Misuse and Abuse Issues Related to Supplements Taken Clinically

1. Misuse and Abuse Issues Related to Supplements Taken Clinically Susan McCabe EdD, RN Associate Professor East Tennessee State University

2. Clinical Use of Botanicals • As old as documented history • 60,000 year old Neanderthal burial site • With phytobotanicals present • Writings of Chinese emperor Huang Di • Relaxing effects of Valerian • Assyrian medical practice • Multiple preparations • Hippocrates • Valerian root for UTI’s • Ancient Greek • St. John’s Wort for insomnia

3. Clinical Use of Botanicals • Common and growing • Multiple Studies with range of 34-44% of adults used one or more botanical CAM within the past year • 1 in 4 persons in US use botanical CAMs • In developing countries as many as 8 in 10 • Out of pocket costs • CAMs • $21.2 billion • Traditional Medical Care • $29.3 billion • St. John’s Wort • 1995 = $20 million • 1997 = $200 million • 1998 = $400 million Eisenberg, Davis, Ettner, et al.; 1998, JAMA; 280: 1569-1575; MacLennan, et al. 2000; Prev Med; 35(2): 166-73. Nat Cent Comp & Alt Med; 1999, St. John’s Wort Fact Sheet; Pub#Z-02: NIH; Mackenzie, et al., 2003. Altern Ther Health Med. 9(4): 50-56.

4. Who Is Using CAM’s • Multiple studies have long supported differences between CAM users and Non-users • Common CAM User • Age 35-54 • Gender female • Education over high school • Income mid to upper • Service utilization higher than non-users • Use phytobotanical as complementary agent not alternative • Perception of CAM botanicals as less “drug-like“ • Medical conditions not easily treated (chronic pain, mental health, cancer, HIV) Astin, JAMA. 1998;279:1548-1553Blais, Maiga & Aboubacar, 1997. Can j Public Health; 88(3): 159-62.; Cauffield, 2000. Pharmacotherapy; 20(11): 1289-94.; Ni, Simile & Hardy. 2002. Med Care; 40(4): 3353-8.; Swartzman, Harsham, Burkell & Lundy, 2002. Med Decis Making; 22(5): 451-2.

5. Who is Using CAM’s • But there is another group of CAM users we are just beginning to understand • Underserved population groups • Self-assessed low health status • Limited to no healthcare access • Self medicating/ self diagnosing • Almost all for psychiatric related concerns • Examples • CAM use in IV drug users • 45% use a CAM regularly • Homeless street kids • 70% use a CAM regularly Breuner, Barry & Kemper, 1998. Arch Pediatr Adolesc Med; 152(11): 1071-5. Gray, et al., 2002; Eff Clin Pract.; 5(1): 17-22.; Manheimer, et al. 2003. Am J Drug Abuse; 29(2): 401-13. ; Wolsko, et al., 2000. J Altern Complement Med; 6(4): 321-26.

6. Who is Using CAM’s • At risk groups taking medicinal herbs • Mentally ill – at risk for mental illness • Three of top ten conditions for which people take CAMs • Depression, anxiety, substance abuse • CAMs used more than conventional therapies in individuals with anxiety & depression • 60-80% of patients seeing mental health providers self-added CAMs to treatment regimes • CAM use highest in individuals with unmeet mental health needs • No conventional care Astin, 1998. JAMA, 279: 1548-1553.; Gray,et al., 2002; Eff Clin Pract.; 5(1):17-22.;Kessler, Soukup, Davis, Foster, et al., 2000. Am J Psychiatry;158(2): 289-94.; Sturm, et al. 2001. J Behav Health Res,28(1):81-8

7. Who is Using CAM’s • CAM Use is also Significant among Children • 12% - 21% of children age 4-18 • Factors influencing use • Maternal age < 31 years • Parent/caregiver born outside USA • Use of CAM by parents • Most common CAM • Herbals = 41% • High dose vitamins = 35% Ottolini, et al. 2001. Ambul Pediatr.; 1(2): 122-5.; Sawni-Sikand, et al.; 2002. Ambul Pediatr.; 2(2): 99-103.

8. Do Not Report CAM use to Providers • 66-72% Do not report use • Reasons for non-disclosure • “It wasn’t important for the doctor to know” = 61% • “The doctor never asked” = 60% • “It was none of the doctors business” = 31% • “The doctor would not understand” = 20% • “The doctor would disapprove” = 14% • “The doctor would not treat me anymore” = 2% Eisenberg, et al. 2001. Ann Intern Med.; 135(5): 344-51.; Sawni-Sikand, et al.; 2002. Ambul Pediatr.; 2(2): 99-103.

