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.

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?

• 375 mg/kg extract Passiflora incarnata (5:1 PE) has anxiolytic effect equivalent to 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 = 1875 mg/kg dried herb.

• HED = 1875 mg /12.3 (conversion factor) = 152.4 mg/kg HED. • 152.4 mg/kg X 70 kg subject = 10.7 grams dried herb equivalence. • Human Equivalent Dose of diazepam = 8.4 mg for a 70 kg subject.

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 = 1875 mg dried herb/kg. • HED = 1875 mg / 12.3 conversion fa ctor = 152.4 mg/kg HED. • 152.4 mg/kg X 70 Kg subject = 10.7 grams of dried herb equivalent (4 doses of the above blend). Human Equivalent Dose of diazepam = 8.4 mg for 70 kg BW.

• 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 . • Tranquilizer spentreceptoron Affinity-time Dose dependent Dose

• Sedative

• Hypnotic Evidence Behind an Effective Botanical-Based Treatment?

ANXIETY SLEEP Choice of herb √ √

Dose √ √ Frequency √ X Absorption of Active Ingredient Oral absorption: acid hydrolysis Plasma concentration (enteric coating: protection of active ingredient)

intravenous 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 Duration of response: 4-6 hours T1/2 = 5.6 hrs Cmax Plasma half-life Tmax

Tmax = 1.3-2.5 hrs Analgesic / Anxiolytic effect

No Analgesic / Cmin Anxiolytic effect

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

Cmin No Efficacy

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

Cmin No efficacy

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 • Tranquilizer spentreceptoron Affinity-time Dose dependent Dose

• Sedative

• Hypnotic 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 ) Sedative - typical Valerian ( Valeriana officinalis L.) Scullcap (Scutellaria lateriflora ) Sedative - atypical Hops ( Humulus lupulus ) Hypnotic - typical California poppy ( Eschscholzia californica ) 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 Double-blind, Randomized, 14 days, Double-blind, Pilot, Randomized, Double-blind Design Placebo controlled Randomized controlled oxazepam Subjects • 60 patients randomized into • Clonidine + passiflora extract • Treatment of GAD: passionflower two groups to receive either versus Clonidine + placebo: 65 extract + placebo vs Oxazepam + oral Passiflora incarnata opiate addicts-detox. passionflower. (500 mg extract) (n = 30) or • All patients met DSM-IV • 36 outpatients diagnosed with placebo (n = 30) as criteria for opioid GAD using DSM IV criteria. premedication 90 min dependence. before surgery. • Healthy volunteers.

Herbs: • Passiflora incarnata or • Daily dose was 60 drops of • The patients were randomized: 18 placebo as premedication passionflower extract and a patients Passiflora extract + 90 min before surgery. maximum daily dose of 0.8 placebo and 18 patients Passiflora mg of clonidine administered + oxazepam 30 mg / day; trial 4 in three divided doses. weeks.

Results: • NRS anxiety scores were • Both were equally effective in • Both treatments were effective significantly lower in the the treatment of the physical (no significant difference). passionflower group symptoms of withdrawal. • Oxazepam showed a rapid onset than in the control group • Passionflower + clonidine of action, impairment of job (P <0.001). showed significant superiority performance. • As premedication over clonidine alone in the • Passionflower extract was reduces anxiety without management of mental effective for GAD; low incidence causing sedation. symptoms of impairment of job performance.

Reference: Movafegh et al. Anesth Analg. 2008 Akhondzadeh et al. J Clin Pharm Ther. Akhondzadeh et al. J Clin Pharm Ther 2001 Jun;106(6):1728-32. 2001; 26(5):369-373 Oct;26(5):363-7. 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 Randomized, double blind, Randomized, double-blind, Randomized, double-blind, placebo Design placebo controlled, crossover placebo controlled balanced controlled trial study crossover study Subjects • Test the stress-relieving • Assess the effects of Melissa • Children's' anxious behaviors during effects of lemon balm officinalis on cognitive dental examination (N=90). extract in healthy subjects function and mood (N=20) • Children aged 6-7 years with a (N=18). dental anxiety diagnosis.

Herbs: • Two separate doses (300mg • Six capsules containing a total of • 3mg/kg dose lemon balm ethanol and 600mg) of standardized 300mg, 600mg, or 900mg of M. extract; 6mg/kg dose ethanol lemon balm extract (or officinalis extract or a placebo extract; or placebo. placebo) on two separate equivalent beginning one hour • Outcome measures were assessed days. After 7-day washout before testing sessions began. 30 minutes after treatment. period, subjects crossed over • 1-week washout period, crossed to alternate treatment. over to other study arms.

Results: • The 600mg dose • Significant effect on accuracy of • Significant between-group significantly increase self- attention tasks (p=0.001) but lacked a difference in dental examination ratings of calmness and significant effect on the speed of behavior (p=0.002). attention. reduce self-ratings of • Significant effect on the quality of • High-dose was significantly different alertness. memory (p=0.003), secondary from both placebo (p=0.008) and • The 300mg dose increased memory factor (p=0.04), working low-dose (p=0.017); however, a speed in a mathematical memory (p=0.01), but significant difference between the low dose test lacking an effect on effect on speed of memory was and placebo group was lacking accuracy. lacking. (p=0.759). • Significant effect on alertness ( p<0.002) and calmness (p<0.002), but lacked significant effect on contentment. Reference: Kennedy et al. Psychosom.Med Kennedy et al. Pharmacol.Biochem.Behav. PARDO-ALDAVE et al. International Journal of 2004;66(4):607-613. 2002;72(4):953-964. Paediatric Dentistry 2009;19(1):66-170 Summary – Lemon balm

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, placebo-controlled Double-blind, placebo-controlled crossover design crossover study

Subjects: • Mood (anxiety states). • 19 healthy volunteers. • N=43 subjects, both males and females.

