The document discusses a herbal compound called XuanXia that is used as a dietary supplement for the detoxification and rehabilitation of opiate addiction. It summarizes TCM and Western medicine theories on addiction and the mechanisms of XuanXia. Clinical studies found XuanXia effective in relieving withdrawal symptoms and craving, with few side effects and no dependency, compared to other established treatments. The composition and pharmacological actions of the herbs in XuanXia support its use for opiate addiction treatment.

1. Efficacy and Mechanism of XuanXia on Opiate Addiction National Foundation for New Drug R & D, China WHO Collaborating Research Center for Psychosocial Factors, Drug Abuse and Health, China Mental Health Institute, Hunan Medical University, China National Institute on Drug Dependence, China Fortune United Enterprises Ltd. 1999.4

2. Outline Introduction TCM theory regarding drug addiction Views of Western Medicine regarding drug addiction Modern TCM theory and mechanisms applied to use of XuanXia as a dietary supplement in detoxification and rehabilitation treatment of drug addiction Mechanisms of XuanXia in relieving protracted (secondary) withdrawal symptoms and psychological craving Pharmacological study of XuanXia Toxicology of XuanXia Clinical studies of XuanXia Contents and ingredients of XuanXia : safe levels of trace heavy metals; no addictive substances A prescriptive dosage of XuanXia

3. Introduction Illicit drug abuse has become a public health problem worldwide. Development of an effective agent for opiate addiction is a crucial mission of pharmacologists. Although many detoxification agents have become available, no established agent meets the preferred criteria of safety, efficacy, and freedom from post-treatment substance dependency. Moreover, there is no satisfactory agent for relieving and treating the protracted (secondary) withdrawal symptoms and psychological craving that cause relapse.

4. Under the guidance of the theory of Traditional Chinese Medicine(TCM), and working from Yang Jitai’s (a famous Chinese doctor 200 years ago) secret recipe, Chinese researchers have developed a pure herbal compound called XuanXia , which consists of twenty herbs. XuanXia has no narcotics, psychotropic agents, or any herb that can produce substance dependency. In comparison with established substitution agents, XuanXia is very effective as a dietary supplement in relieving acute and protracted withdrawal symptoms and psychological craving, with few and typically mild side effects, and with no post-treatment dependency on XuanXia . Moreover, there is no rebound after discontinuation of XuanXia treatment.

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

8. Modern Medicine’s Understanding of Drug Addiction The exact mechanism of addiction is not yet fully understood. There are several hypotheses, including condition theory, enzyme induction hypothesis, receptor hypothesis, nerve and transmitter hypothesis, among others. Each hypothesis has its own bases, and is supported by certain experiments and clinical observations.

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 { + _

12. The essential actions of Chinese medicine are explained as two-way effects and a self-adjustment model. “Two-way effects” means most medical herbs contain ingredients with two-way remedial effects that are opposite to one another. “Self-adjustment” means the body has the functional capability of self-adjusting, self-balancing, and self-maintaining. According to this model, the effectiveness of a medical herb is determined by the condition of the treated organism. When the condition of the organism is very active, the herb’s stimulation of the organism is weakened, but the repression of the herb’s effects is stimulated. Conversely, when the condition of the organism is repressed, the action of the medical herb is strengthened. New TCM Hypothesis Regarding XuanXia ’s Action in Treatment of Opiate Addiction

13. Based upon the aforementioned rule, XuanXia contains several herbs with two-way effects. XuanXia , used as a dietary supplement in detoxification and rehabilitation of opiate addiction, is very effective in restoring the endogenous opioid and monoamine systems directly or indirectly to their baseline condition and function. In consequence, all systems and systemic functions regain a healthy new balance, withdrawal symptoms and craving are relieved, and body resistance is improved.

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

17. A. Normal control group B. Non-treatment group C. Clonidine group D. High-dosage XuanXia gr. E. Medium-dosage XuanXia gr. F. Low-dosage XuanXia gr. Mental Health Institute, Beijing Medical University

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

19. The Composition of XuanXia And Its Actions Composition Rhizome Corydalis, Rhizome Corydalis Decumbentis, Fructose Vschisandrace, Rhizome Gastrodiae, Radis Astragal, Cordyceps, Rhizoma Chuanxing, Radis Codonopsis, etc. Actions Relief of withdrawal symptoms and craving in detoxification and rehabilitation from opiate addiction Strengthening of the body’s resistance

20. Pharmacological Actions of Some of XuanXia ’s Ingredients Actions on the central nervous system Actions on the neuroendocrine system Actions on the cardiovascular system Actions on the digestive system Actions on the immune system Improvement of the organism’s adaptive capability

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

23. Researchers have compared Corydalis B’s five types and 38 analogs. The research results showed that the integrity of Corydalis B’s molecular structure plays an important role in its pharmacological actions. The methoxies in 9 and 10 position have specificity: they are active radicals. The saturation of the third loop is the key to the pharmacological action. Based on the connection between different chemical structures and their curative effects, tetrahydroprotoberberine has been found to have tranquilizing effects. This suggests new paths for the development of new medicines for mental diseases. Relationship Between the Chemical Structure of Corydalis B and Its Pharmacological Actions

24. The actions of Corydalis B are different depending on its different isomers. Levorotation has been shown to ease pain and tranquilize. High doses can induce tremor in monkeys. Both levorotation and dextrorotation can raise the seizure threshold to challenge with strychnine (strychnine is a known pro-convulsant) -- reducing the convulsive action of strychnine .

