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New Botanical Medicinal Breakthroughs for the Management of Anxiety and Sleep Presented by: Guy Chamberland, MSc, PhD, Master Herbalist PARKE DAVIS & CO Objectives of This Workshop – Learn About • Pharmacological mechanism of action • Traditional evidence and clinical evidence supporting the use of herbs in the treatment of anxiety and sleep. • Dose levels and additive effects. • Importance of pharmacokinetics on clinical outcome: – Duration of response – Induction of sedation or hypnosis – Dose level and dosing interval Guy Chamberland, M.Sc., Ph.D., Master Herbalist • B.Sc. In Agricultural Chemistry, McGill University. • M.Sc., Ph.D. in toxicology (Biomedical sciences), University of Montreal. • Natural Health Practitioner & Bioenergetics Practitioner diploma (Oriental medicine), Alternative Medicine College of Canada. • Proficiency in Herbal Prescription, Australian College of Phytotherapy. • Chartered & Master Herbalist, Dominion College of Canada. Guy Chamberland, M.Sc., Ph.D., Master Herbalist • Over 16 years developing new drugs in pharmaceutical industry (Canada & USA). – Drug safety & Drug development. • Research in herbal anxiety, sleep, pain/inflammation & wound treatments. – Since 2007. – Preclinical & clinical research: inflammation/pain; wound healing. – 2 herb-based patents (pending): inflammation/pain; wound healing. – Clinical research treatment anxiety, sleep and pain/inflammation. Insomnia • DSM-IV definition of insomnia: – ‘Difficulty in initiating or maintaining sleep or … nonrestorative sleep’ and as ‘causing clinically significant distress or impairment in social, occupational, or other important areas of functioning’. • Chronic insomnia: – Can lead to significant morbidity. • Both from lack of sleep and medications prescribed. Should your practice consider sleep quality • Pain interferes with sleep. – 50% - 88% patients treated for chronic pain (nonmalignant) reported sleep impairment. – Patients with high pain intensity had less sleep time, more delayed sleep onset, and more nighttime wakening than patients with low pain intensity. • Disturbed sleep lowers pain threshold. • Whether sleep disturbance precedes or follows pain onset is unclear. Should your practice consider sleep quality • Chronic pain: – Pain initiates and exacerbates sleep disturbance. – Disturbed sleep maintains and exacerbates chronic pain and related dysfunction. • Sleep disruption, fragmentation, or restriction produces hyperalgesia (increased sensitivity to pain) and can interfere with analgesic treatments involving opiodergic and serotonergic mechanisms of action. Vicious cycle! Poor sleep Sleep disruption Increases pain sensitivity Increased pain Should your practice consider sleep quality • REM sleep deprivation results in hyperalgesia during the subsequent awake period. • Nonrestorative sleep occurs in 73% to 76% of fibromyalgia patients. • Presence of restorative sleep in patients with fibromyalgia predicted resolution of pain at 15 months. SLEEP AID MEDICATION -Worried about addiction? -Do not tolerate the sleep-anxiety meds? -Concerned about long-term safety? -Patient wants a natural treatment. TRUE or FALSE? Botanical medicines are as efficacious as prescription drugs in the management of insomnia & anxiety. A Sedative effect: True or False? • 170 mg/lb (375 mg/kg) extract Passiflora incarnata (5:1 PE) has anxiolytic effect equivalent to 0.68 mg/lb (1.5 mg/kg) diazepam. • Dose of 375 mg/kg of Passiflora extract in mice converted to Human Equivalent Dose (HED) using body surface area = • • 375 mg / kg X 5:1 = 852 mg/lb (1875 mg/kg) dried herb. HED = 1875 mg /12.3 (conversion factor) = 69 mg/lb (152.4 mg/kg) HED. • 152.4 mg/kg X 70 kg (154 lb) subject = 10.7 grams dried herb. • Human Equivalent Dose of diazepam = 8.4 mg for 154 lb (70 kg) subject. © Guy-Chamberland-MasterHerbalist A Sedative effect: True or False? Benzodiazepines are generally started at a low dose and titrated up as needed based on response: • Clonazepam: started at 0.25 to 0.5 mg 1or 2 daily and titrated up to 1 mg 2 or 3 times daily as needed. • Diazepam: started at 2.5 to 5 mg orally 1 or 2 daily and titrated