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Home , Dihydrokavain, Ginkgo, Luteolin, Safranal, Yangonin

Herbs for Neurology in Restorative Medicine

Kevin Spelman, PhD, MCPP Health, Education & Research in Botanical Medicine Financial Disclosure

•Consultant for Restorative Formulations •I have been a Natural Products and Industry Consultant, for GMPs, Regulatory Issues, Pharmacology, Research Initiatives, New Product Development and Formulation

•I have financial interests in the Natural Products Industry The Herbs

Phytochemistry is Key Botanical Neuro MOAs

• Botanical Medicines may alter neurotransmitter binding and uptake, synthesis, and regulation or supporting healthy function of the endocrine system. • Modulation of neuronal communication – Via specific metabolites binding to neurotransmitter/neuromodulator receptors – Via alteration of neurotransmitter synthesis, breakdown and function • Stimulating or sedating CNS activity • Regulating and supporting the healthy function of the endocrine system • Providing increased adaptation to exogenous stressors (adaptogenic/tonic effects • Epigenetic alteration, for example, modulates similar genetic expressions to a conventional antidepressant

Sarris J, Panossian A. Schweitzer I, Stough C, Scholey A. medicine for depression, anxiety and insomnia: A review of and clinical evidence. Eur Neuropsychopharmacol. 2011 Dec;21(12):841-60 Neuro MOAs In Botanicals

“more sophisticated neuropharmacologic techniques of the future will reveal novel and marvelously subtle pharmacologic activities for herbal medicines that current research methods fail to uncover”

Jerry Cott, PhD Food and Drug Administration Past National Institutes of Mental Health Principal Investigator

The Herbs

Passiflora incarnata Traditional Use

• Specific Indications and Uses – irritation of brain and nervous system with atony – sleeplessness from overwork, worry, or from febrile excitement, and in the young and aged – neuralgic pains with debility – exhaustion from cerebral fullness, or from excitement – convulsive movements – infantile nervous irritation – nervous headache – tetanus – hysteria – oppressed breathing – cardiac palpitation from excitement or shock Felter and Lloyd.1898.Kings American Dispensatory Passiflora Constituents •Amino acids – GABA • – apigenin – luteolin – •Indolamines – harmol

– harmine harmine harmol

•MOAs: – GABA-system mediated anxiolysis – partial – Animal behavioral models have shown non-sedative effects

(Dhawan et al., 2001a, b, 2002; Grundmann et al., 2009; Grundmann et al., 2008; Sena et al., 2009)

Passiflora incarnata Research

• Research: – Anxiety: 4-week RCT (n=36) using 45drops of Passionflower vs. 30mg of (Akhondzadeh et al., 2001) – Anxiety: Acute study RCT (n=60) using 500mg of Passionflower vs. placebo for pre-surgical anxiety (Movafegh et al., 2008) – Insomnia: 3-week RCT^ (n=41) using 2g of Passionflower tea vs. placebo () tea before sleep (Ngan and Conduit, 2011) • Results: – Passionflower was as effective (with less side effects) as oxazepam in reducing anxiety (Akhondzadeh et al., 2001) – Anxiety scores were significantly lower in the passionflower group than in the control group on a numerical rating scale(Movafegh et al., 2008) – Aside from an improvement between groups on subjective sleep quality, no significant differences were found on other sleep outcomes (Ngan and Conduit, 2011)

Passiflora incarnata

•Potential application: – Anxiety – Insomnia Passiflora incarnata Dose

•Dried herb: 2 g TID to QID •Infusion: 2 g in 150 ml water, TID to QID •Fluid extract 1:1 (g/ml): 2 ml, TID to QID •Tincture 1:5 (g/ml): 5-10 ml, TID to QID Drug-Herb Interaction Inclusion Criteria

•Human over Animal Studies •Animal Studies over in vitro •In vitro studies limited to – 10 μg/mL if extract is used in study – 10 μM if single constituent is used in the study Passiflora Drug-Herb Interactions

