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2019 PCB Conference: Strickland

Benzodiazepines (BZDs), Herbal and Alternative Treatments for & Depression BZD Learning Objectives • List at least three uses for • Discuss at least two risk factors associated with prescriptions

Craig Strickland, PhD, Owner Biobehavioral Education and Consultation https://sites.google.com/site/bioedcon

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BZD Pharmacokinetics Clinical Uses of BZDs Generic Name Trade Name Rapidity ½ Life Dose (mg) • Treat a variety of anxiety disorders Xanax Intermediate Short 0.75-4 • • Muscle relaxants chlordiaze- Librium Intermediate Long 15-100 poxide • To produce anterograde amnesia Klonopin Intermediate Long 0.5-4 • & other CNS withdrawal • Anti- therapy Valium Rapid Long 4-40 Halcion Intermediate Very short 0.125-0.5

Restoril Short Short 7.5-30

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1 2019 PCB Conference: Strickland

Issues with BZDs Herbal and Alternative Therapies Used in the Treatment of Depression and Anxiety • Addictive potential • Confusion between “anti-anxiety” effects and the “warm-fuzzy) • Large dose ranges • Comparison of BZDs with like Buspar, etc. • They work, they work well and they work quickly

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Alternative Tx. Learning Objectives Background Information on herbals: Natural does not necessarily mean “safe”

• List several amino acid treatments for depression • Side-effects and adverse reactions • List at least three of the most common herbal – Herbal medications are “” although they treatments used to reduce the symptoms of are considered supplements by the FDA anxiety and depression – These compounds do, for the most part, • List the benefits of vagal nerve stimulation (VNS) act on the CNS for depression • Production of allergic reactions • Describe the relationship between and • Interactions with other and neurogenesis/neuroplasticity with more traditional medications

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2 2019 PCB Conference: Strickland

Background Information on herbals: Background Information on herbals: Natural does not necessarily mean “safe” Natural does not necessarily mean “safe” •Dosing is somewhat more difficult • Because herbals are “supplements”: – % of active ingredients may differ across – Labeling is not regulated manufacturers – Herbal cannot be patented – Herbs are not “pure” • Thus, rigorous testing may or may not be – Variety of administration formulas available • Capsules (regular vs. SR vs. XR) • Data may be missing regarding: • The dried itself – long-term safety • Liquid extract – dose-response curves • Tincture – interactions • Transdermal application

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Some “safe” ways to go re: herbal products Non-Pharmaceutical • Commission E: part of the German Regulatory Authority Approaches to • The Herbal PDR Treating Depression: • Nature’s Way & other companies St. John’s Wort • Vitacost.com • Naturopaths & pharmacists • Peer-reviewed journals • Cross-referencing of sources

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3 2019 PCB Conference: Strickland

Herbal Treatment of Depression: Saint John’s Wort Saint John’s Wort

• Clinical effects: mild anti-depressant – Mechanism of action: MAOI or SSRI • Inhibits of 5-HT, NE, DA • May cause down regulation of 5-HT2 autoreceptors

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Herbal Treatment of Depression: Herbal Treatment of Depression: Saint John’s Wort Saint John’s Wort

• Clinical effects/uses: • Other Clinical effects/uses: –Anxiety – Inflammation of the skin –Depression – Blunt injuries, wounds, burns (has – anti-bacterial properties) –Menopausal mood changes/premenstrual – headaches syndrome • Drug interactions: –OCD – Anti- (especially serotonergic) –Social – Protease inhibitors – Contraceptives 15 16

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4 2019 PCB Conference: Strickland

Herbal Treatment of Depression: Herbal Treatment of Depression: Saint John’s Wort Saint John’s Wort

•Side effects: St. John’s Wort is fairly safe •Therapeutic dose: –Agitation, anxiety, irritability, restlessness –300 mg (3x/day) –Dry mouth – Take 4-6 weeks (trial period) –Dizziness; headache •Cost: $ 4.59/60 300mg tablets (10/2015) –GI discomfort –Hypomania –Fatigue –Abnormal dreams