up to 10 mg 2 or 3 times daily as needed. • Lorazepam: a benzodiazepine with an intermediate onset of action and shorter half-life, can be started at 0.5 to 1 mg orally three times daily and titrated up to 1.5 mg four times daily as needed. Rx Information from www.uptodate.com Passion flower – Tea Bag Average herbal tea: 1-1.5 grams per bag of dried herb top. Would take a tea made with several bags!!! 375 mg / kg Passiflora incarnata extract (5:1 PE) had anxiolytic effect comparable to 1.5 mg / kg diazepam. Dose of 375 mg / kg in mice of an extract of Passion flower converted into human equivalent dose (HED) using body surface area = • 375 mg/kg X 5:1 ratio = 852 mg dried herb/lb (1875 mg/kg). • HED = 1875 mg / 12.3 conversion factor = 69 mg/lb (152.4 mg/kg) HED. • 152.4 mg/kg X 154 lb (70 Kg) subject = 10.7 grams of dried herb (4 doses of the above blend). Human Equivalent Dose of diazepam = 8.4 mg for 154 lb (70 kg) BW. © Guy-Chamberland-MasterHerbalist A Sedative Effect: True or False? • Based on animal data = TRUE! • Caveat: A question of dose level. Not surprising since Drugs mimic herb activities (pharmacology!!!). Tranquilizer Effect: True or False? • Clinical trial in human patients with Generalized Anxiety Disorder. • Double blind • Oxazepam active control Tranquilizer < Sedative < Hypnotic Tranquilizer Effect: True or False? Study Design: Passiflora extract + placebo vs Oxazepam (30 mg/day)+ Passiflora. 36 patients (non-hospitalized). Diagnosed with GAD based on DSM IV. 4-week treatment. Oxazepam (Serax): Anxiety, mild-to-moderate: 10-15 mg 3-4 times daily. Anxiety, severe: 15-30 mg 3-4 times daily. Tranquilizer Effect: True or False? • Both treatments were equally effective. • No significant difference. • Oxazepam group had more rapid onset • Oxazepam group had negative impact on job performance • Passiflora group had negligible impact on job performance Tranquilizer Effect: True or False? • Based on human data = TRUE! • Caveat: A question of dose level. Summary – Botanical Medicines • As efficacious as a drug in the treatment of insomnia & anxiety. • Disadvantage: Speed of onset (applies to management of anxiety conditions). • Advantage: Safety. • • • • No amnesia. No negative effect on cognition or motor coordindation. No addiction. No rebound. Botanical Medicines • Should be used as a First Line in mild-to-moderate conditions • Safety! • Emergency situations – standard of care unless non-tolerated. • Keep in mind delay to onset! Review of the importance of pharmacokinetics on clinical outcome. • Sedative • Hypnotic Dose dependent Affinity-time spent on receptor • Tranquilizer Evidence Behind an Effective Botanical-Based Treatment? ANXIETY SLEEP Choice of herb Dose √ √ √ √ Frequency √ X Absorption of Active Ingredient Plasma concentration intravenous Oral absorption: acid hydrolysis (enteric coating: protection of active ingredient) Cmax Tmax X Hypnosis No Hypnosis Low bioavailability of active ingredients. 24 hour period Oral dosing © Guy-Chamberland-MasterHerbalist Pharmacokinetics: Dosing Interval Efficacy dependent on plasma concentration Plasma concentration Cmax Tmax Duration of response: 4-6 hours T1/2 = 5.6 hrs Plasma half-life Tmax = 1.3-2.5 hrs Analgesic / Anxiolytic effect No Analgesic / Anxiolytic effect Cmin 24 hour period Oral dosing © Guy-Chamberland-MasterHerbalist Dosing Frequency/Interval Dependent on Plasma Half-life Plasma concentration Cmax Analgesia Cmin No Analgesia Optimize dosing interval to avoid periods of no efficacy 24 hour period Oral dosing © Guy-Chamberland-MasterHerbalist Side Effects Dependent on Plasma Concentration Plasma concentration Cmax Intolerable AE Efficacy No Efficacy Cmin 24 hour period Oral dosing © Guy-Chamberland-MasterHerbalist Accumulation & Side Effects Plasma concentration Half-life ranges from 24-36 hours for hypericin Cmax Intolerable AE Efficacy No efficacy Cmin 24 hour period Oral dosing © Guy-Chamberland-MasterHerbalist Minimal Effective Dose 2 g California poppy – sedation 4 g Scullcap - sedation ↑Sedation Minimal effective dose Maximal effective dose ↑ Plasma Concentration of active ingredient(s) © Guy-Chamberland-MasterHerbalist Are there herbs that allow