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Many Shades of Grey: The Herb/Drug Interaction Continuum
A Primer for Naturopathic Physicians
and Herbalists
GLEN NAGEL, ND
SW BOTANICAL CONFERENCE
2020
GLEN NAGEL, ND
• Herbalist since 1984, Registered Herbalist with American Herbalist Guild.
• Former Associate Professor of Botanical Medicine at National College of Natural Medicine in Portland, Oregon, 10 years of teaching
• Former Assistant Professor at Bastyr University, in Kenmore Washington
• Adjunct professor at NUNM (formerly NCNM)• Consultant to the herbal industry
WORLD VIEW:PARADIGM OF NATUROPATHY
• How would you answer this question?
• Who would you trust to butter your bread?
• The Cow or the Chemist?
• Butter or Margarine
• Natural or Man made ?
IN NATURE WE TRUST
This is our paradigm……
• There is a surge in global sales – reaching a milestone of $1 trillion in 2014 – and forecasts continued growth with the expectation of sales
reaching $1.3 trillion by 2018.
• CMR INTERNATIONAL 2015 PHARMACEUTICAL R&D FACTBOOK
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US PHARMACEUTICAL SALES
Source: Statista.com
WORLD PHARMACEUTICAL MARKET
• US Pharmaceutical Sales are 464 billion in 2018
• Sales are up 11 to 13%
• Nutritional Supplement sales in 2018 are 62 billion total.
• Herbal supplements are 8.8 billion (1.9% of Drugs)
• Herbal supplement sales are 98.1% smaller
SOURCE: AMERICAN BOTANICAL COUNCIL8
SOURCE: AMERICAN BOTANICAL COUNCIL
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TOP 20 SELLING HERBS 2018
Source Herbal Gram
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• Herbal supplement sales in the United States experienced record growth in 2018, increasing by an estimated 9.4% from 2017, according to the Nutrition Business Journal (NBJ).
• Consumers spent a total of $8.842 billion on herbal supplements across all market channels in 2018 — an increase of roughly $757 million in sales from the previous year. This marks the strongest US sales growth of herbal supplements since 1998.
Retail Herbal Dietary Supplements
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For Drug / Herb Interaction potential….
Let’s follow the money trail
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WHAT IS THE GREATER PROBLEM?
• Based on 2018 sales for every $2 dollars of herbal product in a patient's medicine cabinet there are $98 dollars of Prescription drugs.
• Drug / Herb interaction potential ?
• Drug / Drug interaction potential ?
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HERBAL PRODUCTS SAFETY: WHAT IS THE MEDIA PERCEPTION?
SEPTEMBER 2012 ISSUE OF CONSUMER REPORTS
• According to the article, “More than 6,300 reports of serious adverse events associated with dietary supplements, including vitamins and herbs, streamed into the FDA…between 2007 and April 2012.
• The reports themselves don’t prove the supplements caused the problems, but the raw numbers are cause for concern.”
• Consumer Reports goes on to say that even though there’s no proof, the use of supplements during this five-year period “was associated with 112 deaths.”
DEATHS FROM SUPPLEMENTS
• U.S. National Poison Data System’s annual report from 2016 that shows zero deaths from nutritional supplements.
• How big of a problem are herb and supplement interactions today?
• Who is providing the data?
• How credible?
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CONCLUSIONS An estimated 23,000 emergency department visits in the United States every year
are attributed to adverse events related to dietary supplements. Such visits commonly involve
cardiovascular manifestations from weight-loss or energy products among young adults and
swallowing problems, often associated with micronutrients, among older adults.
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PLOS ONE | DOI:10.1371/journal.pone.0150089 February 29, 2016
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Source:PLOS ONE | DOI:10.1371/journal.pone.0150089 February 29, 2016
21PLOS ONE | DOI:10.1371/journal.pone.0150089 February 29, 2016
HERB SAFETY: PERSPECTIVE
• Natural does not equal “safe”• They are many “All Natural” poisons
• Herb does not equal “Danger”• Herbal medicine is 50 shades of grey• Very few black and white issues
• Herb and Drug Interactions• Negative interactions
• Positive or Adjunctive interactions
• Herb Toxicology • Safety of herbal products
• Quality assurance: Contamination and potency issues
BOTANICAL TOXICITY: FACTORS AFFECTING
• Relative toxicity & concentration of compounds in botanical.
