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PATHOPHYSIOLOGY AND HERBAL INTERVENTIONS

DR JILLIAN STANSBURY FINANCIAL DISCLOSURE: CONSULTANT TO RESTORATIVE FORMULATIONS CHASING THE DRAGON  The are at least 4 million opiate addicts in the US alone.

 “ is a multibillion dollar business  At least 1.5 Million people supported by powerful interests, which undergo treatment for heroine requires a steady and secure addiction in the US each year. commodity flow. One of the “hidden” objectives of the war [in Afghanistan] was precisely to restore the CIA  Opiate addiction is a leading sponsored drug trade to its historical cause of homelessness and a levels and exert direct control over the myriad of other social issues. drug routes.”

 Global Research, Center for Research on Globilization The Spoils of  Opiate addiction may be a hidden War: Afghanistan’s Multibillion Dollar Heroin Trade Washington's agenda in Afghanistan. Hidden Agenda: Restore the Drug Trade Prof Michel Chossudovsky OPIATE ADDICTION

 Chasing the dragon, is the phenomenon where escalating quantities of drug are necessary to achieve the same level of satisfaction.

 There are around 30-40,000 opiate associated deaths per year in the US.

 Treatment for heroine and opiate addiction has the worst success rate – just 2-5% - of all addictive disorders. AN OPIATE EPIDEMIC IN THE US

 CDC reports that opiate sales, hospital MMWR Morb Mortal Wkly Rep. admissions, and opiate overdose deaths 2011 Nov 4;60(43):1487-92. Vital have tripled in the last 30 years and now signs: overdoses of prescription relievers---United exceed motor vehicle deaths per year. States, 1999--2008.Centers for Control and Prevention (CDC).  New York City health statistics reported BMC Public Health. 2012 Jun 18;12:443. Estimating the 21,600 incidents of inpatient and emergency prevalence of illicit opioid use in room admissions for opiate related issues all New York City using multiple data sources. McNeely J, Gourevitch years prior to 2006, and over 126,000 in a 6 MN, Paone D, Shah S, Wright S, year period after 2006. Heller D. J Addict Med. 2013 May- Jun;7(3):177-82. Opiate-  Some communities report waiting lists for dependent patients on a waiting list for maintenance admission to methadone maintenance treatment are at high risk for treatment programs. mortality until treatment entry. Peles E, Schreiber S, Adelson M. A BRIEF HISTORY OF

 Byzantine alchemists produced -based medicinal syrups and seeds have been unearthed in ancient burial sites.

 Opium has been a pain remedy for thousands of years.

 Ancient opiate remedies include and Andromache, also known as Venice Treacle.

 Opium is mentioned in the Eber’s Papyrus and the writings of Dioscorides, , and Avicenna. A BRIEF HISTORY OF OPIATES

 Opium was once thought of as a panacea for emotional disorders, problems, snake bites, and pain.

 Opium has been referred to as lachryma papaveris or poppy tears.

 In India, opium was traditionally harvested by licensed farmers.

 In the 1700s, the East India Company was greatly involved in the opium trade through India, and later, in distribution. A BREIF HISTORY OF OPIATES

 The recreational use of opium began in Asia began in the 1400s.

 Opium smoking began as a privilege of the elite and remained a great luxury into the early 19th century.

 As the opium trade became established over the next several hundred years, opium use became more common and opium “dens” emerged throughout .

 Users would often smoke opium laying on their sides, to prevent choking on their own saliva due to respiratory suppression when laying on the back. FROM OPIUM TO TO HEROIN

 The English physician Thomas Sydenham developed Rev Hist Pharm (Paris). 2010 an opiate called laudanum, in 1683. Apr;58(365):81-90. The opiate pharmacopeia in  Laudanum became the leading pain France from its origins to the 19th pharmaceutical for several hundred years. century. Warolin C.

 Paracelsus, however, used the term “laudanum” 150 years prior for his own opiate-based pain remedy, and chose the name from the Latin verb “laudare”, meaning to praise. A BREIF HISTORY OF OPIATES

 Both Papaver orientale and bracteatum have been bred for greater content and are in great demand by the pharmaceutical and drug industry alike.

 Raw opium is refined into morphine or heroin close to the grow fields as it is less bulky and easier to smuggle.

 Black tar heroin is produced especially in Mexico and is common in the western states of the US. A BRIEF HISTORY OF OPIATES

 By the 1700s the use of opium was so widespread and problematic that China outlawed the practice, but with little effect.

 A Chinese emperor attempted to confiscate opium stores in what became known as the Opium Wars in 1839 and 1858.

 Chinese immigrants brought opium smoking to San Francisco and the US government quickly attempted to control consumption.