us to develop a botanical medicine that is similar in potency to a prescription drug? Evidence behind an effective Botanical-based treatment? ANXIETY SLEEP Choice of herb √ √ Dose √ √ Frequency √ X • Sedative • Hypnotic Dose dependent Affinity-time spent on receptor • Tranquilizer Herbs: Sedative or Hypnotic • Many clinical trials. • Main problems: • Studies performed with combination of 2 herbs. • ‘Traditional recipe’ and not a drug development concept. • Dose is critical for efficacy. • Herbs used according to their pharmacology: • mu1, benzodiazepine, serotonine. • Activity = ‘atypical’ • eg., mu1 + 5-HT1 / 5-HT7 ou 5-HT1 + GABA-A Herbs – Sedative or Hypnotic Lemon balm (Melissa officinalis) Passionflower (Passiflora incarnata) Valerian (Valeriana officinalis L.) Scullcap (Scutellaria lateriflora) Hops (Humulus lupulus) California poppy (Eschscholzia californica) Sedative - typical Sedative - atypical Hypnotic - typical Hypnotic - atypical Allows to fall asleep & remain asleep. Improves quality of sleep. Botanics: Targets and Therapy 2012:2 21–39 Passionflower (Passiflora incarnata) • Anti-anxiety effect demonstrated using benzodiazepine receptor antagonist. • GABA-mediated anxiolytic activity; Sedation and potentiate pentobarbital-induced sleep (animal model). • Beware: Strong additive effect with drugs!!! Clinical trials: • See table. Natural Standard: • 0.5-2g of dried passion flower has been used 3-4 times daily. • No single herb study to support sleep quality indication. Many combo with 1 other herb. Study Design Double-blind, Randomized, Placebo controlled 14 days, Double-blind, Randomized Pilot, Randomized, Double-blind controlled oxazepam Subjects • 60 patients randomized into two groups to receive either oral Passiflora incarnata (500 mg extract) (n = 30) or placebo (n = 30) as premedication 90 min before surgery. • Healthy volunteers. • Clonidine + passiflora extract versus Clonidine + placebo: 65 opiate addicts-detox. • All patients met DSM-IV criteria for opioid dependence. • Treatment of GAD: passionflower extract + placebo vs Oxazepam + passionflower. • 36 outpatients diagnosed with GAD using DSM IV criteria. Herbs: • Passiflora incarnata or placebo as premedication 90 min before surgery. • Daily dose was 60 drops of passionflower extract and a maximum daily dose of 0.8 mg of clonidine administered in three divided doses. • The patients were randomized: 18 patients Passiflora extract + placebo and 18 patients Passiflora + oxazepam 30 mg / day; trial 4 weeks. Results: • • Both were equally effective in the treatment of the physical symptoms of withdrawal. • Passionflower + clonidine showed significant superiority over clonidine alone in the management of mental symptoms • Both treatments were effective (no significant difference). • Oxazepam showed a rapid onset of action, impairment of job performance. • Passionflower extract was effective for GAD; low incidence of impairment of job performance. Akhondzadeh et al. J Clin Pharm Ther. 2001; 26(5):369-373 Akhondzadeh et al. J Clin Pharm Ther 2001 Oct;26(5):363-7. • Reference: NRS anxiety scores were significantly lower in the passionflower group than in the control group (P <0.001). As premedication reduces anxiety without causing sedation. Movafegh et al. Anesth Analg. 2008 Jun;106(6):1728-32. Summary – Passionflower • As efficacious as a drug in the treatment of anxiety. • Clinical evidence in combo for sleep. • Speed of onset. Important in severity of condition! • • • • Achieved reduction anxiety without sedation. Was effective for GAD. Low incidence of impairment of job performance. Reduced physical symptoms of withdrawal syndromes. No addiction. No rebound. • • Lemon balm (Melissa officinalis) • Binds GABA-A receptor & Inhibits GABA transaminase. • Dose-dependent sedation, inducing sleep & potentiating subhypnotic and hypnotic doses of pentobarbital (animal model). • Beware: Strong additive effect with drugs!!! Clinical trials: • See table. Natural Standard: 1.5-4.5 g herb doses several times a day. • Human evidence supports anxiety. • No single herb study for sleep quality indication. Study Design Randomized, double blind, placebo controlled, crossover study