No known interactions that fall within the established inclusion criteria for this data set Zizyphys jujuba Ziziphus Traditional Use •Tonifies the spleen and augments the qi •Nourishes the blood and calms the spirit •Moderates and harmonizes the harsh properties of other herbs Ziziphus Constituents •Major active constituents: Jujuboside A – jujubosides – jubanines – nummularines Jubanine B – sanjoinines – triterpenoids – flavonoids

Nummularine F

Sanjoinine IB Ziziphus jujuba • MOAs – Inhibits glutamate-mediated pathways in the hippocampus – Jujubosides increased total sleep time when given orally in rats – Animal models using suanzaoren (a TCM formula containing Z. jujuba as the principle herb) have found modulation of central monoamines and limbic system interaction

(Cao et al., 2010; Chen et al., 1985; Hsieh et al., 1986a; Hsieh et al., 1986b; Morishita et al., 1987)

Ziziphus jujuba

•Potential application: – Insomnia – Anxiety Jujuboside A and Spinosin Synergy Sanjoinine A Ziziphus Dosing

•Traditional usage of Jujube is taking 50g of the fruits, hot water extract, either as a soup of a beverage Ziziphus Drug-Herb Interactions

No known interactions that fall within the established inclusion criteria for this data set Crocus sativus Crocus Traditional Use

• liver tonic and hepatic deobstruent • facilitate difficult labors • management of premenstrual syndrome, dysmenorrhea, and irregular menstruation • enlivening the essence of the spirit and inducing happiness is great • aphrodisiac, used in impotence • treats cataract and conjunctivitis and to improve vision • improve respiratory function, asthmatic problems, and as a lung tonic • heart tonic, treats palpitatin • treats uterus malignancies Crocus sativus Constituents

•Major active constituents: – Crocetin – Crocins –

Crocin 1 Safranal Crocus sativus

•MOA: – Increased reuptake inhibition of monoamines (dopamine, norepinephrine, serotonin) – NMDA receptor antagonism – GABA- agonism – Anxiolytic effects in animal models (elevated plus maze and open field test)

(Hosseinzadeh and Noraei, 2009; Lechtenberg et al., 2008?; Schmidt et al., 2007) Crocus sativus Research

• Research: – Depression: Five 6-week RCTs: • Two trials using 30–90 mg of vs. placebo; Three trials using Saffron vs. synthetic antidepressants (Akhondzadeh et al., 2005; Moshiri et al., 2006; Akhondzadeh et al., 2004; Noorbala et al., 2005; Akhondzadeh et al., 2007) • Results: – Significant improvement for depression over placebo on HAMD for Saffron petals and stamen – An equivalent therapeutic response occurred with Saffron vs. and on HAMD depression • (Akhondzadeh et al., 2005; Moshiri et al., 2006; Akhondzadeh et al., 2004; Noorbala et al., 2005; Akhondzadeh et al., 2007) Crocus sativus

•Potential application: – Depression – Anxiety Crocus sativus Dose

15mg of saffron BID Crocus Drug-Herb Interactions

No known interactions that fall within the established inclusion criteria for this data set variety hemp Cannabis sativa Traditional Use

•Specific Indications and Uses: •19th century India treatment of , morphine and dependencies (Reynolds 1890).

Information is for a low THC , high CBD Chemovar Cannabis Constituents • – CBD – CBG – CBC •Flavonoids CBG – Cannflavin A/B •Terpenes – - – limonene Cannflavin A -caryophyllene Cannabis sativa (low THC chemotype)

•MOAs: – GABAA (+ allosteric – CB1 (negative ) modulator) – FAAH Inhibition

– 5HT2 – reuptake inhibitor – TRPV1 – iNOS inhibition – TRPA 1 – NFkB inhibition – TRPM 8 – adenosine reuptake – PPARg inhibitor