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Herbal Treatment of Depression: Non-Pharmaceutical (Ginkgo) Approaches to • Not listed in the “herbal PDR” for use as Treating Depression: an anti-depressant Ginkgo Biloba • Clinical effects: mild anti-depressant – Mechanism of action is not fully known – Increase in # of 5-HT receptors • Via increase in synthesis • Via antioxidant mechanism (decrease in free radical activity which damages cell membranes)

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5 2019 PCB Conference: Strickland

Ginkgo and Metabotropic Herbal Treatment of Depression: Mechanism? Ginkgo Biloba (Ginkgo)

•Increase in vascular flow (increases nutrients/O2 to • Increase in receptors, via increase in protein the brain) synthesis, is a metabotropic effect • Works well in persons over 50 years old (5-HT •Decrease in free radical receptors decrease with age) activity may also be such an effect

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Ginkgo Biloba (cont.) Ginkgo Biloba (cont.) • Other indications (Commission E) – Symptomatic relief of organic brain •Side effects: generally a safe herb to use syndrome/Alzheimer’s disease – Increased bleeding time – Intermittent claudication – Mild GI complaints – Vertigo (vascular origin) – BP problems (maybe related to – Tinnitus (vascular origin) reported dizziness/headaches) • Drug interactions – Allergic skin reactions – Can take with traditional anti- – Adverse effects on oocytes depressants (unlike St. John’s Wort) – Anticoagulants/ASA (bleeding time)

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6 2019 PCB Conference: Strickland

Depression: Amino Acid Treatment Non-Pharmaceutical • Amino acids used to treat depression include Approaches to , tyrosine, , and Treating Depression: methionine – Phenylalanine & tyrosine are precursors to DA Amino Acid Treatment (converts to NE) – Tryptophan (and 5-hydroxytrytophan) are precursors to serotonin (5-HT)

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Depression: Amino Acid Treatment

•Methionine gets converted to s-adenosyl-methionine Non-Pharmaceutical (SAM) Approaches to – The extract of this is SAMe (“sammy”) Treating Depression: • SAM increases levels of the monoamines Nutritional supplements • Improves monoamine binding naturally – SAM levels-lower in depressed persons – Side effects include nausea/vomiting • Dose Maximum dose of 400 mg 4x/day to be reached gradually

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7 2019 PCB Conference: Strickland

Depression: Nutritional Supplements Depression: Nutritional Supplements • Other supplements to consider: the “B” vitamins • Eicosapentaenoic acid (EPA) and docosapentaenoic including folic acid, B6 & B12 acid (DHA) : found in fish oils • Iron supplements – Enhances levels of omega-3 fatty acids – Omega-3 levels have been shown to be reduced in • Take note: people with depression – Deficiencies in the levels of these supplements can – Amount to take unclear although 3 grams/day worsen mood (3000mg) is of EPA/DHA not unusual – Thus, such supplements – Side effects: high and increased blood • can decrease depressive symptoms • but will have little effect on depressed people with normal levels of the B vitamins & iron

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Polyvagal Theory, Vagal Nerve The Vagus Nerve Stimulation (VNS) and Trauma & Picture provided by Peter Jurek, MA, MS Depression http://www.peterjurek.com

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8 2019 PCB Conference: Strickland

Polyvagal Theory Polyvagal Theory: Dr. Stephen Porges

• Cortical Control of brainstem • Brainstem regulation of the autonomic nervous system • Autonomic nervous system – Sympathetic nervous system – Parasympathetic nervous • Mammals versus reptiles and vagal evolution (and the freezing response)

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Polyvagal Theory Social Engagement System

• In what clinical conditions might you expect to • Changes in cardiopulmonary function see the freezing response? • Voice quality: prosody – Traumatic exposure – Intonation and tone – Depression – Stress and rhythm – Anxiety diagnoses – Vocalizations in our pets – Other? (my lovely Noelle!) • Eye contact and movement • Facial and head muscles

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9 2019 PCB Conference: Strickland

Polyvagal Theory in Practice: what can we do? What is vagal nerve stimulation (VNS)?