• Presence of toxic compound in herb or solubility in preparation.
• Route of administration.
• Absorbability with oral consumption.
• Tenacity of the compound to survive metabolism.
• Potential for the compounds to form more toxic compounds after metabolization.
• Potential for accumulation.
• Rate and efficiency of excretion.
WHAT IS THE TRUTH ABOUT THE SAFETY OF HERBS?
• Details are important, generalizations can get us into trouble
• Don’t rely on someone else to do your work
• Inherently safe with limitations
• The truth is that there are many shades of grey, very few black and white issues
• Remember, what's your paradigm
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FIVE POINTS SYSTEM TO DETERMINE HERBAL/ DRUG INTERACTION POTENTIAL
• 1) Understand the Herb/ Supplement Label.• 2) Understand the dose /potency of the product.• 3) Understand p 450 detox pathway of drug and
herb.• 4) Is the herb an Inducer or Inhibitor or neutral in
respect of the detox pathways?• 5) Does the herb increase or decrease the drug absorption.• Determine if the combination has significant,
moderate or minimal risks. • Referral or Reference materials needed.
POINT #1:UNDERSTAND THE PRODUCT LABEL!
Must Read the details!
UNDERSTAND THE HERB/ SUPPLEMENT LABEL
• Herb Quality and Potency Important
• Herbal Forms: Not all are the same
• Dry Herbs, Extracts, Isolated extracts, Standardized extracts
• Quality Control and manufacturing issues
• Not all supplements are the same
• Highly variable
• Under DSHEA 1994, Nutritional Supplements not Drugs.
• Structure function claims only.
• Different than prescription pharmaceuticals
• Have patients bring bottles into your office and read them all !
HOW TO READ SUPPLEMENT LABELS
• D The Serving Size indicates the recommended amount per serving.
• E. This indicates how many Servings are in the container.
• F. The Other Ingredients List indicates the other ingredients necessary to complete the delivery system, and to ensure product freshness and stability.
• G. The Amount Per Serving indicates how much of each nutrient the body gets per recommended serving.
• H. The Daily Values are the percentage of the recommended daily intake established by the FDA as the amount the average American needs daily to maintain good health. Nutrients with an asterisk in this column do not have an established daily value.
HOW TO READ SUPPLEMENT LABELS• I. The Manufacture Date
printed on the label represents the date the product was produced in compliance with Good Manufacturing Practices (GMP) regulations.
• J. This indicates the item number for the brand items only.
• K. The Suggested Useindicates manufacturer recommendation for taking this product.
UNDERSTANDING WHAT IS IN THE BOTTLE
• Then…. All supplements or herbs are dangerous? (Black)
• All supplements or herbs are safe? (White)
• Or all Herbs and Supplements are many shades of grey. ( The Truth)
• You must have the time to understand the product, form and potency or all supplements become dangerous.
PLANT PHYTOCHEMISTRY
• The study of plant chemicals
• more precisely called metabolites
• Plants produce a vast diversity of
metabolites
• Plants are chemical factories
• 100% Solar powered
PHOTOSYNTHESIS
• Influx of Carbon from atmospheric CO2
• Made into GLUCOSE
• Stable storage of solar energy
All other organic molecules are made from glucose
PRIMARY PLANT METABOLITES
• Molecules that are essential to the basic functions of a plant
• Carbohydrates
• Amino acids, nucleic acids
• Proteins
• Lipids
• Vitamins
PLANT SECONDARY METABOLITES
• Compounds produced by a plant that are not essential to its growth or reproduction.
• These are the medicinal aspects of herbal Medicines.
• Defensive compounds• Anti-feedants
• Anti-microbials
• Anti-oxidants
• Signaling molecules• Hormones
• Attractants• Volatile oils
PLANTS ARE COMPLEX SOLAR CHEMICAL FACTORIES
• Most whole plant complexes contain 300-1000 identifiable chemical compounds.
• Generalizations are difficult to make about the total nature of all chemicals.
• Potential for interactions and synergy is high but what is the reality?
