# Presentation: 631889

## Misuse and Abuse Issues Related to Supplements Taken Clinically

- Susan McCabe EdD, RN
- Associate Professor
- East Tennessee State University

## 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

## 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

*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.*

- St. John’s Wort
-    1995 = $20 million
-    1997 = $200 million
-    1998 = $400 million

## 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;279:1548-1553* *Blais, 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.*

##  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.*

## 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*

## 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.*

## 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.*

## 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.*

## 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.*

## 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**

## 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. *

## 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., 1998** **Genetic toxicology of abused drugs: a brief review Nov;13(6):557-65.**)*

## 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. *

## 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

## Misuse and Abuse: All Categories of Substances

**Psychoanaleptic (stimulant)**
**Psychodysleptic (hallucinogenic)**
**Psycholeptic (anxiolytic)**

## Psychoanaleptic (stimulant)

## 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)

## Psychoanaleptic

**Guarana**
- Brasilian coca
- Traditional use
- Now Internet
- Indicated for
- Weight loss
- Herbal viagra
- Chronic fatigue
- ADHD

**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.

## 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 *

## FDA has proposed limits on the dose and duration of use of such supplements So.....NEW....Guarana extract as a replacement for ma huang

**TWINLAB METABOLIFT **
**NO MA HUANG 120 CAPS**

## 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.** )*

## 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.; *

## Psychodysleptic (hallucinogenic)

## 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

## 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.)

## 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

## Psycholeptic (anxiolytic)

- Most familiar
- Most common

## Psychoactive CNS action of botanicals

**Psycholeptic**
- Used to achieve analgesic or anxiolytic affect
- Valeriana officinalis L.
- Piper methysticum
- Betel nut

## 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.*

## 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

**Micronesia**

**Kava Bar**

**After Hours Hut**

## 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

## Multiple Forms

## 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.** )*

## 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. *

## 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.

## 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.** **) *

## 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

## 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**** **

## Thank You