• Explain the roles the different systems play • Note: this is an FDA approved technique (2005) • Educate that what their nervous systems/bodies are for refractory depression; also approved (1997) as doing is based on survival, trying to keep the person adjunctive therapy for partial-onset safe (minimize disappointment, shame or anger • A pulse generator is surgically implanted in the about these biological responses) left chest area under the clavicle • Discuss that interpersonal interactions can change • The leads from the generator are “wrapped” nervous system function around the left vagus nerve branch; the right branch is avoided since it controls some aspects • Minimize “older” circuit activity (next slide) of cardiac function • Intermittent pulses are delivered to the nerve

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How does VNS work? Other uses for VNS? • Exact anti-depressant mechanism unknown • Various anxiety disorders – Stimulation does affect blood flow in various • Alzheimer’s disease regions of the brain • – As a result, activity increases, • Fibromyalgia including 5-HT and NE which would have an anti- depressant affect • Side-effects: alteration of voice quality & loudness (during pulses only), hoarseness, throat pain, dyspnea (shortness of breath) & paresthesia • Enhance social engagement system???

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10 2019 PCB Conference: Strickland

The Biochemistry of Anxiety

Treating Anxiety

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The Biochemistry of Anxiety Anxiety •Traditional treatment of anxiety •Important – Medications/substances acting on the GABA – Gamma-aminobutyric acid (GABA: cortical and complex limbic areas • Alcohol – (sympathetic nervous system) • & non- – Serotonin • Benzodiazepines •Neurohormones: e.g. corticotropic releasing factor (CRF) inhibitors & the hypothalamic pituitary adrenal axis (HPA)

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11 2019 PCB Conference: Strickland

Kava Non-Pharmaceutical Approaches to Treating Anxiety: Kava Kava

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Herbal Treatment of Anxiety: Kava Kava Herbal Treatment of Anxiety: Kava Kava

• Clinical effects: – , anticonvulsive, anti-spasmodic • Drug interactions: – /, , and anti-anxiety – Can potentiate effects of most CNS – Effects are mediated via GABA system depressants – Compare these effects with benzodiazepines – May potentiate St. John’s Wort, • Other clinical effects: & traditional anti-depressants – Antithrombitic, asthmatic, nervous tension, – Antagonizes effects of meds. designed stress and agitation to increase (e.g. L-Dopa)

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Herbal Treatment of Anxiety: Kava Kava (cont.) Herbal Treatment of Anxiety: Kava Kava (cont.)

• Side Effects: dose dependent (occur primarily with • Side Effects (cont.): higher dosages) –Liver damage including: – Yellowing of the skin, hair, nails • Hepatitis – AM tiredness (early in tx. phase) • Liver failure – Minor movement inhibition/impaired motor • Cirrhosis reflexes; dyskinesia –Some European countries have banned the sale – Weight loss (only from high doses over an of Kava Kava extended period –Those at risk for or with known liver disease – Increased risk of suicide in persons with an should not take Kava Kava endogenous depression 50 49

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Herbal Treatment of Anxiety: Kava Kava (cont.) Non-Pharmaceutical •Therapeutic doses: Approaches to – Anxiety: 50-70 mg 3x/day – Insomnia: 150-210 mg kavalactones in a single Treating Anxiety: dose before bed Valerian

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13 2019 PCB Conference: Strickland

Herbal Treatment of Anxiety: Valerian Herbal Treatment of Anxiety: Valerian

• Clinical effects: •Other effects: anti-spasmodic & anti-ulcerogenic – CNS depressant, hypnotic/sedative, anti-anxiety – Re: the latter reduces stress related hormone and muscle relaxant production – Humans: reduces induction time – Perhaps through the HPA? – Similar to Kava Kava and/or benzodiazepines • Drug interactions: – Increase GABA activity by binding to GABA – Can potentiate the effects of the CNS receptors depressants (like Kava Kava) – Valerian also contains (which the – No hard evidence regarding potentiation of brain converts into GABA) alcohol, however

