA Enhancer: Piper methysticum • Kava • Social beverage, served to visitors in South Pacific (Fiji, Vanuatu, Polynesia, Micronesia) as an indication of hospitality and friendship • Consumed during village meetings to facilitate consensus decision making, communication, and harmony • Kava consumption is of similar social importance to tea, coffee, and matte consumption in other parts of the world

28. GABA Enhancer: Piper methysticum • kavain and dihydrokavain are kava lactones that most easily pass through blood-brain barrier and enter into brain • kava lactones appear to enhance GABA levels in CNS; also inhibit re-uptake of norepinephrine and act as reversible MAO inhibitors • therapeutic uses include: • anti-anxiety • sleep enhancer

29. GABA Enhancer: Valeriana officinalis • Valerian • native to Europe • root traditionally used as sedative and sleep enhancer • active chemicals: valepotriates, enhance GABA levels in CNS • used as a sedative and sleep enhancer

30. Other putative GABA Enhancers • Melissa officinalis (Lemon Balm) • Humulus lupulus (hops) • Lavandula augustifolia (lavender) • All these herbs used in various combinations (often with valerian) as sedatives, sleep aids and anti-anxiety treatments

31. Endorphins • bind to opiate receptors in brain and have analgesic (pain reducing) effects

32. Opiate receptor agonists: Papaver somniferum • opium, opium poppy • originated in western Mediterranean & Near East • dried latex from immature fruit capsules traditionally used as an analgesic, inebriant, hypnotic, and treatment for diarrhea

33. Opiate receptor agonists: Papaver somniferum • opium contains 20 alkaloids, including: • morphine ( heroin) • codeine • papaverine ( verapamil) • thebaine ( etorphine HCL) • noscapine ( narcatine)

34. Opiate receptor agonists: Papaver somniferum Therapeutic uses: • morphine = analgesic • codeine = analgesic, antitussive • noscapine (narcotine) = antitussive • Mechanism of analgesis: • stimulation of opiate receptors inhibits the release of substance P, the neurotransmitter responsible for inflammatory responses and pain

35. Cannabinoids • Type-1 cannabinoid receptors (CB1) are found in CNS • stimulation of these receptors has analgesic and anticonvulsant effects as well as antiemetic/antinausea effects

36. Cannabinoid receptor agonist: Cannabis sativa • marijuana • origin in Asia, now grows worldwide • active compounds in inflorescences and leaves: • tetrahydrocannabinol (THC) • marinol & dronabinol

37. Cannabinoid receptor agonist: Cannabis sativa mechanism of action: stimulate cannabinoid receptors in CNS (brain cortex, hippocampus, striatum and cerebellum) therapeutic uses include: • antinausea • antiemetic • analgesic • glaucoma • muscle relaxant • anticonvulsant

38. Cannabinoid receptor agonists: Theobroma cacao • Cacao, chocolate • contains three unsaturated N-acylethanolamine compounds including anandamide, an endogenous cannabinoid in the human CNS • all three compounds may act as cannabinoid mimics

39. Glutamate • Naturally occurring salts of glutamic acid (Glu or E, a non-essential amino acid) • Most abundant excitory neurotransmitter in the brain • Glutamate receptors involved in cognitive functions like learning and memory • The synthetic drugs PCP and Ketamine antagonize glutamate receptors in the brain, resulting in strong dissociative and hallucinogenic effects

40. Glutamate • Glutamate was discovered in 1908 by a Japanese chemist who isolated the substance (in brown crystal form) from the seaweed kombu (Saccarina japonica) • The brown crystals tasted great! In this way the essential taste umami was discovered • Soon after, the salt monosodium glutamate was synthesized as a flavor enhancer

41. General CNS Stimulants • Caffeine (and other methylxanthines, theobromine and theophylline) – affect multiple pathways, including stimulation of norepinephrine receptors and modulation of dopamine release. May also affect serotonin receptors • most commonly consumed psychoactive compound • many plant sources ( methylxanthines act as a natural deterrent to herbivorous insects)

42. General CNS Stimulants • plant sources of methylxanthines include: • Coffea robusta (coffee) • Camellia sinensis (tea) • Theobroma cacao (chocolate) • Cola acuminata (cola nut) • Ilex paraguariensis (mate) • Paullinia cupana (guarana)

43. Coffea arabica, C. robusta

44. Camellia sinensis

45. Theobroma cacao

46. Cola accuminata

47. Ilex paraguariensis

48. Paullinia cupana

49. CNS Stimulants: Catha edulis • khat, qat • cultivated in Ethiopia, Somalia & Yemen • fresh leaves chewed socially as a stimulant • active compounds are cathine (d-norisoephedrine) and cathione

50. CNS Stimulants: Catha edulis • appears to slow the re-uptake of norepinephrine, leading to stimulation of CNS / wakefulness • cathione also has a high affinity for serotonin receptors, which is likely responsible for euphoria produced by qat use