COMPLEXITY REDUCED TO ISOLATED COMPOUND
The Structure of Berberine
found in Oregon Grape Root
Oregon Grape Root and Flower
SIMPLICITY VERSUS COMPLEXITY
Just because an herb is placed in capsule or tablet, it looks simple
and drug-like. But it is a complex phyto--chemical mixture.
HYPERICUM PERFORATUM: 168 CHEMICALS WITH ACTIVITYANOTHER 120 WITH OUT KNOW ACTIVITY
TOTAL OF 288 CHEMICALS IN HYPERICUM
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Source: Dr Dukes Phytochemical database
HERBAL MEDICINE DIVERSITY A STRENGTH
• Herbal medicines’ diversity of compounds is a strength, not a weakness.
• Natural herbal products (whole and native extracts) are more like food than drugs.
• Less likely to cause interactions
Chemical activity in plant cells
NATIVE EXTRACTS: COMPLEX FRACTIONS
• Native Extracts: The primary soluble portion of phytochemicals removed from the herb by a liquid solvent and/or heat and/or pressure, used to draw multiple types of compounds out of herb tissue matrix and into solution.
• Quality at the beginning of product
• Types:• Fresh extracts:
• Fresh juice, Bottled juice, freeze-dried juice, green tincture, mother tincture.
TYPES OF NATIVE EXTRACTS
• Liquid extracts of dried plant parts
• Decoctions, Infusions
• Hydro-alcoholic (tinctures) 1:2 to 1:10
• Spagyric extracts (hydro–alcoholic with marc added back)
• Fluid extracts 1 to 1 strength.
Solid Extract: Concentrated standardized with original solvent removed, often 2:1 or higher (Evaporated with heat or vacuum)
TYPES OF EXTRACTS
• Simplified Fractions: Secondary extracts of complex fractions to concentrate select compounds, specific chemical portions separated from extracts. Focus on quality at the end product, not the beginning. Often thought of as uniform mediocrity
• Standardized extracts to specific chemical and ratio: 10 to 1, 50 to 1.
• Volatile oils: Steam or solvent-extracted.
TYPES OF EXTRACTS
• Isolated Constituents: Isolates, Purified Compounds: Phytochemicals that have been separated from their complex natural matrices, single molecular components removed from complex mixture.
• Crystalline drug salts
• Prescription drugs from natural sources.
PRODUCT CONTENT TRENDS
Source: Brinker, F. Complex herbs- Complete medicines. 2004
Whole Herb Native Extracts
Simplified Fractions
Isolated Constituents
BioactiveConstituents XXXXXX XXXX XX X
Constituents Lost X XXX XXXXX XXXXXX
Number of Additives X XX XXXX XXXXXX
NAME THAT PRODUCT FORM!
Native Extract: Complex
fraction Tincture/Extract
Isolated constituent,
not whole herb
ECHINACEA PRODUCTS OF DIFFERENT TYPES
• 45 different Echinacea products available commercially.
• Echinacea is not Echinacea, so many forms.
• We must understand the details.
Source: Brinker, F. Complex herbs- Complete medicines. 2004
HEADLINES STATE“ECHINACEA INEFFECTIVE FOR COLDS”
• The details are important!
• Echinacea purpurea juice of the flower and leaves, standardized to cichoric acid is not effective.
• What about the other 44 forms of Echinacea?
HERBAL PRODUCT QUALITY VARIABILITY• Echinacea Purpurea Allium Sativum: Garlic
Vieira MdLT and Huang S-M. Botanical-Drug Interactions: Planta Med 2012; 78: 1400–1415
Total phenolic compounds, including echinacoside,
cattaric acid, chologenic acid, and cichoric acid;
HERBAL PRODUCT QUALITY VARIABILITY
• Grapefruit Juice Hypericum perforatum
Vieira MdLT and Huang S-M. Botanical-Drug Interactions: Planta
Med 2012; 78: 1400–1415
POINT ONE: SUMMARY: YOU CANT EASILY STANDARDIZE NATURE
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• There are natural limitations to working with herbs
• Herbs are more like veggies than drugs.
• It is hard to compare one herb to herb, as well as herb to drugs.
• The first point: Herbal potency / Form is the most important
SECOND POINT: HERBAL DOSE
• The Herbal supplement form and dose are critical in potential interactions.
