5. TCM Overview of Normal Human Physiology The kidney is the origin of the congenital constitution The spleen provides the material basis of the acquired constitution Conge- nital Qi Qi and Blood Five Zang - organs Six Fu - organs Meridians transforms into nourishes warms promotes Yin Yang Balance

6. TCM’s Understanding of drug addiction Narcotic Ingested Pungent and perfume Bitter and warm All channels boiling Qi -Blood quickly flowing Zang-Fu organs pseudo-vigorous Narcotic Cut off Kidney fails to transform into vital essence Spleen fails to nourish vital essence Further damage to vital essence and Qi Disorder of Qi -Blood Disharmony of Zang-Fu Imbalance of Yin-Yang Withdrawal symptoms Congenital Qi fails to rise Euphoria Impairs spleen and kidney Damages vital essence and Qi Causes insufficiency of congenital Qi Deficiency in root and Excess in superficiality Upward Floating of Deficiency- Yang

7. Action Position of XuanXia Narcotic Ingested Pungent and perfume Bitter and warm All channels boiling Qi -Blood quickly flowing Zang-Fu organs pseudo-vigorous Narcotic Cut off Kidney fails to transform into vital essence Spleen fails to nourish vital essence Further damage to vital essence and Qi Disorder of Qi -Blood Disharmony of Zang-Fu Imbalance of Yin-Yang Congenital Qi fails to rise Euphoria XuanXia Impairs spleen and kidney Damages vital essence and Qi Causes insufficiency of congenital Qi Deficiency in root and Excess in superficiality Upward Floating of Deficiency- Yang

9. Opiate receptors 1. DA system (dopaminergic: central nervous system) 2. NA system (noradrenalin: nor-adrenergic system) 3. 5-HT system (serotonergic system: heart, brain, blood vessels, liver) 4. Ach system (acetyl choline: cholinergic system) 5. GABA system 6. H--Y system 7. Thyroid system 8. Ca 2+ passage system (blood vessel caliber; heart rate; myocardial compliance) 9. AC-cAMP system (intracellular messenger) 10.G-protein system Endogenous opioid peptides Balance Physiological Actions of Endogenous Opioid Peptides

10. Endogenous opioid Exogenous opiate Opiate receptors 1. NA system 2. DA system 3. 5-HT system 4. Ach system 5. GABA system 6. H--Y system 7. Thyroid system 8. Ca 2+ passage system 9. AC-cAMP system 10.G-protein system New Balance + + _

11. Endogenous opioid Exogenous opiate Opiate receptors 1.NA system 2.DA system 3.5-HT system 4.Ach system 5.GABA system 6.H--Y system 7.Thyroid system 8.Ca 2+ passage system 9.AC-cAMP system 10.G-protein system Withdrawal symptoms Balance Cut Endogenous opioid off Exogenous opiate { + _

14. The Mechanism of XuanXia in Relieving Protracted Withdrawal Symptoms and Psychological Craving XuanXia After detoxification Damaged Organism: Deficiency of both Spleen and Kidney; Cardiovascular, Renal, and Immune Disregularities Psychopathia: Social Maladjustment Alteration of Values Risk-Taking Behavior Persistent Up-Regulation of Opiate and Dopamine Receptors Multi-System Imbalances (Continued Underlying Dependency Drug-Seeking Behavior Psychosocial Maladjustment Deficiency of vital Qi ) Psychological craving Taking narcotic Brief comfort/relief Protracted Withdrawal Symptoms Anxiety Insomnia Physical pain Indigestion

15. Endogenous Opioid Opiate Receptors 1.NA system 2.DA system 3.5-HT system 4.Ach system 5.GABA system 6.H--Y system 7.Thyroid system 8.Ca2+passage system 9.AC-cAMP system 10.G-protein system Reduced withdrawal symptoms and craving Mechanism of XuanXia in Opiate Detoxification Treatment XuanXia New Health Balance

16. Efficacy of XuanXia in Alleviating Acute Withdrawal Symptoms in Morphine-Dependent Rats

18. Naloxone Challenge Test XuanXia Naloxone Morphine-dependent Monkey Challenge Test No withdrawal symptoms were induced

21. The Actions of XuanXia Within the Central Nervous System Pain relief XuanXia + + + + Corydalis B Gastrodin Schisandrin C Quinquonoside Sedation and sleep induction Anticonvulsant Neuroendocrinic regulation