25. Pharmacological Actions of Corydalis B Central nervous system actions Pain alleviation Sedation and sleep induction Anti-convulsant action Neuro-transmitter regulation in brain Neuroendocrine system actions Regulation of hypothalamic-pituitary-adrenal axis Regulation of hypothalamic-pituitary- gonadal axis Regulation of hypothalamic-pituitary- thyroid axis

26. Pharmacological Action of Rhizome Corydalis Total Alkalid Cardiovascular effects Dilation of coronary arteries Increase in coronary blood flow Decrease in blood pressure and peripheral vascular resistance Anti-arrhythmic effect Digestive effects Anti-ulcerative effect Inhibition of gastric secretion Regulation of gastric and intestinal mobility

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

29. Actions on the cardiovascular system Dilation of coronary arteries Increase in coronary blood flow Decrease in myocardial oxygen consumption Reduction in peripheral vascular resistance Actions on the blood/brain barrier (“BBB”) Increase in cerebral blood flow Decrease in brain tissue damage Pharmacological Actions of Tetramethylpyrazime

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

32. Actions of XuanXia On the Cardiovascular System Dilation of coronary arteries Increase in myocardial blood flow Increase in myocardial contraction Decrease in myocardial oxygen (MVO 2 ) consumption Anti-arrhythmic effect Decrease in peripheral vascular resistance Improved microcirculation Reduction in blood pressure XuanXia + + Pannaquilon Angelic acid Tetramethylpy- razime

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

36. The Toxicology of XuanXia Pharmaceutical Research Institute, Hunan, China

37. Toxicity Tests On XuanXia Acute toxicity test The highest tolerance dose tested was 600g/kg/day of XuanXia (equal to 150 times the clinical dose for XuanXia ). The test found no toxicity or side effects in the XuanXia test subjects. Long-term toxicity test XuanXia was infused into rats’ stomachs at the dose of 200g/kg/day (equal to 50 times the clinical dose for XuanXia ), for 30 days. No toxicities or side effects were observed in the test-subject rats. Routine blood examinations and pathological examinations of liver, kidney, heart, stomach, spleen, adrenal gland, pancreas, ovum, testis, and lung in the test-subject rats were normal .

38. Clinical Research Mental Health Institute, Hunan Medical University WHO Collaborating Research Center for Psychosocial Factors, Drug Abuse and Health

39. A Comparative Study of the Effect of XuanXia on Withdrawal Symptoms and Craving for Heroin Objectives To evaluate XuanXia’s efficacy as a dietary supplement in relieving withdrawal symptoms and craving in detoxification and rehabilitation from heroin addiction. To determine side effects of XuanXia in using it as a dietary supplement in detoxification and rehabilitation from heroin addiction. Method Forty-two heroin addicts were randomly assigned to two groups for detoxification and rehabilitation: a XuanXia group (21 cases) and a buprenorphine group (21 cases). All patients in the two groups received relapse prevention counseling in the 2- week inpatient phase.

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.

45. Table1. The effective rates(%) of treatment ___________________________________________________________ Controlled trial Controlled trial Open trial Day of Treatment XuanXia Lofexidine XuanXia Placebo XuanXia (n=69) (n=70) (n=31) (n=31) (n=203) _____________________________________________________________________ 3-4 31.88 24.29 25.81* 6.45 15.27 5-7 69.57 55.71 58.06** 9.68 63.05 8 86.96 91.43 74.19*** 12.90 78.82 9 97.10 94.29 74.19*** 12.90 87.19 10 100.00 98.57 83.87* 19.35 91.63 _____________________________________________________________________ *P<0.05; **P<0.01; ***P<0.001

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

55. Contents of XuanXia : Safe Levels of Trace Heavy Metals; No Additive Substances Heavy metals Traces of thirteen kinds of heavy metals such as Hg,Sn,Se,Li, etc. can be detected in XuanXia. All levels of the heavy metals in XuanXia meet health standards for safe use. Addictive substances No narcotics or other addictive herbs or other substances are present in XuanXia . Beijing Medical University

56. Future Research Planned on XuanXia Exploration of XuanXia ’s biological mechanisms in detoxification and rehabilitation treatment of opiate addiction Identification of the active ingredients in the formula of XuanXia and monomers for relieving withdrawal symptoms and psychological craving Identification of the active ingredients from various Chinese medicinal materials; development of a chemical database related to XuanXia Intensification of research and development on the applications of fundamental theories of modern Chinese herbal medicine to treatment of alcohol and drug addiction

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

58. Use of XuanXia Indication Symptoms of withdrawal from opiate addiction, e.g. nausea or vomiting, muscle-ache, lacrimation or rhinorrhea, pupillary dilation, piloerection, sweating, diarrhea, yawning, fever, insomnia, etc. Psychological craving after quitting use of opiate Physical weakness associated with drug abuse Dosage/use The dosage schedule should be determined individually and adapted to the patient’s drug use history and treatment responses, and should consider the concentration of XuanXia in the capsules to be used. Day 1 - Day 5: 6 pills/6 hours Day 6 - Day10: 4 pills/8 hours Take XuanXia at least 5 hours prior to symptoms of withdrawal occur.

59. Characteristics of XuanXia Safe Effective Results in no substance-dependency Convenient: Can be administered on an outpatient basis Precautions: Use under supervision of physician for pregnant women or patients with history of serious heart disease or high blood pressure. Increase nourishment and avoid raw, cold, or acidic food. Drink honey-water before taking each dose of XuanXia to increase efficacy and reduce constipation. Insomnia, restlessness, and anxiety may be experienced; in such cases, mild tranquilizers are recommended under supervision of physician. For rehabilitation (maintaining abstinence and further reducing psychological craving), it is recommended that patients should continue to take a half-dosage of XuanXia for another 20 days following 10-day detoxification treatment. Dosage: 3 times each day, 3 pills each time, depending on individual patient’s drug use history, treatment response, and concentration of XuanXia capsules used.