• Supplement label suggested dosing is just a suggestion, not based on actual herb activity!
• Everything as poison potential based on dosing!
• Self-prescribing can lead to overdosing.
• Most interactions happen via excessive dosing.
HERBAL MEDICINE DOSING SYSTEMS• Three traditions of administering herbs• European: Focuses on higher pharmacological amounts of
plant constituents. 5 mls, 3 times a day of a liquid hydro-alcoholic extract. • Moderate likelihood for interactions
• Physiologic: Moderate amounts of medicine. 30 to 60 drop doses of a liquid hydro-alcoholic extract. More Physiological• Minimal likelihood for potential interactions.
• Low (Drop dosing )(Homeopathic or hormetic ): Small amounts of medicine. 1 to 5 drop doses. • Insignificant or low potential for interactions
• Most likely interaction come from Pharmacological dosing, over a long period.
GENERAL RULES ON DOSING
• Most herbal products that are native complex fractions, dosed at label recommendation, have a low potential for interactions.
• This includes most hydro-alcoholic extracts (tinctures) in a retail setting.
• Includes most teas, and capsules and tablets which are whole ground herb.
• There are always exceptions, especially with the young, old and ill.
DOSING: MODERATE TO HIGH POTENTIAL FOR INTERACTIONS
• These include all so-called “ Standardized extracts, isolated and concentrated phyto-drugs, or isolated simplified compounds.
• Examples are the Standardized products of St. Johns Wort , Ginkgo, Kava Kava, Ginseng.
• These products are concentrated in their manufacturing process and contain significant levels of so-called active ingredients which are often isolated out of the natural matrix and complex.
POINT #3:DURATION OF HERB GIVEN
• How long is the herb prescribed?
• The longer the more potential for increase absorption andincreased interactions
POINT #3:DURATION: GENERAL RULES
• Herb duration under 4 weeks lower risk (1 point)
• Herb duration 4 to 12 weeks moderate risk (2 points)
• Herb duration 12 or more weeks highest risk. (3 points)
POINT #4:UNDERSTAND THE CYTOCHROME P-450 ISOENZYME SYSTEMS AND HERBAL CHEMISTRY
• Human Cytochrome P450 isoenzymes
• 57 know CYP proteins, data available on over 42
• 1A1, 1A2,1B1, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6,2E1,
• CYP 3A4 metabolizes most drugs (>50%)
• 2C9 & 2C19 (>25%), 2D9, 1A2,and 2E1
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SUPERCYP DATABASE IS AVAILABLE AT HTTP://BIOINFORMATICS.CHARITE .DE/SUPERCYP
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THE TRANSFORMER DATABASE
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(http://bioinformatics.charite.de/transformer
POLYMORPHISMS
Genetic differences among individuals
Incidence>1 %
Results with substrates can vary with the same isozyme
Variations occur between races and is great between species
Polymorphism exist for 1A2, 2B6, 2C9,2C19,2D6 and 3A5.
• CYP 1A2 concentrations varies 40 fold in humans
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IN VITRO PREDICATIONS AND IN VIVO REALITIES
• Most of the published research has focused on herb-drug interaction on in vitro evaluations of botanical constituents.
• In addition to in vitro studies, numerous in vivo investigations have been carried out in both animals and humans. Significant discrepancies exist between the two.
• Animal studies may not always coincide with clinical findings.
• Clinical human studies represent the only reliable means for realistically assessing a botanical drug interaction potential.
POINT #4: INDUCTION OR INHIBITION OR NEUTRAL TO P 450 SYSTEMS
• Inhibition results in increased plasma concentrations of drug
• Usually rapid, often due to direct competition for same CYP
• Inhibitor binding to isozyme prevents drug binding, a common cause of drug to drug interactions.