9. Clinical Use of Botanicals • Widespread use of botanicals • Little participation with health care system • Questions about • Quality, safety and efficacy of these products • Opens potential for misuse and abuse • Many phytobotanicals easily available • Lots of advise and “thought” available • Little evidence available to providers or patients • Some phytobotanicals dangerous • Some exotic • Substance use migrates from traditional cultural areas of use • Abuse potential of non-culturally bound use is area of concern Eisenberg, et al.; 1998. JAMA. 280:1569-75.; Mahady 2001;J Nutr;131(3s):1120S-3S.

10. Hard for providers to get information • Amount of reliable information is limited • Few authoritative sources • Searching databases is challenging • Inconsistent use of controlled vocabulary and indexing procedures • Lack of standardized terminology • Multiple names of several botanicals • Kava, Yaqona, Grog • Khat, Qat • Study of health professionals • Of those seeking CAM references • 26% Internal Medicine/ primary care providers • 15% Psychiatric/ mental health providers Murphy, et al., 2003. BMC Complem & Altern Med; 3(3): 917-28. Owen & Fang, 2003. J Med Libr Assoc.; 91(3): 311-21.

11. Framing the Issues • Botanical CAM use is high • Users of Cam’s fall roughly into two categories • One category is arguably already at-risk for substance misuse/ abuse • Hard for providers to get accurate information to help, advise, or monitor patients CAM use

12. Misuse and Abuse • Spectrum • Misuse • Self medicated/ regulated • Over treated, under treated, wrong treatment • Unintended consequences of use • Unintended synergism • Clinically significant botanical-drug interactions • Abuse • Psychoactive • Intentional synergism • Addictive? • Difficult to find reliable data on the abuse potential of phytobotanicals • Makes rational, evidence-based decision-making difficult in clinical settings International Centre for Mental Health Policy : Hum Psychopharmacol. 2002 Apr;17(3):131-40.

13. Misuse • Unintended consequences of use • Unintended synergism & clinically significant botanical-drug interactions • Consequences • Physical • Hepatotoxicity - potential risk of severe liver injury with KAVA • Psychiatric • Neurotoxicity – potential risk of mania from St. John’s wort • Genetic • Mutagenic genotoxicity- Betel quid and Khat (Li JH, Lin LF., 1998Genetic toxicology of abused drugs: a brief review Nov;13(6):557-65.)

14. Misuse • Phytobotanicals with no clear addictive potential • Example • Vitamin supplements in self-medication • Long History Documented Misuse • Rational for use • Attempts to compensate for an unhealthy life style • Attempts to maximize health or performance • No evidence of nutritional benefit derived from excess consumption of vitamin supplements • Misuse occurs in the intentional daily intake in excess of recommended by various international and national expert committees • Potential consequences • Toxicity in vitamins such as vitamin A and vitamin D • To a lesser extent, vitamin C and nicotinic acid Jarvis, 1985. Vitamin use and abuse.; Bol Asoc Med P R.; 77(4):168-70 ; Briggs & Brigggs, 1977. The use and misuse of vitamin supplements.; Aust Fam Physician; 6(2):145-7, 151-2. ; Rudman, et al., 1983. Megadose vitamins. Use and misuse. N Engl J Med. 25;309(8):488-90; Can Med Assoc, 1971. The use and abuse of vitamin An Can Med Assoc J. ; 20;104(6):521-2. ; Maitai, 1984. The craze for additional vitamin intake. East Afr Med J.; 61(9):661-2.

15. Abuse & Psychoactive Botanicals • Often about ethnopharmacology • Movement of indigenous drugs • Deritualization for clinical or recreational intent • Movement of drug without symbolic, religious, or other cultural mediators • Hard for providers to get information • Often miss the abuse aspect of clinical presentation • Phenomenon of modern age • Service access issues • Internet • Travel

16. Misuse and Abuse: All Categories of Substances • Psychoanaleptic (stimulant) • Psychodysleptic (hallucinogenic) • Psycholeptic (anxiolytic)

17. Psychoanaleptic (stimulant)

18. Psychoactive CNS action of botanicals • Psychoanaleptic (stimulant) • Uses • Weight reduction • Adaptogenic uses • Chronic fatigue – secondary to MDD • Adult ADHD • Guarana (Paullinia cupana) • Ma Huang (Ephedra spp.) • Khat [Qat] (Catha edulis Forssk)

19. Psychoanaleptic • Guarana • Brasilian coca • Traditional use • Now Internet • Indicated for • Weight loss • Herbal viagra • Chronic fatigue • ADHD

20. Guarana Naturale® is the original guarana powder ready to mix with drinks Guarana Active® is the original guarana powder but in tablet form, and is available in blister packs of 20 or 60 capsules.