22. Corydalis B and Its Molecular Structure (one of the active ingredients in XuanXia ) C 12 H 25 NO 4 335.42 Corydalis B

27. Comparison Between Corydalis B’s Actions and Morphine’s Actions On the Central Nervous System -------------------------------------------------------------------------------- Corydalis B Morphine -------------------------------------------------------------------------------- Active Receptor Position extensive specific Selectivity weak powerful Analgesic effect weak powerful Sedation powerful less powerful Duration of action long short Mechanism blocks DA morphine - receptor in brain receptors --------------------------------------------------------------------------------

28. One of the Active Ingredients in XuanXia , Tetramethylpyrazime and Its Molecular Structure

30. Mechanism of Tetramethylpyrazime: Acceleration of Endogenous Opioid Peptide Excretion Enhanced permeability of BBB versus other alterations in BBB Tetramethylpyrazime Increase in cerebral blood flow Reduction in brain damage Improved recovery of brain cell function ? Improved production of endogenous opioid peptides? Blood/Brain Barrier

31. Actions of XuanXia On the Neuroendocrine System H ypothalamus ↓ Pituitary ↓ Gonad H ypothalamus ↓ Pituitary ↓ Adrenal Hypothalamus ↓ Pituitary ↓ Thymus XuanXia + + + Lcariin Zingerone Radix Morindae Officialis

33. Actions of XuanXia On the Digestive System Anti-ulcerative effects Inhibition of gastric secretion Regulation of gastric and intestinal motility XuanXia + + + Polysaccharide of Radix Codonopsis glycyrrhizic acid, etc.

34. Weight of immune system organs Humoral immunity Cellular immunity Mononuclear phagocyte Natural killer T lymphocytes XuanXia + + +  Polysaccharide of Herba Epimedii Polysaccharide of Cordyceps Polysacharide of Radix Angelicae Sinensis Polysaccharide of Ganoderma Astraglan + Actions of XuanXia On the Immune System

35. XuanXia ’s Support of an Organism’s Adaptive Capability Tolerance to oxygen deficit Tolerance of high or low temperature Anti-stress Anti-radiation Anti-fatigue XuanXia + + + + + Ginsenosides Polysaccharide of Cordyceps Astraglan

40. Withdrawal Symptoms

41. Psychological Craving

42. Clinical Trial of XuanXia in Heroin Detoxification Treatment National Institute on Drug Dependence Beijing Medical University

43. Required criteria for development of new TCM for opiate detoxification 1. New TCM compound must be non-narcotic without any ingredient with dependence-producing properties; 2. The individual herbs composed in the compound should accord with TCM theory; 3. It should be effective for detoxification and without severe adverse drug reactions; 4. Its pharmaceutical quality should be stable and controllable .

44. Method a multi-center, double blind and double dummy controlled clinical trial and open trial of XuanXia Total of 404 cases (male 305, female 99) of heroin addicts with range of ages 18-48 years old were included. 201 cases were in controlled trial group (100 cases with XuanXia , 70 cases with lofexidine as a positive control and 31 cases with placebo as a negative control), 203 cases were in open trial group with XuanXia.

46. Total scores of withdrawal syndromes before and during treatment. Day of medication **P<0.01; ***P<0.001

47. Total scores of withdrawal syndromes before and during treatment. Day of medication *P<0.05

48. Scores of craving before and during treatment. Day of medication

49. Scores of craving before and during treatment. Day of medication

50. Scores of anxiety before and during treatment. Day of Medication

51. Scores of insomnia before and during Treatment Day of medication

52. Scores of ostealgia and myalgia before and during treatment Day of medication

53. Scores of lacrimation before and during treatment . Day of medication

54. Scores of diarrhea and abdominal pain and diarrhea. Day of medication *P<0.05

57. Comparison Between XuanXia and Traditional Therapy for Relief from Opiate Addiction Agent Course Process Result XuanXia (pure natural 7-10 days Safe, no pain, Relief of withdrawal plant without consciousness symptoms and any opiate) tolerant psychological craving; improved physical recovery Substitution therapy (narcotic 7 days Safe, no pain, No relief of psychological substitution drug) the rate of taking craving; substitute drug- drug again is higher dependence or relapse after stopping treatment Hibernation therapy (sedative-hypnotic) Additional Dangerous No relief of withdrawal post- symptoms and hibernation psychological craving; treatments frequent relapse