Subjects • Test the stress-relieving • Assess the effects of Melissa effects of lemon balm officinalis on cognitive extract in healthy subjects function and mood (N=20) (N=18). • Children's' anxious behaviors during dental examination (N=90). • Children aged 6-7 years with a dental anxiety diagnosis. Herbs: • Two separate doses (300mg and 600mg) of standardized lemon balm extract (or placebo) on two separate days. After 7-day washout period, subjects crossed over to alternate treatment. • Six capsules containing a total of 300mg, 600mg, or 900mg of M. officinalis extract or a placebo equivalent beginning one hour before testing sessions began. • 1-week washout period, crossed over to other study arms. • 1.36 mg/lb (3mg/kg) dose lemon balm ethanol extract; 2.73 mg/lb (6mg/kg) dose ethanol extract; or placebo. • Outcome measures were assessed 30 minutes after treatment. Results: • • Significant effect on accuracy of attention tasks (p=0.001) but lacked a significant effect on the speed of attention. • Significant effect on the quality of memory (p=0.003), secondary memory factor (p=0.04), working memory (p=0.01), but significant effect on speed of memory was lacking. • Significant effect on alertness ( p<0.002) and calmness (p<0.002), but lacked significant effect on contentment. • Significant between-group difference in dental examination behavior (p=0.002). • High-dose was significantly different from both placebo (p=0.008) and low-dose (p=0.017); however, a difference between the low dose and placebo group was lacking (p=0.759). Kennedy et al. Pharmacol.Biochem.Behav. 2002;72(4):953-964. PARDO-ALDAVE et al. International Journal of Paediatric Dentistry 2009;19(1):66-170 • Reference: The 600mg dose significantly increase selfratings of calmness and reduce self-ratings of alertness. The 300mg dose increased speed in a mathematical test lacking an effect on accuracy. Kennedy et al. Psychosom.Med 2004;66(4):607-613. Randomized, double-blind, placebo controlled balanced crossover study Randomized, double-blind, placebo controlled trial Summary – Lemon balm • As efficacious as a drug in the treatment of anxiety. • Clinical evidence in combo for sleep. • Speed of onset. Important in severity of condition! • Achieved reduction sedation. • No addiction. • No rebound. anxiety without Skullcap (Scutellaria lateriflora) Its mechanism of action is not yet fully elucidated however the pharmacology of several of the active ingredients have been studied. The flavonoids baicalein and scutellarein bind to GABA-A benzodiazepine receptor sites and cross the blood brain barrier (Liao et al. 1998; Hui et al. 2000; Barceloux 2008). Other pharmacological studies have described binding/inhibits to the serotonin receptor 5-HT(7) (Gafner et al. 2003). Liao J.F., Wang H.H., Chen M.C., Chen C.C. & Chen C.F. (1998) Benzodiazepine binding site-interactive flavones from Scutellaria baicalensis root. Planta Medica 64, 571-2. Hui K.M., Wang X.H. & Xue H. (2000) Interaction of flavones from the roots of Scutellaria baicalensis with the benzodiazepine site. Planta Medica 66, 91-3. Barceloux D.G. (2008) Medical Toxicology of Natural Substances: Foods, fungi, medicinal herbs, plants, and venomous animals. John Wiley & Sons Inc., Hoboken, N.J. Gafner S, Bergeron C, Batcha LL, Reich J, Arnason JT, Burdette JE, Pezzuto JM, Angerhofer CK. Inhibition of 3H-LSD binding to 5-HT7 receptors by flavonoids from Scutellaria lateriflora. J Nat Prod 2003; 66(4):535-7. Study Design Randomised, crossover study Subjects: • Mood (anxiety states). placebo-controlled Double-blind, placebo-controlled crossover design • 19 healthy volunteers. • N=43 subjects, both males and females. Herbs: • S. lateriflora (capsule with 350 mg of dried herb) or placebo three times daily (6 hour interval). • Placebo (2 capsules), 350-mg capsule freeze-dried skullcap, 100-mg capsule skullcap extract prepared, 2 capsules of 100 mg skullcap extract. Results: -Reduces symptoms of anxiety and enhances mood in some individuals - Reduction in anxiety scores on Beck Anxiety Inventory (BAI) and Tension-Anxiety (T-A) scores in healthy volunteers. - Skullcap had significant anxiolytic and mood enhancing effects