Herbs: • S. lateriflora (capsule with 350 mg of dried • Placebo (2 capsules), 350-mg capsule freeze-dried herb) or placebo three times daily (6 hour skullcap, 100-mg capsule skullcap extract prepared, 2 interval) . capsules of 100 mg skullcap extract.

Results: -Reduces symptoms of anxiety and enhances • A clear anxiolytic property with consistency for all 19 mood in some individuals subjects for all 3 versus placebo. - Reduction in anxiety scores on Beck Anxiety • No adverse reaction to the skullcap. Inventory (BAI) and Tension-Anxiety (T-A) • Impact on energy and cognition was mild. scores in healthy volunteers. • A diminution of perceived anxiety without major -Skullcap had significant anxiolytic and mood impairment of intellect or vitality. enhancing effects in some people. • With increase in dosage —the 2 versus the single -There were no adverse reactions or side- capsule—there was a notable impact on cognition effects. ratings, suggesting a greater degree of sedation at the -There were no rebound reactions such as higher dose. tolerance, dependability or excitability. • Duration of action: - Dose dependent - Mild anxiolytic at 2 hrs.

Reference: American Skullcap (Scutellaria lateriflora L): a study Wolfson et Hoffmann. Alternative Therapies in Health and Medicine of its effects on mood in healthy volunteers. 2003 Mar-Apr;9(2):74-8 Christine A. Brock, Ph.D., Medical Herbalist Summary – Skullcap

• As efficacious as a drug in the treatment of anxiety. • Speed of onset. Important in severity of condition! • Achieved reduction anxiety without sedation. • Was effective for GAD. • Low incidence of impairment of job performance . • No addiction. • No rebound.

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 = 81.3 mg/kg. – For a 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 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 = 81.3 mg/kg. – For a 70 kg subject: 5.7 grams of dried herb (1140 mg extract (5:1)).

• Anxiolytic effect demonstrated at 25 mg/kg (125 mg dried herb per kg). – For a 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 50, 100, 200, 400 and 800 mg/kg. – For a 70 kg subject (200 mg/kg): 5.7 grams of dried herb (1140 mg extract (5:1)). – For a 70 kg subject (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 Proof-of-concept; multicentre; pain pain open-label Subjects: • 10 patients • 10 patients • 20 patients • Patients with acute pain • Patients with chronic pain • Uncontrolled, moderate-severe, (VAS > 4) (VAS > 4) chronic pain • No drug therapy • No drug therapy • Fibromyalgia with/without myofascial syndrome • Arthritis • NSLBP • Neuropathic pain Herbs: • California poppy (1 at • California poppy (1 at night) • California poppy (1 or 2 daily) night) • Devil’s claw (tid) • Concomitant pain meds. • Devil’s claw (tid) • Scullcap (tid) • Short form McGill Pain Scale • Scullcap (tid) • Gel • Sleep questionnaire Results: • Improved sleep • Improved sleep • Approximately 50% patient • Significantly reduced • Significantly reduced pain obtained a significant clinical pain • Significant ↑ mobility & benefit in pain relief or sleep. • ↓ swelling flexibility • Delta-VAS: 2.4 (VAS <1.0 = • ↓ tenderness • ↓ swelling failure) • ↓ tenderness • Improved sleep (night pain): • ↓ stiffness 67% • Improved sleep (all): 45% • Significant improvement pain: 55% Reference: Chamberland G. unpublished Chamberland G. unpublished Chamberland G. unpublished © Guy-Chamberland-MasterHerbalist 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 sleep- maintaining 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 500 or 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).

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 = 1875 mg dried herb/kg. • HED = 1875 mg / 12.3 conversion fa ctor = 152.4 mg/kg HED. • 152.4 mg/kg X 70 Kg subject = 10.7 grams of dried herb equivalent (4 doses of the above blend) . Human Equivalent Dose of diazepam = 8.4 mg for 70 kg BW.

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 = 1875 mg dried herb/kg. • HED = 1875 mg / 12.3 conversion fa ctor = 152.4 mg/kg HED. • 152.4 mg/kg X 70 Kg subject = 10.7 grams of dried herb equivalent (4 doses of the above blend) . Human Equivalent Dose of diazepam = 8.4 mg for 70 kg BW.

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 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

• 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.

Plasma concentration Start of PANIC attack . Consider delay Cmax Tmax to Cmax .

Tmax = 1.3-2.5 hrs

Cmin

• 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 Mild insomnia grams dried herb top Passion flower = 50% additive activity/intake.

– 5.6 grams DHE Lemon balm + 4.8 grams Moderate DHE Passion flower = 75% additive insomnia activity/intake.

– 5.6 grams DHE Lemon balm + 4.8 grams DHE Passion flower (75% Additive) + 4 Severe insomnia grams DHE Scullcap (33% Additive) = 108% additive activity/intake. Safe Daily Dose: 13.5 g/day DHE Lemon balm 8 g/day DHE Passion flower

• 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

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.