– GPR55 Information(putative is forCB3) a low antagonist THC , high CBD Chemovar– BDNF elevation Cannabis sativa Research

• Research: – blocking NMDA receptors in glutamate toxicity – anxiolytic activity – seizures – inflammation • Results: – significant neuroprotection – significant anxiolytic activity – significant anti-seizure activity – significant anti-inflammatory

Information is for a low THC , high CBD Chemovar

Cannabis sativa

• Potential application: – Addiction – Anxiety – Autoimmune conditions – Depression – Inflammatory conditions – Insomnia – Neurological damage – AD, PD, etc. – Seizures Information is for a low THC , high CBD Chemovar Cannabis sativa Dose

Flower (assuming ~15% CBD) •Inhalation: 300-1000 mg (15-45 mg) •Encapsulated: 1000-3000 mg (15-45 mg)

Oil (assuming ~50% CBD) This is not infused oil •Inhalation: 50-150 mg (15-45 mg) •Encapsulated: 150-900 (15-45 mg)

Information is for a low THC , high CBD Chemovar Cannabis sativa Drug Interactions Theoretical

• CYP450 inhibition (Stout & Cimino, 2013) – CBD: 2C19, 3A4 – Warfarin, most statins, erythromycin, azole antifungals, & other AEDs

Information is for a low THC, high CBD Chemovar Cannabis Drug-Herb Interactions

• In extensive clinical application including complex drug regimens with opioids, tricyclic antidepressants, etc, no drug interactions have been observed that would contraindicate or preclude the use of cannabinoids with any specific pharmaceutical, although additive sedative effects are always possible.

• Recently expert opinion suggest that there is no drug that cannot be used with cannabis, if necessary.

Russo, E.B. Current therapeutic cannabis controversies and clinical trial design issues. Front. Pharmacol. 2016, 7, 309. MacCallum, C.A.; Russo, E.B. Practical considerations in administration and dosing. Eur. J. Intern. Med. 2018, 49:12-19. Hericium erinaceus Hericium Traditional Use Fortify the spleen Nourish the gut, promotes good digestion gastric and duodenal ulcers, as well as chronic gastritis Anti-cancer Good for the 5 internal organs (liver, lung, spleen, heart, kidney) general vigor, strength, and nutrition; Known for its effects on the central nervous system - Insomnia Vacuity (weakness) Hypodynamia

Spelman K, et al. 2017. Neurological Activity of Lion’s Mane Hercium erinaceus. Restorative Med J 6:19-26

Hericium Constituents •Major active constituents: – hericenones (fruiting body) Hericenone A – erinacines (mycelia) – sterols – polysaccharides (immune active)

Erinacine A

Spelman K, et al. 2017. Neurological Activity of Lion’s Mane Hercium erinaceus. Restorative Med J 6:19-26 Hericium • MOAs – neurite outgrowth stimulation – induces NGF gene expression and secretion – inhibits -site Amyloid Precursor Protein-Cleaving Enzyme 1 – stimulation of myelin sheath formation – up-regulation of lipoxin A4 – enhanced the acetylcholine and choline acetyltransferase concentrations – down regulation of inflammatory cytokines in CNS

Spelman K, et al. 2017. Neurological Activity of Lion’s Mane Hercium erinaceus. Restorative Med J 6:19-26 50 MOA of H. erinaceus in Alzheimer’s disease

Increased Attenuation NGF of cerebral mRNA Aβ plaque burden Diminished expression plaque-activated microglia and Nutrient astrocytes Deficiencies Alzheimer’s Disease Up-regulation of liopxin A4 Increased Acetylcholine (LXA4) in (Ach) and choline brain acetyltransferase (ChAT) Down regulation concentrations of Tau tangles Hericium Research •Research – MCI: RCT, placebo controlled, 50-80 y/o – Anxiety/Depression in menopausal women

•Results – Marked improvement in Hasegawa Dementia Scale vs placebo – Significant improvement in Indefinite Complaint Index, trend in anxiety, concentration and irritability