 US president Harrison was treated with opium in 1841 and the Union Army used 2.8 million ounces of opium tincture and powder, and about 500,000 opium pills to treat soldiers in the Civil War. FROM OPIUM TO MORPHINE TO HEROIN

Upon its initial discovery, morphine was thought helpful for opium addiction and alcoholism but was quickly realized to be more addictive than either opium or .

Morphine was used widely during the American Civil Was and resulted in some 400,000 soldiers with morphine addiction. Thomas de Quincey published Confessions of an English Opium-Eater in 1821, inciting a national debate on opiate drugs. PAIN AND ADDICTION The Sweet Sister of Sleep

 Opiates ease pain and bring on blissful sleep.  Some users find their way to heroin following a long relationship with prescription opiates.  Pain is exacerbated upon withdrawal from opiates and chronic opiates use causes physical pain to escalate overtime.

Addict Biol. 2013 Dec 13. Chronic CRF1 receptor blockade reduces heroin intake escalation and dependence-induced hyperalgesia. Park PE, Schlosburg JE, Vendruscolo LF, et al. FROM OPIUM TO MORPHINE TO HEROIN

 Morphine was one of the first  The sale of Morphine became even plant alkaloids to be isolated more popular after the development and purified in 1804 by Friedrich of the hypodermic needle in 1857. Sertürner.  Heroin was first synthesized from  Sertürner distributed morphine Morphine in 1874 and bought to as an himself for a market by Bayer in 1898. decade until it was  It became possible to synthesize commercially available from a morphine from petrochemicals in the small independent 1950s. that has since grown into the pharmaceutical giant Merck. THE OPIATE SYSTEM BASICS

 The opioid system helps regulate pain, temperature, mood, and Opiate drugs bind hormones. opiate receptors and  The opioid system plays a role in activate the “reward” complex social behaviors including the formation of committed sensation, and emotional and reproductive pair unfortunately, can act relationships and attachment in as a higher priority bonding between and mother and child/offspring. reward than the  The opioid system plays a role in the emotional bonding “reward pathway”. opiate pathways have evolved to encourage.  Neuroimage. 2016 Sep;138:242-247. Social touch modulates endogenous μ- opioid system activity in humans.

 Hum Brain Mapp. 2015 Sep;36(9):3621-8. Adult attachment style is associated with cerebral μ- availability in humans. TYPES OF OPIATES

ENDOGENOUS OPIATES PRESCRIPTION OPIATES NATURALLY OCCURING PLANT OPIATES COMMONLY ABUSED OPIATES OPIOID ANTAGONISTS THE OPIOID MAINTENANCE (OMT) DRUGS THE ENDOGENOUS OPIATES

 Enkephalins – mediate reward pathway  Dynorphins – mediate general mood, tone, and emotional affect.  Endorphin – help temper the discomfort of stress and trauma, both mental and physical.  – helps mediate pain  Morphine – occurs endogenously but its role as yet unclear. THE PRESCRIPTION OPIATES

– an early opiate  and - Anti- tussives derived drug used to treat - Anti-diarrheals  Laudanum – an early alcohol  macerated tincture of opium used  /meperidine to treat pain and induce sleep.  Morphine – usually used in hospital settings for extreme pain.  Vicodan – Commonly prescribed  The Morphinan family of agonist-antagonist analgesic drugs (, dextromethorphan and  - Analgesic others)  Trivalin - a European drug combining  Oxycontin/ - Analgesic morphine and a Valerian derivative used for sleep.  (Dilaudid, Hydal)  Tetravalin – A compound combining  (Numorphan, codeine and valerates. Opana) THE NATURALLY OCCURING PLANT OPIATES

Opium Codeine Morphine Thebaine  THE COMMONLY ABUSED OPIATES

 Opium  Hydrocodone (Oxycodone)  Heroin - is classified as a short acting opiate.  (Krokodril) Russian semi-synthetic opiate, 8 times more potent than morphine and associated with horrifying decay of tissue called “Krokodril Korrosion”, 

“Krokodril Korrosion” from gallopingbeaver blogspot OPIOID ANTAGONISTS INCLUDE:

(Narcan) - typically used parenterally in research.  (Vivitrol, Trexan) - administered as a long acting injection  Naltrexonediprenorphine (M5050, the reversing agent for the Immobilon dart)  (Nalline) THE OPIOID MAINTENANCE THERAPY (OMT) DRUGS

 Methadone – long acting opiate agonist  l-alpha- (LAAM) – long acting opiate agonist  (Subutex) – long acting opiate agonist  Buprenorphine-Naloxone (Suboxone) - Partial agonist and partial antagonist. OPIATE RECEPTORS, ANANDAMIDE There are several subtypes of MORs:

 μ1: involved in analgesia and physical dependence  μ2: can depress respiration and GI motility, can promote and is associated with physical dependence.  μ3: May help control vasodilation ENDOGENOUS OPIATE AGONISTS ANANDAMIDE

 ANANDAMIDE is a neurotransmitter involved in the regulation of stress responses and pain.  Anandamide was so-named after the Sanskrit word for bliss, Ananda.  Anandamide binds to cannabinoid receptors in the brain.  Animals experience greater stress symptoms when Anandamide is blocked.  ENDOGENOUS OPIATE AGONISTS ANANDAMIDE

 Anadamide may also bind to Transient Receptor Potential (TRP) Vanillioid receptors and researchers believe that this also may mitigate conditioned fear responses.  Anadamide may help mitigate and lasting effects from negative events to help prevent them from becoming emotionally crippling. Behav Brain Res. 2013 Nov 1;256:101-7. Effects of endocannabinoid and endovanilloid systems on aversive memory extinction. Laricchiuta D, Centonze D, Petrosini L. OPIATE SIDE AFFECTS, TOLERANCE, AND WITHDRAWAL SYMPTOMS OPIATE SIDE EFFECTS COMMON OPIATE LESS COMMON OPIATE SIDE AFFECTS SIDE AFFECTS   Pruritis, Picking, and  Sedation Scratching  Confusion  Hyperalgesia  and GI Upset  Respiratory Depression  Hallucination  Urinary Retention  Sweating  Delirium  Dry Mouth  Seizures  Myoclonus OPIATE TOLERANCE

TOLERANCE OCCURS DUE TO SEVERAL MECHANISMS INVOLVING: The euphoria-promoting  Changes in the number of opioid receptors, the effects of heroin and phosphorylation responses of the receptors, other opiates wear off  Up-regulation of cyclic AMP pathways, and fairly quickly necessitating higher and  Molecular changes involving the G proteins and higher doses to yield  Molecular changes involving beta-arrestins to results – a phenomena which the opiate receptors are coupled. referred to as tolerance. cAMP up-regulates as a counter-regulatory mechanisms to oppose the sedating effects of opiates. AGENTS THAT SLOW OR PREVENT OPIATE TOLERANCE

 Olea -Olive contain oleuropein shown to prevent tolerance to morphine by preventing the up-regulation of calcium channels.

 Zingiber may potentiate morphine’s analgesic effect via calcium channel blockade and many other mechanisms. OPIATE WITHDRAWAL SYMPTOMS

 Hot and cold flashes, with goose The cessation of heroin causes bumps and shivering is where marked physical withdrawal symptoms: the term “cold turkey” comes from and are typical with opiate  6-14 hrs: Anxiety, irritability, , drug craving, and possibly perspiration withdrawal.  14 to 18 hours from last dose, yawning, heavy perspiration, lacrimation and runny nose, and trance-like state where sleep is  The pupils become dilated, the desired but rarely achieved. pulse is elevated, and  1 to 1 ½ days from the last dose, restlessness occurs, often with headaches, nausea, , diarrhea, and intestinal cramps that may worsen spastic and restless legs, where and persist for a full 24 to 72 hours. the term “kicking the habit” is derived. SYMPTOMS OF OPIATE WITHDRAWAL

 Increased pulse rate  Yawning, several times  Dilated pupils per minute at times  Bone and Joint pain  Anxiety and Irritability  Runny nose and tearing  Goosebumps  Tremors, shaky hands  Intestinal cramps and diarrhea  Perspiration NALOXONE FOR HEROIN OVERDOSE

Naloxone, an opiate blocking drug, is the drug most commonly given for acute heroin and prescription opiate overdose and can be lifesaving. Naloxone is used for acute overdose symptoms, but will, of course, also initiate acute and severe opiate withdrawal symptoms.

MMWR Morb Mortal Wkly Rep. 2012 Feb 17;61(6):101-5. Community-based opioid overdose prevention programs providing naloxone - United States, 2010. Centers for Disease Control and Prevention (CDC). BOTANICAL OPTIONS FOR HEROIN ADDICTION, WITHDRAWAL, AND MAINTENANCE PLANTS THAT BIND OPIATE RECEPTORS

 Actaea racemosa – Black Cohosh  Corydalis species – A poppy family genus  Eschscholzia californica – The California Poppy  Maytenus rigida – Chuchuwasa  Mitrigyna speciosa – Kratom  - – Magic Mint  Trifolium pratense – Red Clover CBD MAY TREAT PAIN AND MINIMIZE THE SYMPTOMS OF ACUTE OPIATE WITHDRAWAL sativa