in some people. -There were no adverse reactions or sideeffects. -There were no rebound reactions such as tolerance, dependability or excitability. • A clear anxiolytic property with consistency for all 19 subjects for all 3 versus placebo. • No adverse reaction to the skullcap. • Impact on energy and cognition was mild. • A diminution of perceived anxiety without major impairment of intellect or vitality. • With increase in dosage —the 2 versus the single capsule—there was a notable impact on cognition ratings, suggesting a greater degree of sedation at the higher dose. • Duration of action: - Dose dependent - Mild anxiolytic at 2 hrs. Reference: American Skullcap (Scutellaria lateriflora L): a study of its effects on mood in healthy volunteers. Christine A. Brock, Ph.D., Medical Herbalist Wolfson et Hoffmann. Alternative Therapies in Health and Medicine 2003 Mar-Apr;9(2):74-8 Summary – Skullcap • As efficacious as a drug in the treatment of anxiety. • Speed of onset. condition! • Achieved reduction anxiety without sedation. Important in severity of • Was effective for GAD. • Low incidence of impairment performance. • • No addiction. No rebound. of job California poppy (Eschscholzia californica) Historical Use: • Relaxing nervine in anxiety and nervousness • Sedative in insomnia; and • Anodyne in pain. • A more recent usage is in the treatment of heroin addiction and withdrawal. Although remedies such as Opium Poppy are of great use as an anodyne and analgesic, Felter and Lloyd considered Eschscholzia to be an “…analgesic and soporific without the dangers attending opiates, quieting pain and producing (a) calm sleep” (1893). California poppy (Eschscholzia californica) • Pharmacologic Class: – Opioid & 5-HT1A + 5-HT7 – Analgesic + Hypnotic/sedative • Key clinical advantage: – Safety profile: • No addiction/physical dependence • High tolerability versus conventional narcotics. • 3 key alkaloids: – At least 0.8% Isoquinoline alkaloids: • Californidine • Escholtzine • Protopine Pharmacology - 5:1 extract of California poppy - mice • Sedative activity at 200 mg/kg in mice – 200 mg/kg X 5:1 extract ratio = 1000 mg dried herb per kg. – Conversion to Human Equivalent Dose: • 1000 mg/kg / 12.3 = 37 mg/lb (81.3 mg/kg). • For a 154 lb (70 kg) subject = • 5.7 grams of dried herb (1200 mg extract (5:1)). – partly antagonized by flumazenil. • Equivalent to 2 capsules of a 500 mg standardized extract. © Guy-Chamberland-MasterHerbalist Pharmacology - 5:1 extract of California poppy - mice • Sedative activity at 90.9 mg/lb (200 mg/kg) in mice – 200 mg/kg X 5:1 extract ratio = 1000 mg dried herb per kg. – Conversion to Human Equivalent Dose: 1000 mg/kg / 12.3 = 37 mg/lb (81.3 mg/kg). – For a 154 lb (70 kg) subject: • 5.7 grams of dried herb (1140 mg extract (5:1)). • Anxiolytic effect demonstrated at 11.4 mg/lb (25 mg/kg) (125 mg dried herb per kg). – For a 154 lb (70 kg) subject: • 0.7 grams of dried herb (142 mg extract (5:1)). • Use of a 500 mg 5:1 standardized PE: – 1 capsule too strong to be used as a calmative! • 8-fold stronger than dose tested. © Guy-Chamberland-MasterHerbalist Pharmacology - 5:1 extract of California poppy - mice • Antidepressant: No effect against reserpine*-induced ptosis, akinesia or hypothermia, when it was tested at 22.7, 45.5, 90.9, 181.8 and 363.6 mg/lb (50, 100, 200, 400, 800 mg/kg). – For a 154 lb – 90.9 mg/lb (70 kg subject - 200 mg/kg): • 5.7 grams of dried herb (1140 mg extract (5:1)). – For a 154 lb – 363.6 mg/lb subject (70 kg - 800 mg/kg): • 22.8 grams of dried herb (4553 mg extract (5:1)). NO ANTIDEPRESSANT-LIKE EFFECT. Explains in part the good tolerability in patients versus meds! *Reserpine irreversibly blocks the vesicular monoamine transporter. This normally transports free intracellular norepinephrine, serotonin, and dopamine in the presynaptic nerve terminal into presynaptic vesicles for subsequent release into the synaptic cleft. © Guy-Chamberland-MasterHerbalist California poppy (Eschscholzia californica) • Pharmacological properties demonstrated: – Dose-response effect observed for analgesia. – Opioid & 5-HT1A & 5-HT7 serotonin activity. – Dose-dependent sedative & anxiolytic properties. – No