INDUCTION CAN BE SLOW
• Results in decreased plasma concentrations of drug
• Usually slow (7-10 days) due to indirect increase in CYP by stimulating mRNA leading to isozyme synthesis
• Causes increased intracellular concentration of isozymes
• Example: Hypericum
EFFECTS OF BOTANICALS ON ISOZYMES
Vieira MdLT and Huang S-M. Botanical-Drug Interactions: A… Planta Med 2012; 78: 1400–1415
EFFECTS OF BOTANICALS ON ISOZYMES
Vieira MdLT and Huang S-M. Botanical-Drug Interactions: A… Planta Med 2012; 78: 1400–1415
BOTANICAL INFLUENCES ON CYP ISOZYMES
Brinker:BOTANICAL PHARMACOKINETIC INTERACTIONS with DRUGS
and BOTANICAL ADJUNCTS, Lecture NCNM June 2011
BOTANICAL INFLUENCES ON CYP ISOZYMES
Brinker:BOTANICAL PHARMACOKINETIC INTERACTIONS with DRUGS
and BOTANICAL ADJUNCTS, Lecture NCNM June 2011
POINT #5:HERB CAN INCREASE OR DECREASE DRUG ABSORPTION
• Herbs naturally contain compounds that effect drug absorption.
• High fiber- decrease absorption
• High tannins- decrease absorption
• Laxative effects- decrease absorption
• May inhibit or induce the action of P glycoprotein pumps
POINT #5 ADD UP ALL THE CONCERNS
•Minimal Risk: Highly unlikely to cause interactions 1-7 pts
•Moderate Risk: minimal potential to cause interactions 8-14 pts
• Significant Risk Potential: moderation potential for interactions. 15-22 pts
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ADD UP THE POINTS
DRUG / HERB INTERACTION FLOW CHART
GLEN NAGEL, ND
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DETAILED HERBAL INTERACTION POTENTIALS
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Ardjomand-Woelkart K, Bauer R. Review and Assessment… Planta Med
Altogether, the differentevaluated Echinacea preparations are well-tolerated
herbal medicines in the management in children and adults alike. It is noteworthy that all safety data reported
are as product specific as the pharmacologicalor efficacy data are. In pharmacokinetic
herb-drug interaction studies performed in vivo,no significant inhibitions of human CYP2D6 and
CYP3A4 isoforms have been found after the administrationof standardized E. purpurea preparations.
ECHINACEA: BAUER 2015
• Adverse events reported during clinical trials following administration of Echinacea spp. mono-preparations were generally mild and mostly without causality.
• Moreover, the contraindications in cases of autoimmune diseases and immune- suppression are questionable, since lipophilic Echinacea preparations containing alkamides suppress cellular immune responses, and beneficial effects in autoimmunity were reported.
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ECHINACEA: BAUER 2015
• Due to published long term studies with continuous ingestion of different Echinacea preparations up to 6 month with no reported toxicological concerns, Echinacea can be recommended also for long-term use.
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PIPER METHYSTICUM: KAVA, ROOT AND TEA
Despite the link to kava and liver toxicity demonstrated in vivo and in vitro, in the history of Western kava use, toxicity is still considered relatively rare. Only a fraction of the handful of cases reviewed for liver toxicity could be, with any certainty, linked to kava consumption and most of those involved the co-ingestion of other medications/supplements . That means that the incident rate of liver toxicity due to kava is one in 60- 125 million patients.
A.F. Showman et al. / Fitoterapia 100 (2015) 56–67* These statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure or prevent any disease
KAVA CONCLUSIONS:
THE ENTOURAGE EFFECT
• Kava plants are likely to contain a diverse secondary metabolome, with hundreds of compounds that can impact the physiological responses of human cells and tissues. *
• The focus of the kava field upon the kavalactones is linked to the strong likelihood that these compounds' ligation of CNS GABA receptors is responsible for the relaxant and anxiolytic effects of the drink and its supplements. *
• However, the physiological (and possibly pathophysiological) effects of kava may be underestimated by a unilateral focus upon the kavalactones. The secondary metabolome of Cannabis sativa provides an analogy here. Similarly, the Kava field may now benefit from examination of the P. methysticum ‘entourage’.
A.F. Showman et al. / Fitoterapia 100 (2015) 56–67
* These statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure or prevent any disease
DOES KAVA IMPAIR DRIVING?