21. Psychoanaleptic: Ma Huang • Widely promoted as weight reduction and energy enhancement herb • Form • Dietary supplements available on web sites and in dietary shops • Chinese ephedra • Black Caffeine • Ma Huang alone or combined • With Guarana, St John's wort • Numerous reports of adverse reactions and acute intoxication related to product use • Resulted in permanent injury and death • 47%, CV; 18% CNS • Severe hypertension single most frequent adverse effect Arditti J, Bourdon JH, Spadari M, de Haro L, Richard N, Valli M; Acta Clin Belg Suppl. 2002;(1):34-6

22. FDA has proposed limits on the dose and duration of use of such supplementsSo…..NEW….Guarana extract as a replacement for ma huang TWINLAB METABOLIFT NO MA HUANG 120 CAPS

23. Psychoanaleptic: Khat • Stimulating effect of leaves of the Khat bush • Leaves contain a variety of sympathomimetics • Alkaloid cathinone is main active principle of this drug • Similar in structure and pharmacological activity to amphetamine • Are chewed in several East African countries and in Yemen • Since only fresh leaves are active, until recently, Khat abuse was almost unknown outside the regions where the plant grows (Giannini, Miller, & Turner; 1992. J Subst Abuse Treat; 9(4):379-82. )

24. Khat • Recently, however, khat has made its appearance in the United States and in several European countries • U.S., American soldiers stationed in the Arabian peninsula may be exposed to it because of the alcohol interdiction during the first Gulf War • Became popular alternative recreational drug • Increasingly prohibited • Importation of qat is illegal in France and Switzerland • But legal in the United States, Great Britain and most African countries • Growing concern with addictive potential • Extensive literature base of support • Growing use in Club Drug Scene as a bumper drug Al-Motarreb, et al., 2002. Phytother Res. 16(5): 403-13.; Krikorian, 1984. J Ethnopharmacol. 12(2): 115-78.; Griffiths, et al., 1997. Br J Psychiatry, 170: 281-4.; Gianninni, et. Al., 1992. J Subst Abuse Treat. 9(4): 379-82.;

25. Psychodysleptic (hallucinogenic)

26. Psychoactive CNS action of botanicals • Psychodysleptic (hallucinogenic) • Used to achieve mind distortion states • Visionary • Phenethylamines • Indole alkaloids • Isoaxzoles • Imagery • Coumarins • Dibenzyopyrans • Trance-like • Ergolines • Opiates • Delirium-like • Tropane Alkaloids

27. Psychodysleptic • Strong religious use in indigenous cultures • Alter thought, perception, and mood • Seldom produce • Mental confusion • Memory loss • Disorientation • Strong History of Sacramental & Medicinal Use • EXAMPLE • Cacti • Peyote • San Pedro (T. Terschechii) • Salvia Divinorum (Mexican mint) • Same characteristics fuel non-sacramental use • Common botanicals with wider abuse • Cannabis sativa • Tabernanthe iboga (Eboka) • Banisteriopsis caapi (Spruce ex Griseb.)

28. Psychodysleptic: Tabernanthe iboga • Eboka (Iboga) • West African shrub • Long history cultural use of root as stimulant • Action from complex indole alkaloids derived from tryptamine • Use • Communication with ancestors • Divination of illness • Internet availability • As aphrodisiac • Memory enhancer • To treat active substance abuse

29. Psycholeptic (anxiolytic) Most familiar Most common

30. Psychoactive CNS action of botanicals • Psycholeptic • Used to achieve analgesic or anxiolytic affect • Valeriana officinalis L. • Piper methysticum • Betel nut

31. Psycholeptic • Valerian • Strong neuropsychiatry use • High-affinity dopamine reuptake inhibitor • Synthesized in the late 1970s • Initially tested in Europe as a potential antidepressant • Common uses • Insomnia • Anxiety • Depression • Little data for abuse • Some reports “hangover effect” • No reports associated with habituation or abuse • Rare questionable reports of withdrawal symptoms Krystal & ressler, 2001. CNS Spectrum6(10): 841-47.