antihistaminic effects. – No anticonvulsant or myorelaxant effects. – No anticholinergic effects. – No muscle relaxant and antipsychotic properties. – No antidepressant-like properties. Study Pilot study; 7-day acute Pilot study; 28-day chronic pain pain Proof-of-concept; multicentre; open-label Subjects: • 10 patients • • Patients with acute pain • (VAS > 4) • No drug therapy • 10 patients • Patients with chronic pain • (VAS > 4) No drug therapy • 20 patients Uncontrolled, moderate-severe, chronic pain Fibromyalgia with/without myofascial syndrome • Arthritis • NSLBP • Neuropathic pain Herbs: • California poppy (1 at night) • Devil’s claw (tid) • Scullcap (tid) • • • • California poppy (1 at night) Devil’s claw (tid) Scullcap (tid) Gel Results: • • • • • Improved sleep Significantly reduced pain Significant mobility & flexibility swelling tenderness stiffness • • Reference: Improved sleep Significantly reduced pain swelling tenderness Chamberland G. unpublished • • • Chamberland G. unpublished © Guy-Chamberland-MasterHerbalist • • • • California poppy (1 or 2 daily) Concomitant pain meds. Short form McGill Pain Scale Sleep questionnaire • Approximately 50% patient obtained a significant clinical benefit in pain relief or sleep. • Delta-VAS: 2.4 (VAS <1.0 = failure) • Improved sleep (night pain): 67% • Improved sleep (all): 45% • Significant improvement pain: 55% Chamberland G. unpublished Summary – California poppy • Induces sleep at correct dosage. • Clinical evidence effective treatment night pain. • • • • No impact on cognition. No impact on motor incoordination. No addiction. No rebound. Recommended & Current Uses California poppy (Eschscholzia californica) • Night Pain: – – – – 1 or 2 capsules at night. Analgesic & Hypnotic. Better sleep quality. Reduced doses of morphine at night. • Co-analgesic (Adjuvant): – 1 capsule bid (off-label use by physicians). – Patients intolerant to meds such as Lyrica and/or Cymbalta. • Reduce doses of other pain meds. • Insomnia: – 1 or 2 capsules 30 minutes before bedtime. – Sedative & Hypnotic. *capsule = 500 mg extract (dried herb top, 0.8% standardized, 5:1 PE) Current Clinical Research California poppy (Eschscholzia californica) • Focus is on Night Pain • Rationale: – It induces fantastic dreams on 30-40% of occaisons used. – Patients reported ‘restorative’ sleep. • Hypothesis: – Treatment with California poppy will favor restorative sleep in patients with chronic pain. – Will favor quality of life in patients. – Superior healing due to restorative sleep. *capsule = 500 mg extract (dried herb top, 0.8% standardized, 5:1 PE) Hops (Humulus lupulus) • Sedative & hypnotic effects; • Dose-dependent reduction of locomotor activity and increase in narcotic-induced sleep duration (animal model). • Activity similar to Methylpentynol (ingredients similar activity). • Beware: Strong additive effect with drugs!!! Hops (Humulus lupulus) Clinical trials: • • • Mainly combos. Improved sleep latency and quality of sleep. Anxiolytic, Sedative & Hypnotic effects. • Using quantitative topographical EEG: • increase in delta-, decrease in alpha-, and a weak decrease in beta-power. • Acted via a central adenosine mechanism, which is possibly the reason for its sleep-inducing and sleepmaintaining activity. • Possibly reduce alertness. Herbs – Insomnia - Valerian • Clinical Studies in humans with valerian: – Did not have a negative impact on reaction time, alertness & concentration morning after – Overall evidence supports that valerian is safe but does not support efficacy of valerian as sleep aid for insomnia • Valerian contains valerenic acid: – Interacts with the GABA(A)-ergic system, a mechanism of action similar to the benzodiazepine drugs – Valerian clinical trial: C(max) and AUC decreased and T(1/2) increased with increased body weight. – Human trial: Large variability in pharmacokinetics valerenic acid. Explain inconsistent effect of valerian as sleep aid • Up to maximum dosages of 227 mg/lb (500 mg/kg) or 455 mg/lb (1000 mg/kg) BW none of the valerian extracts displayed sedative effects. • Anxiolytic and antidepressant activity of valerian demonstrated Designing an Effective Treatment ANXIETY SLEEP Choice