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 Cannabis 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 plant 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, Hypericum perforatum modulates similar genetic expressions to a conventional antidepressant Sarris J, Panossian A. Schweitzer I, Stough C, Scholey A. Herbal medicine for depression, anxiety and insomnia: A review of psychopharmacology 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 Passiflora 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 •Flavonoids luteolin – apigenin apigenin – luteolin – chrysin •Indolamines – harmol – harmine harmine harmol Passiflora incarnata •MOAs: – GABA-system mediated anxiolysis – Benzodiazepine receptor partial agonist – Animal behavioral models have shown non-sedative anxiolytic 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 oxazepam (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 (parsley) 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 – Safranal 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 Saffron 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. imipramine and fluoxetine 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 Cannabis sativa variety hemp Cannabis sativa Traditional Use •Specific Indications and Uses: •19th century India treatment of alcohol, morphine and cocaine dependencies (Reynolds 1890). Information is for a low THC , high CBD Chemovar Cannabis Constituents •Cannabinoids – CBD – CBG – CBC •Flavonoids CBG – Cannflavin A/B Cannabidiol •Terpenes – -caryophyllene – limonene Cannflavin A -caryophyllene Cannabis sativa (low THC chemotype) •MOAs: – GABAA (+ allosteric – CB1 (negative allosteric modulator) modulator) – FAAH Inhibition – 5HT2 – anandamide 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, clobazam & 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, anticonvulsants 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 medical cannabis administration and dosing. Eur. J. Intern. Med. 2018, 49:12-19. Hericium erinaceus Hericium Traditional Use Fortify the