Only recently, two German administrative courts decidedthat the decision of the regulatory authority
to ban kava as a measure to ensure consumersafety was inappropriate and even associated
with an increased risk due to the higher risk inherentto the therapeutic alternatives. This ruling
can be considered as final for at least the Germanmarket, as no further appeal has been pursued by
the regulatory authorities
Planta Med 2015; 81: 1647–1653
Kava Safety:
The CB1 receptor affinity of yangonin
suggest that the endocannbinoid system
might contribute to the complex human
psychopharmacology of the traditional
kava drink and the anxiolytic preparations
obtained from the kava plant
Pharmacological Research 66
(2012)163-169
This study reports that yangonin, is a relatively good ligand of cannabinoid CB1
receptors, although weaker than THC
Pharmacological Research 66
(2012)163-169
KAVA SAFETY 2015• 450 million daily doses of Kava over 10 years
• Possible liver damage over last 12 years can be summarizes in these five major lines of thought
• Human genetic variability
• Metabolic toxification theory
• Organic solvent theory
• Wrong plant part theory
• Adulteration theory: 2 day Kava used more verses noble variety
Planta Med 2015; 81: 1647–1653
ABC KAVA GUIDELINES
• Products containing kava should be formulated and labeled to limit consumption of total kavalactones to 240 mg a day
• Product Label states: Caution Ask a healthcare professional before use if you have or have had liver problems, frequently use alcoholic beverages, or are taking any medication. Stop use and see a doctor if you develop symptoms that may signal liver problems. (Jaundice, fever, dark urine) Not for use by persons under 18 years of age, or by pregnant or breastfeeding women. Not for use with alcoholic beverages.
SAINT JOHN’S WORT: HYPERICUM PERFORATUM
• Naturalized in North America from Europe
• Found widely in dry, sunny environments
• From Hypericon –‘above the image’, used to protect from demons, witchcraft and lightning.
SAINT JOHNSWORTREVIEW ARTICLE: CYTOCHROME P450 ENZYME MEDIATED HERBAL DRUG INTERACTIONS 2014 (PART 1 &2)
• St. John's wort affects the pharmacokinetics of several drugs by inducing CYP isozymes, such as CYP3A4, CYP2C19, CYP2C9, and the drug transporter protein P-gp. This causes St. John's wort to be a highly problematic botanical with regard to CYP-mediated herbal drug interactions
• St. John’s wort contains numerous pharmacologically active compounds, including hyperforin, hypericin, pseudohypericin, and flavonoids (e.g., quercetin, quercitrin and I3,II8-biapigenin). Hyperforin, the principal mediator of St. John’s wort antidepressive action, and is the main reason for St. John’s wort herbal drug interaction potential.
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SAINT JOHNSWORTREVIEW ARTICLE: CYTOCHROME P450 ENZYME MEDIATED HERBAL DRUG INTERACTIONS 2014 (PART 1 &2)
• St. John’s had no appreciable effect on CYP1A2, CYP2C9 and CYP2D6
• Furthermore, short-term (1-3 days) administration of St. John’s wort did not induce CYP3A4 or P-gp, and long term (14 days) treatment is generally required to show the inductive effect
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GARLIC
• Collectively, there is sound consistent evidence that recommended doses of many varieties of garlic preparations do not have any significant effect on CYP3A4 activity in vivo. To our knowledge, the question of whether garlic preparations might be engaged in transporter-based drug interactions has not yet been dealt with in human pharmacokinetic studies.
• With the limited existing evidence from human in vivo drug interaction studies, there is no indication that garlic may present any remarkable or clinically important metabolism-based pharmacokinetic interactions with drugs, mainly cleared by CYP1A2, CYP2D6, CYP2E1, or CYP3A4 enzymes.
92Review article: CYTOCHROME P450 ENZYME MEDIATED HERBAL DRUG INTERACTIONS 2014 (PART 1 &2)Sompon Wanwimolruk, Virapong Prachayasittikul
MILK THISTLE
• Overall, the existing evidence from clinical interaction studies is reasonably consistent and suggests that milk thistle or silymarin products consumed at recommended doses; do not change the activities of CYP3A4, CYP1A2, CYP2D6, and CYP2E1 enzymes.
• The evidence supporting a lack of interaction potential is most strong for CYP3A4.
• On the other hand, the available evidence regarding CYP2C9 from a well-designed study in Chinese subjects convincingly proposes the possibility of significant inhibition of CYP2C9 by milk thistle or silymarin products.