Hericium erinaceus

•Potential application: – Neurotrophic activity – Dementia – TBI (theoretical) – Stroke (preclinical) – Multiple Sclerosis (preclinical) Hericium Dosing

Traditional Dosing

3 g (98% H. erinaceus powder) showed significant improvement in dementia rating scale in general cognitive decline subjects in a clinical trial 3–5 g/day dried fruiting body of H. erinaceus for increasing NGF production

Spelman K, et al. 2017. Neurological Activity of Lion’s Mane Hercium erinaceus. Restorative Med J 6:19-26 Hericium Drug-Herb Interactions

No known interactions that fall within the established inclusion criteria for this data set. Valeriana officinalis Valeriana spp. Constituents

•Major active constituents: – valepotriates (Iridoids) – essential oil Valepotriate • , bornyl acetate • beta-bisabolene, valerenal – – GABA – flavonoids, amino acids, Valerenic Acid Valeriana spp.

• MOAs: – Adenosine (A1) receptor interactions – GABA modulation (increased binding and decreased degradation of GABA) – Valerenic acid from has demonstrated GABA-A receptor (B3 subunit) agonism

– 5-HT5a partial agonism – Animal models have shown anxiolytic effects (elevated plus maze)

(Benke et al., 2009; Dietz et al., 2005; Murphy et al., 2009; Ortiz et al., 1999; Sichardt et al., 2007; Trauner et al., 2008)

Valeriana spp. Research

• Methodology: – Insomnia: Systematic review 16 RCTs (N=1093) and meta-analysis. Valerian vs. placebo or vs. active controls (Bent et al., 2006) – Insomnia: Systematic review and meta-analysis of 18 RCTs, Valerian vs. placebo or active controls (Fernandez-San-Martin et al., 2010) • Results: – Six studies included in meta-analysis revealed significantly improved quality over placebo on the dichotomous outcome of sleep quality (RR of improved sleep = 1.8, 95% CI: 1.2, 2.9) However the review revealed 9/16 studies revealed no positive outcomes (Bent et al., 2006) – Valerian reduced sleep latency over placebo by only 0.70 min (95% CI −3.44, 4.83), with the standardised mean differences between the groups measured being statistically equivocal −0.02 (95% CI −0.35, 0.31) (Fernandez-San-Martin et al., 2010) Valeriana spp.

•Potential application: – Insomnia – Anxiety – Somatic tension – CNS stimulant withdrawal Valeriana spp. Dose

•3 to 9 g/day dried root/rhizome •2 to 6 mL/day of 1:2 liquid extract, 5 to 15 mL/day of 1:5 tincture or equivalent solid doses. Valeriana officinalis Valerian Drug-Herb Interactions

Healthy volunteers administered 375 mg of valerian, daily for 28 days, alongside , , chlorzoxazone and debrisoquin showed no significant changes in CYP1A2, CYP2D6, CYP2E1 or CYP3A4/5.

Gurley, B. J., et al. (2005). In vivo effects of , kava, black cohosh, and valerian on human cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes. Clin Pharmacol Ther, 77(5), 415- 426. doi: 10.1016/j.clpt.2005.01.009 Ginkgo Ginkgo Traditional Use

•Pen T’sao Ching – Memory loss and breathing ailments – Skin sores and parasitic diarrhea Ginkgo Constituents

–

– Biflavones Ginkgolide C – Terpene lactones • ginkgolides and bilobalides

Rapin, J. R., Lamproglou, I., Drieu, K., & DeFeudis, F. V. (1994). Demonstration of the "anti-stress" activity of an extract of (EGb 761) using a discrimination learning task. Gen Pharmacol, Apigetrin25(5), 1009-1016.