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Herbal Treatment of Anxiety: Valerian (cont.) Rauwolfia Serpentina • Side effects: – Long term use: headaches, restless states, sleeplessness, disorders of cardiac function – Not recommended during pregnancy nor in nursing mothers • Therapeutic doses – Restlessness: 220mg extract 3x/day (dosage for anxiety would be similar) – Sleep aid: 400mg to 900mg extract 30-45 minutes before bed – Cost: $5.89 (60 servings)

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14 2019 PCB Conference: Strickland

Herbal Treatment of Anxiety: Rauwolfia Herbal Treatment of Anxiety: Rauwolfia • Drug Interactions: • Clinical effects: – Alcohol: increase in impairment – Anti-anxiety – Neuroleptics/Barbiturates: an  in drug effect • Blocks NE storage & other monoamines within occurs with these meds. the nerve ending in both the CNS and PNS – Digitalis-glycosides: bradycardia • Due to reserpine like (medically, – Levodopa (L-Dopa) reserpine is used to lower blood pressure) • Decrease in the drugs’ effects • The bottom line is similar to & Inderal (a reduction in NE activity) • Increase in EPS (movement side-effects) • Other clinical effects: treat hypertension & snakebites, – Cough, flu remedies & appetite suppressants: etc. (India) may cause  BP 57 58

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Herbal Treatment of Anxiety: Rauwolfia Other Herbal Products for Reducing Anxiety (recommended by Commission E) •Side effects: few for normal dose ranges • Bugleweed – Depression (like reserpine); in fact, Rauwolfia • Camphor Tree contraindicated in depression • English Lavender – Tiredness, erectile dysfunction, nasal • Hops congestion and drowsiness • – Should not be used with pregnant/nursing • Lily of the Valley women nor in depressed individuals • Passion Flower (taken in combination with Valerian) Passion Flower

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15 2019 PCB Conference: Strickland

Anxiety and Lactic Acid Treating Anxiety by Reducing Lactic Acid • Normal metabolic processes (involved with producing energy) are as follows: 1. Glucose  Pyruvic acid + energy 2. Pyruvic acid + 02  H20 + C02 If no 02 is available (which occurs during strenuous exercise) then: 3. Pyruvic acid  H20 +C02 + lactic acid • In people who suffer from panic attacks: – High lactic acid/pyruvic acid ratio – Lactate (soluble lactic acid) sensitivity 61 62

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Anxiety and Lactic Acid

• Methods of reducing anxiety by reducing lactic acid levels: – Reduce , alcohol and sugar intake Clinical Use of Substances Of – Increase intake of B-vitamins, , Abuse? pyridoxine, thiamin, calcium and Ketamine Infusion Therapy

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Substantial History of Using Ketamine: What is it? Substances of Abuse Clinically • Freud and • Ketamine is a • Benzodiazepines/barbiturates • Uses include: – • ( and to lesser degree, Suboxone) Starting or maintaining – Analgesic • Psychostimulants (ADHD) – • A whole host of – Treatment of bronchospasm • THC: glaucoma, anti-emetic (chemo) – • More currently: Ecstasy & Ketamine • Substance of abuse

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Ketamine: Effect on BDNFs? Ketamine: How does it work?

• Has an effect on the glutamate system in the • What are brain-derived neurotrophic factors brain (BDNFs)? – A protein encoded by the BDNF gene. BDNF is a – Is an N-methyl-D-aspartate (NMDA) member of the neurotrophin family of growth antagonist factors, which are related to Nerve Growth Factor. – ἁ-amino-3-hydroxy-5-methyl-4-isoxazolepropionic Neurotrophic factors are found in the brain and acid (AMPA) the periphery. – Other glutamate receptors – Inhibitor of monoamine (DA, 5HT, NE) reuptake – receptors (weak)

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Ketamine Ketamine • What are brain-derived neurotrophic factors (BDNFs)? • Ketamine enhances neuroplastic changes in – Psychological & immune system stressors may – interact with genetic vulnerability The hippocampus – • This decreases BDNF activity The cortex • • Neuroplastic processes decrease The result is enhanced cellular connections and functioning which reduces depressive symptomology – Result can be depression • Effects of ketamine infusion can be seen within hours of treatment • Effects may last up to 2 weeks

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And that’s all she wrote….good luck in your personal lives and your professional careers!!!

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