32. Psycholeptic • Piper methysticum (kava kava) • Plant native to the Pacific Island region • Has been used ceremonial for thousands of years for resolution of political and social disputes • Active ingredients are a group of substances know as kava lactones • Found to have significant analgesic and anesthetic effects via non-opiate pathways • Common uses • Natural anxiolytic, comparing favorably in several studies to a number prescription medications, including benzodiazepines • Known to produce severe motor and psychiatric responses • These are not well-understood • Include psychotic and severe dystonic reactions • Yet without interruption in normal cognitive processes

33. Micronesia

35. Kava Bar

36. After Hours Hut

37. Kava • Action is unclear • GABA-receptor-binding capacity found to occur in some studies • In vitro kava has been found to block norepinephrine uptake • Appears to have some anti-convulsant capabilities • Mediated by Na+ channel receptor sites • Animal studies show that kava lactones alter neuronal excitation through direct interactions with voltage-dependent ion channels • Giving rise to kava's muscle relaxant, anesthetic, anxiolytic and anticonvulsive properties • Most common side effect of use • Usually seen only with long-term, heavy usage of the herb • Include • Scaly skin rash called "kava dermopathy." • Potentiate other medications such as barbiturates and Xanax • Raising fast in Club Drug Scene

38. Multiple Forms

39. KAVA Abuse Potential • Physical affects of sustained use /abuse • Dermopathy characteristic of heavy use • Abnormally low body mass index (BMI) • Low blood lymphocytes • Abnormally high gamma-glutamyl transferase (GGT) • These acute effects emerge at average consumption levels of from 310-440 g/week of kava powder. • Economics of abuse well documented • Average consumption of 240-425 g/week • 19% of available cash resources were spent on kava • 11% of cash resources leaving the local community economy • The proportion of men drinking kava reached 70% and women 62% • 20% of the population spending unprecedented amounts of time (14 + hours/week) in activities where kava was consumed • These parameters may be useful to monitor kava's adverse health, social and economic effects (Clough; 2003, Drug Alcohol Rev.;22(1):43-51. )

40. KAVA • Increasingly widespread use of kava • Intentional mixing in club drug scene • Further investigation is necessary to gain an understanding of its immediate neuropsychiatry effects and long-term cognitive effects Cairney S, Maruff P, Clough; Aust N Z J Psychiatry. 2002 Oct;36(5):657-62.

41. Betel Nut • Pan Asian problem • Uses • Improved concentration • Intestinal parasites • Social setting symbol • Areca catechu (nut) & Piper betel (leaf) • Arecoline + Piperine alkaloids • Unclear action • Effects thought to be related to the actions of Arecoline • However the actual chewing may produce complex reactions and interactions • Commonly chewed in the presence of lime • Arecoline and guvacoline in Areca nut • Hydrolyzed into arecaidine and guvacine • Are strong inhibitors of GABA uptake • Piper betle flower or leaf contains aromatic phenolic compounds • Have been found to stimulate the release of catecholamines in vitro are also activated by chewing • Thus, betel chewing may affect parasympathetic, GABAnergic and sympathetic functions.

42. Betel Nut • Chewing betel chewing mainly affects the central and autonomic nervous systems producing • Sense of well-being • EEG shows widespread cortical desynchronization indicating a state of arousal • Euphoria • Increases plasma concentrations of norepinephrine and epinephrine • Increase in heart rate, blood pressure • Heightened alertness • Sweating with increased temperature • Salivation • Hot sensation in the body • Increased capacity to work • Chewing also leads to habituation, addiction and withdrawal • Mechanisms underlying these effects remain poorly understood • Betel nut withdrawal syndrome well documented in Pacific Medical Literature Source: National Science Council, ROC and S. Karger AG, Basel; Chu ;J Biomed Sci. 2001 May Jun; 8(3):229-36.; Wiesner Med J Aust. 1987 Apr 20;146(8):453.)

43. Betel Quid • An estimated 10% to 25% of the world's population chews betel quid • Practice is little recognized in the United States • Growing in areas of immigration • Groups such as • Immigrants and refugees from India, New Guinea, and Southeast Asia • Physical hazards associated with the chewing of the various ingredients of the quid include • oral cancer • addictive potential as strong as for cigarettes

44. Conclusions • Patients are using herbal remedies for a variety of health conditions without medical supervision • Psychiatric mental health problems are one of the largest reasons people seek botanical CAMs • Often intentionally do not inform providers • Information is hard for providers to obtain • Very little evidence on which to base clinical decision making • Almost no awareness of abuse potential of several commonly used botanicals • More research is needed on herbal remedy use among patient populations and on outcomes in patients who use herbal remedies to treat primary health conditions

45. Thank You