of herb √ √ Dose √ √ Frequency √ X Why use Lemon balm + Passion flower • Established combined use in traditional medicine. • Health Canada recognizes that these herbs are effective at adequate doses to help relieve nervousness, as a sleep aid for cases of restlessness or nervousness, or for insomnia due to mental stress. • According to Health Canada, these herbs are considered safe for use in adults and adolescents 13 years and older. • Sleep: Trials were randomized & placebo controlled & combination of 1 or 2 herbs. • Several trials in humans demonstrated the use of Lemon balm for treating anxiety and insomnia. • Several double-blind clinical studies showed the benefits of Passion flower for treating restlessness or anxiety. Why use Lemon balm + Passion flower BASE DOSE: extract equivalent to 2.8 grams dried herb top Lemon balm (Melissa officinalis) and 2.4 grams dried herb top Passion flower (Passiflora incarnata). 170 mg/lb (375 mg/kg) extract Passiflora incarnata (5:1 PE) has anxiolytic effect equivalent to 0.68 mg/lb (1.5 mg/kg) diazepam. • Dose of 375 mg/kg of Passiflora extract in mice converted to Human Equivalent Dose (HED) using body surface area = • 375 mg / kg X 5:1 = 852 mg/lb (1875 mg/kg) dried herb. • HED = 1875 mg /12.3 (conversion factor) = 69 mg/lb (152.4 mg/kg) HED. • 152.4 mg/kg X 70 kg (154 lb) subject = 10.7 grams dried herb. • Human Equivalent Dose of diazepam = 8.4 mg for 154 lb (70 kg) subject. © Guy-Chamberland-MasterHerbalist Why Use Lemon balm + Passion flower Average herbal tea: 1-1.5 grams per bag of dried herb top. Would take a tea made with several bags!!! • 170 mg/lb (375 mg/kg) extract Passiflora incarnata (5:1 PE) has anxiolytic effect equivalent to 0.68 mg/lb (1.5 mg/kg) diazepam. • Dose of 375 mg/kg of Passiflora extract in mice converted to Human Equivalent Dose (HED) using body surface area = • 375 mg / kg X 5:1 = 852 mg/lb (1875 mg/kg) dried herb. • HED = 1875 mg /12.3 (conversion factor) = 69 mg/lb (152.4 mg/kg) HED. • 152.4 mg/kg X 70 kg (154 lb) subject = 10.7 grams dried herb. • Human Equivalent Dose of diazepam = 8.4 mg for 154 lb (70 kg) subject. © Guy-Chamberland-MasterHerbalist http://www.uptodate.com 1 capsule (1 Base Dose) of blend of herbs is equivalent to 3.3 mg Diazepam Diazepam dosing for anxiety: 2 to 10 mg 2-4 times daily if needed. 1 capsule with Base Dose every 4-6 hours as needed. © Guy-Chamberland-MasterHerbalist Treating Anxiety • Example using Lemon balm + Passion flower: – 2.8 grams dried herb top Lemon balm + 2.4 grams dried herb top Passion flower = 50% additive activity / intake. Doses below will cause too much sedation (be careful not to give hypnotic dose!): 5.6 grams Dried Herb Equivalent (DHE) Lemon balm + 4.8 grams DHE Passion flower = 75% additive activity/intake. Safe Daily Dose: 13.5 g/day DHE Lemon balm 8 g/day DHE Passion flower © Guy-Chamberland-MasterHerbalist Treating Anxiety - Scullcap • Scutellaria lateriflora – dried herb top – All very safe if on a as needed basis. • 2 grams DHE = 17% - mild symptoms of anxiety • 4 grams DHE = 33% - moderate symptoms of anxiety • 6 grams DHE = 50% - severe symptoms of anxiety • Dosing: Balance drowsiness - tranquilization versus anxiety. • Prescribe every 4 to 6 hours, as needed. If taken 3 times a day: • 2 g DHE = 51% additive • 4 g DHE = 99% additive • 6 g DHE = 150% additive – When just treating anxiety, regimen is very safe if no contraindications. © Guy-Chamberland-MasterHerbalist Treating Anxiety Better dose range between tranquilization dose and hypnotic effect than with Passionflower + Lemon balm. © Guy-Chamberland-MasterHerbalist Pharmacokinetics: Time-to-Cmax (Tmax) Plasma concentration Start of PANIC attack. Consider delay to Cmax. Cmax Tmax Tmax = 1.3-2.5 hrs Cmin 24 hour period Oral dosing © Guy-Chamberland-MasterHerbalist Botanical Medicines - Anxiety • Should be used as a First Line in mild-to-moderate conditions: • Safety! • Emergency situations – standard of care unless non-tolerated. • Keep in mind delay to onset! Botanical Medicines - Insomnia • Always implement: • Good sleep hygiene • A SCT therapy Botanical Medicines - Insomnia • To avoid addiction to meds, physicians try to have patient take