Ginkgo biloba

•MOAs – Modulation of cholinergic and monoamine pathways – Antioxidant, anti-PAF, anti-inflammatory effects – GABAergic effects – activity

(Di Renzo, 2000; Woelk et al., 2007) Ginkgo (Ginkgo biloba)

• Potential application: – Cognitive impairment – Anxiety – Depression – Vascular disorders – Tinnitus – Asthma – Acute Mountain Sickness Ginkgo Research

•Research: – Anxiety: 4-week RCT (n=107) 240mg, 480mg Ginkgo extract EGb761 vs. placebo (Woelk et al., 2007) •Results: – Dose-dependent significant reduction of anxiety over placebo of 2.2 and 6.5 points on HAMA for 480mg and 240mg doses of EGb 761, respectively (Woelk et al., 2007) Ginkgo Pharmacological Human Studies

• Effects on CNS • Increase in alpha activity & cognitive activating type response • Cognition enhance effects are more likely to be apparent in older subjects • Ginkgo produced characteristic “cognitive activator” EEG profiles in more responders (8 of 18) than tacrine (3 of 18) – Effects on cognition and memory • Ginkgo improves memory processes, particularly working memory speed, memory consolidation & executive functoning

2003. ESCOP Monographs The Scientific Foundation for Herbal Medicinal Products 2nd Ed p187-8 Ginkgo

Chronic treatment with oral ginkgo extract reduces stress- induced impairments in learning and elevation of stress hormones, in both young and old rats

Rapin, J. R., Lamproglou, I., Drieu, K., & DeFeudis, F. V. (1994). Demonstration of the "anti-stress" activity of an extract of Ginkgo biloba (EGb 761) using a discrimination learning task. Gen Pharmacol, 25(5), 1009-1016. Ginkgo

Ginkgolide B is one of the constituents responsible for the enhanced learning effect, by reducing the binding and expression of peripheral-type benzodiazepine receptors in the adrenal cortex

Amri, H., Drieu, K., & Papadopoulos, V. (1997). Ex vivo regulation of adrenal cortical cell steroid and protein synthesis, in response to adrenocorticotropic hormone stimulation, by the Ginkgo biloba extract EGb 761 and isolated ginkgolide B. Endocrinology, 138(12), 5415-5426. Amri, H., Ogwuegbu, S. O., Boujrad, N., Drieu, K., & Papadopoulos, V. (1996). In vivo regulation of peripheral-type benzodiazepine receptor and glucocorticoid synthesis by Ginkgo biloba extract EGb 761 and isolated ginkgolides. Endocrinology, 137(12), 5707-5718. Papadopoulos, V., Widmaier, E. P., Amri, H., Zilz, A., Li, H., Culty, M., . . . Drieu, K. (1998). In vivo studies on the role of the peripheral benzodiazepine receptor (PBR) in steroidogenesis. Endocr Res, 24(3-4), 479-487. Ginkgo

Reduces production of glucocorticoids, and may also act at the hypothalamic level to inhibit the HPA axis

Marcilhac, A., Dakine, N., Bourhim, N., Guillaume, V., Grino, M., Drieu, K., & Oliver, C. (1998). Effect of chronic administration of Ginkgo biloba extract or Ginkgolide on the hypothalamic-pituitary-adrenal axis in the rat. Life Sci, 62(25), 2329-2340. Ginkgo Synergy Ginkgo Dose

120-240 mg/d (24/6 extract) 40 – 120 mg TID often suggested (24/6 ext) Dose must be titrated in older adults to due hypotensive effects Ginkgo HDI, The Dogma

Ginkgo (ginkgo biloba) interactions include bleeding when combined with warfarin raised blood pressure when combined with a thiazide diuretic and coma when combined with

Schmidt M, Narstadt A. 2001. SourceDrugs 61(15):2163-2175 Ginkgo Drug-Herb Interactions