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Review article: CYTOCHROME P450 ENZYME MEDIATED HERBAL DRUG INTERACTIONS 2014 (PART 1 &2)Sompon Wanwimolruk, Virapong Prachayasittikul
Cannabis and Drug
Interactions
What should we know?
CANNABIS
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Medicines 2019, 6, 3; doi:10.3390/medicines6010003
In general, cannabinoids are usually well tolerated, but bidirectional effects may be expected with concomitantadministered agents via affected membrane transporters(Glycoprotein p, breast cancer resistance proteins, and multidrug resistance proteins) and metabolizing enzymes(Cytochrome P450 and UDP-glucuronosyltransferases).
CANNABIS AND DRUG INTERACTIONS
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Medicines 2019, 6, 3; doi:10.3390/medicines6010003
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Practical considerations in medical cannabis administration and dosingCaroline A. MacCalluma, Ethan B. Russob,
https://doi.org/10.1016/j.ejim.2018.01.004
ABSTRACT:
• In this article, the authors endeavour to present concise data on cannabis pharmacology related to tetrahydrocannabinol (THC), cannabidiol (CBD) et al., methods of administration (smoking, vaporisation, oral), and dosing recommendations. Adverse events of cannabis medicine pertain primarily to THC, whose total daily dose-equivalent should generally be limited to 30 mg/day or less, preferably in conjunction with CBD, to avoid psychoactive sequelae and development of tolerance. CBD, in contrast to THC, is less potent, and may require much higher doses for its adjunctive benefits on pain, inflammation, and attenuation of THC-associated anxiety and tachycardia. Dose initiation should commence at modest levels, and titration of any cannabis preparation should be undertaken slowly over a period of as much as two weeks. Suggestions are offered on cannabis-drug interactions, patient monitoring, and standards of care, while special cases for cannabis therapeutics are addressed: epilepsy, cancer palliation and primary treatment, chronic pain, use in the elderly, Parkinson disease, paediatrics, with concomitant opioids, and in relation to driving and hazardous activities.
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https://doi.org/10.1016/j.ejim.2018.01.004
TAKE HOME MESSAGE WITH CANNABIS
• THC can cause induction of CYP increasing metabolism and lowering serumdrug levels
• CBD and likely high levels of CBD can cause inhibition of CYP3A4 and increase serum drug levels
• Practical use of THC and CBD together less likely to have effects
• Uncommon concerns with dose of 30 mg or less of THC
• Watch patients labs and symptoms with use of anti epileptic, chemotherapeutic, psychotic meds, hypertension and immune suppressive medication.
• Caution with the use of opioids and pain meds , codominant use can lead tosedation
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REFERENCE MATERIALS
• Francis Brinker, ND
• Eclectic Medical Pub.
• Best overall clinical guide
• Gives detail A-Z listing of top herbs
• Extensive appendices and lists of action
• Only book with Complementary Adjuncts
• Free updates online.
• Available as Kindle also
REFERENCE MATERIALS
• Herb, Nutrient, and Drug Interactions: Clinical Implications and Therapeutic Strategies
• Mitchell Bebel Stargrove ND Lac
• Jonathan Treasure MA MNIMH RH (AHG) MCPP Dwight L. McKee MD
• Mosby 2007• Covers 30 herbs in detail plus
nutrients and vitamins.
REFERENCE MATERIALS
• Kerry Bone, Simon Mills, Publisher: Elsevier Health Sciences, Date of Publication 2005
• Good overview of safety issues in use of botanicals
• 8 years old some material out of date.
REFERENCE MATERIALS
• AHPA's Botanical Safety Handbook
• Second Edition, hardcover edition
• Published by CRC Press - 904 Pages
• Editors: Zoë Gardner, University of Massachusetts; Michael McGuffin, American Herbal Products Association
• 2013 Publication pending
• 500 herbs listed
HERBAL ONLINE DATABASE
• Natural Standard
• www.naturalstandard.com
•
• Natural Medicines Comprehensive Database
• http://naturaldatabase.therapeuticresearch.com/home.aspx?cs=&s=ND
• Or Via www.herb-pharm.com
• HerbMed Pro • http://cms.herbalgram.org/herbstream/lib
rary/HerbMedPro/
• Interactions Guide
• http://interactionsguide.com/