drugs only several times a week. • With herbs, no addiction problem but try to cycle use to avoid tolerance. Sleep Hygiene • Avoid caffeine, alcohol, nicotine • No large meals close to bedtime • No clock watching • A quiet, dark and comfortable sleep environment • Winding down for 1-2 hours before bedtime • Maintain a sleep routine: bed and wake time Stimulus Control Therapy • To reduce the state of arousal at night and emphasize that the bed is for sleep. – 1. Lie down to sleep ONLY when sleepy. – 2. Do not use bed for anything except sleep, sex, and sickness. – 3. If unable to fall asleep for ≥ 10 minutes, get up and go into another room and return to bed when sleepy. AVOID CHECKING THE CLOCK. – 4. Repeat step 3 as often as necessary throughout the night. – 5. Set alarm and get up at the same time every morning, respective of how much sleep was achieved at night. – 6. Do not nap during the day. Treating Insomnia (anxiety-associated) • Example using Lemon balm + Passion flower: – 2.8 grams dried herb top Lemon balm + 2.4 grams dried herb top Passion flower = 50% additive activity/intake. Mild insomnia – 5.6 grams DHE Lemon balm + 4.8 grams DHE Passion flower = 75% additive activity/intake. Moderate insomnia – 5.6 grams DHE Lemon balm + 4.8 grams DHE Passion flower (75% Additive) + 4 grams DHE Scullcap (33% Additive) = 108% additive activity/intake. Severe insomnia Safe Daily Dose: 13.5 g/day DHE Lemon balm 8 g/day DHE Passion flower © Guy-Chamberland-MasterHerbalist California poppy (Eschscholzia californica) • Night Pain: – 1 or 2 capsules at night. – Analgesic & Hypnotic. – Better sleep quality. • Insomnia: – 1 or 2 capsules 30 minutes before bedtime. – Sedative & Hypnotic. *capsule = 500 mg extract (dried herb top, 0.8% standardized, 5:1 PE) Treating Insomnia - Scullcap • Scutellaria lateriflora – dried herb top • 2 grams DHE = 17% - tranquilizer • 4 grams DHE = 33% - tranquilizer, sedative dose in some • 6 grams DHE = 50% - sedative, hypnotic dose in some © Guy-Chamberland-MasterHerbalist Safety Comparison • Common with all hypnotics (benzodiazepines et nonbenzodiazepines): – Residual sedation , drowsiness, dizziness, vertigo, cognitive impairment, motor incoordination, dependence. • Herbs: fantastic dreams (remembering dreams). • Long-term use: – Dependence; rebound insomnia. – Herbs: No physical or pharmacological dependence. No rebound observed. • Nonbenzodiazepines - AE similar to those of benzodiazepines, but their frequency and severity is less. – Associated with their shorter half-life. – Herbs: shorter half-life could partially explain the safety profile, but also because of the atypical pharmacology. Case Study #1 – Insomnia 43 year old female with insomnia (inability to fall asleep) due to over-thinking. Patient falls asleep very late and sleeps only a few hours; wakes up for work. Tried Imovane and Rivotril. On the combo she wakes up for work (6:30 am) but is still very tired and has difficulty being functional. Takes medication after not being able to fall asleep; around midnight. Claims not to be dependent on drugs. Initial intervention: - 1 to 2 Base Doses of Lemon balm + Passion flower 30 minutes before bedtime. Base Dose = 2.8 g DHE Lemon balm + 2.4 g DHE Passion flower. - Explain to patient need for relaxing before bedtime; making sure room dark with no small lights from a DVD player or television; etc. - If wake up around 2 or 4 am, take 1 Base Dose of Lemon balm+ Passion flower. Case Study #2 – Anxiety 47 year old female with anxiety and insomnia; inability to fall asleep due to the anxiety. Patient’s work environment creates the anxiety. Patient does not want to take Ativan because of fear of becoming dependent but has daily episodes of high anxiety. Initial intervention: - 2 g DHE tablet of Scutellaria lateriflora every 4 to 6 hours as needed (17% Additive Intake per tablet). - Episodes of strong anxiety: 4 g DHE. Important to explain ‘feeling’ of tranquilizing effect to patient. - Sleep critical: 1 Base Dose of Lemon balm + Passion flower (50% Additive Intake). 30 minutes before bedtime. energy & resistance. - Increase resistance to anxiety – supplements: patient did not respond to Ayurvedic remedies.