•Clinical studies have shown no interaction with numerous drugs – Healthy volunteers administered six ginkgo tablets, containing approximately 2 g of ginkgo each, for 7 days, then administered the same dose of ginkgo concomitantly with 25 mg warfarin daily, showed no significant changes in plasma levels of warfarin, as well as no changes in platelet aggregation or international normalized ratio of prothombin time Jiang, X., Blair, E. Y., & McLachlan, A. J. (2006). Investigation of the effects of herbal medicines on warfarin response in healthy subjects: a population pharmacokinetic-pharmacodynamic modeling approach. J Clin Pharmacol, 46(11), 1370-1378. doi: 10.1177/0091270006292124 Jiang, X., Williams, K. M., Liauw, W. S., Ammit, A. J., Roufogalis, B. D., Duke, C. C., . . . McLachlan, A. J. (2005). Effect of ginkgo and on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Br J Clin Pharmacol, 59(4), 425-432. doi: 10.1111/j.1365-2125.2005.02322 Ginkgo Drug-Herb Interactions

•Healthy volunteers orally administered single doses of 120 mg ginkgo with 100 mg cilostazol or 75 mg clopidogrel showed no significant inhibition of platelet aggregation; prolonged bleeding time was observed with the combination of ginkgo and cilostazol, however no changes where noted in clotting time or platelet count

Aruna, D., & Naidu, M. U. (2007). Pharmacodynamic interaction studies of Ginkgo biloba with cilostazol and clopidogrel in healthy human subjects. Br J Clin Pharmacol, 63(3), 333-338. doi: 10.1111/j.1365- 2125.2006.02759. Ginkgo Drug-Herb Interactions

Adults with either peripheral artery disease or at a high risk for cardiovascular disease administered 325 mg of aspirin alone or alongside 300 mg of ginkgo extract daily for four weeks showed no significant changes in platelet function analysis, platelet aggregation, bleeding or bruising episodes

Gardner, C. D., et al.(2007). Effect of Ginkgo biloba (EGb 761) and aspirin on platelet aggregation and platelet function analysis among older adults at risk of cardiovascular disease: a randomized clinical trial. Blood Coagul Fibrinolysis, 18(8), 787-793. doi: 10.1097/MBC.0b013e3282f102b1 Ginkgo Drug-Herb Interactions

•RCT, 50 ♂ pt – ASA (500 mg) alone vs ASA + Ginkgo (240 mg) exerted similar effects on • bleeding time • PAF-induced platelet aggregation

2003. ESCOP Monographs The Scientific Foundation for Herbal Medicinal Products 2nd Ed p197 Ginkgo Drug-Herb Interactions

The gingkolides A,B,C have demonstrated a reduction in the nephrotoxic effects of cyclosporine in an animal model

Pirotzky E, et al. 1988. Transplant Proc 20(3; Suppl 3):665-9 Hypericum perforatum Piper methysticum Piper methysticum Constituents

• /Kavapyrones – –

– Kavain – 11-methoxy-yangonin – –

Dihydromethysticin

(Lebot et al. 1997; Boonen et al. 1997; Cass and McNally 1998) Ethnobotany

•Ceremonial beverage •Ceremonies welcomed royalty/guest •Social beverage •Beneficial for health

Piper methysticum

• MOAs – GABA channel modulation (lipid membrane structure and sodium channel function) – Weak GABA binding (increased synergistic effect of [3H]muscimol binding to GABA- receptors) – B-adrenergic downregulation – MAO-B inhibtion – Reuptake inhibition of norepinephrine in the prefrontal cortex • (Boonen and Haberlein, 1998; Davies et al., 1992; Jussofie et al., 1994; Magura et al., 1997; Uebelhack et al., 1998) Piper methysticum Research • Methodology: – Anxiety: Review of 11 RCTs (n=645) and a meta-analysis of 6 RCTs (n=345) (Pittler and Ernst, 2003) – Anxiety: Meta-analysis Kava WS1490 extract 6 RCTs included (Witte et al., 2005) • Results: – Significantly greater anxiolysis from Kava than placebo; 5.0 point reduction over placebo on HAMA (95% CI: 1.1–8.8) Odds ratio in favour of Kava= 3.3 (95% CI: 2.09–5.22) (Pittler and Ernst, 2003; Witte et al., 2005) Kava vs. Placebo

35

30

25

20 Kava 15

10 Placebo

5

0 week 0 week 4 week 8 week 12 week 24

adapted from Pharamacopsychiatry 1997;30:1-5 Piper methysticum

•Potential application: – Anxiety – Comorbid depression – Anxious insomnia – ADHD – Pain Piper methysticum Synergy

When a kava resin is administered (containing combined kavapyrones), levels of kavain and yangonin in the brain are multiplied 2 and 20 times, respectively, as compared to individual administration

Results from studies using individual kavalactones must be generalized cautiously, because they do not account for the magnified effects of the naturalistic combined administration of kavalactones.

Keledjian, J., Duffield, P.H., Jamieson, D.D., Ligard, R.O. & Duffield, A.M. (1988) Uptake into mouse brain of four compounds present in the psychoactive beverage kava. J. Pharm. Sci.,77(12), 1003-1006

Piper methysticum Dose

•1.5 to 3 g/day of dried root or in decoction •Standardized preparations containing 100 to 200 mg/day of kava lactones

Schmidt M, Narstadt A. Is kava hepatotoxic? Deutsche Apotheker Zeitung 2002;142(9):58-63

Piper methysticum Drug-Herb Interactions

In a clinical trial, single doses of 0.5 mg digoxin before and after a two week supplementation period of 1227 mg/day of kava showed no statistically significant changes on the pharmacokinetic parameters of digoxin

Gurley, B. J., et al. (2007). Effect of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on digoxin pharmacokinetics in humans. Drug Metab Dispos, 35(2), 240-245. Piper methysticum Drug-Herb Interactions

In a clinical study, co-administration of 9 mg/day with 400 mg/day kava standardized extract did not produce significant differences in well-being or mental performance when compared with the control

Herberg, K. (1996). Safety-related performance after intake of kava-extract, bromazepam and their combination. Ztschr. Allgemeinmed(72), 973-977. Piper methysticum AEs

• 250 million daily doses of ethanolic kava extract products have been provided in the previous decade

• Only two cases in which a causal relationship appears probable with one resulting from overdosing at levels exceeding the recommended dose

Schmidt M, Narstadt A. Is kava hepatotoxic? Deutsche Apotheker Zeitung 2002;142(9):58-63 Piper methysticum AEs

• Based on these two cases, an incidence rate of 0.008 AERs to kava in 1 million daily doses

• Compared to known reports for : 0.90 AERs for 1 million daily doses of bromazepam, 1.23 for oxazepam, and 2.12 cases for .

Schmidt M, Narstadt A. Is kava hepatotoxic? Deutsche Apotheker Zeitung 2002;142(9):58-63 Piper methysticum AEs

"A prohibition of Kava and a consequent increase in change-over of patients to benzodiazepines would therefore increase the risk of adverse events and not reduce them."

Schmidt M, Narstadt A. Is kava hepatotoxic? Deutsche Apotheker Zeitung 2002;142(9):58-63 The results indicate that a medicinal dose of kava containing 180 mg of kavalactones does not impair driving ability, whereas 30 mg of oxazepam shows some impairment. Other Herbs: Neuro-Trophorestoratives Plant remedies traditionally used as nervous system trophorestoratives • Avena sativa (oat latex, NOT oat straw) • Centella asiatica (gotu kola, brahmi) • Hericium erinaceus (lion’s mane) • Hypericum perforatum (St John’s wort) • Schisandra chinensis (schizandra) • lateriflora (skullcap) • Turnera diffusa (damiana) • officinalis (vervain) • Withania somnifera (Indian ) Thank you for our attention.

Questions?

Kevin Spelman, PhD, MCPP Health, Education & Research Ashland, OR [email protected] http://phytochemks.com/