 Endocannabinoid receptors are bound by CNS Neurol Disord Drug Targets. 2009 cannabinols such as THC . Dec;8(6):422-31. Signal transduction via cannabinoid receptors. Dalton GD, Bass CE, Van Horn CG, Howlett AC. Br J Pharmacol. 2009 Sep;158(1):225-  Cannabinoids such as THC and anandamide 31..Central antinociception induced by mu-opioid receptor agonist morphine, promote the release of endogenous . but not delta- or kappa-, is mediated by cannabinoid CB1 receptor. Pacheco Dda F, Klein A, Perez AC, et al Life Sci. 2009 Aug 26;85(9-10):351-6.  Endocannabinoid receptors interact with Opioid receptor and NO/cGMP pathway as a mechanism of peripheral opioid receptors and are found within close antinociceptive action of the cannabinoid receptor agonist proximity to one another and the two systems anandamide. Reis GM, Pacheco D, may share G proteins in common and both Perez AC, Klein A, Ramos MA, Duarte ID. Int Rev Psychiatry. 2009 Apr;21(2):143-51. interact with dopamine. Interaction of the cannabinoid and opioid systems in the modulation of nociception. Welch SP. Cannabis sativa

 Cannabinoids evoke the release of endogenous opioids and promote mild analgesia via mu- opiate agonism.  Some researchers report an “anti-nociceptive synergy” between cannabinoids and opioids.

Cannabinoids include: * N-acyl ethanolamines, such as N- arachidonoyl ethanolamide (anandamide), oleoylethanolamide and palmitoylethanolamide, * monoacylglycerols, such as 2-arachidonoyl . Cannabis sativa

 The endocannabinoid system modulates cognitive processes, including memory formation, retrieval and extinction, but the details remain unknown. Neurobiol Learn Mem. 2013 Dec 29. pii: S1074-  Cannabinoids are involved in nociceptive processing 7427(13)00266-9. The endo- and the many uses of medical marijuana include cannabinoid chronic pain, nausea, and possibly opiate withdrawal. system: An emotional buffer in the modulation of memory function.  Cannabinoids may serve as an “emotional buffer”, Morena M1, moderating our experiences as they are put through Campolongo P2. cognitive processes. Corydalis species: C. yanhusuo, C. bungeana, Corydalis humosa

 Corydalis is a genus in the Poppy family long J Asian Nat Prod Res. 2013 Nov;15(11):1158-62. Two new alkaloids from Corydalis humosa. used as sedatives and . Zheng XK, Li DD, Yan H, Li M, He JL, Feng WS.  Corydalis contains many isoquinoline Nat Prod Res. 2011 Sep;25(15):1418-22. alkaloids such as tetrahydropalmatine, Acetylcholinesterase inhibitors from Corydalis yanhusuo. Xiao corydaline, , berberine, palmatine, HT, Peng J, Liang Y, Yang J, Bai X, Hao XY, Yang FM, Sun QY. jatrorrhizine, coptisine, and Arzneimittelforschung. 1995 Feb;45(2):127-31. Modulation of dehydrocorydaline, that may affect limbic key reactions of the catecholamine metabolism by and reward pathways. extracts from Eschscholtzia californica and Corydalis cava. Kleber E, Schneider W, Schäfer  Corydalis cava may promote adrenaline HL, et al. breakdown and metabolism, as well as the synthesis of melanin from DOPA. Corydalis and Stephania Alkaloid Tetrahydropalmatine

 The alkaloid tetrahydropalmatine occurs in both Future Med Chem. Corydalis and Stephania species and both plants are 2012 Feb;4(2):177- helpful for opiate . 86. l-tetrahydro- palamatine: a  Tetrahydropalamatine has been produced into a potential new medication for the prescription drug in China marketed under the name treatment of Rotundine. addiction. Wang JB, Mantsch  Tetrahydropalmatine is a dopamine 1 and 2 antagonist JR. and a D3 agonist.  Tetrahydropalmatine also acts as a agonist at adrenergic and serotonin receptors, and possibly GABA. Stephania intermedia

Neurosci Lett. 2013 Nov 20. l-  Stephania is a traditional Chinese herb. Stepholidine, a natural dopamine receptor D1 agonist and D2 antagonist, inhibits heroin-induced  The alkaloid l-Stephanolidine is both a dopamine reinstatement. Ma B, D1 receptor agonist and a D2 antagonist. Neuroreport. 2014 Jan 8;25(1):7-11. L-Stepholidine, a naturally occurring dopamine D1 receptor agonist and D2 receptor  Animal studies suggest Stephania may be helpful antagonist, attenuates heroin self-administration for opiate addiction reducing heroine seeking and cue-induced behavior in primed animals. reinstatement in rats. Yue K,

 This also suggests the herb may help prevent relapse in heroin addicts attempting to recover. TETRAHYDROPALMATINE

Pharmacol Biochem Behav. 2012 Jul;102(1):1-5. The dopamine receptor antagonist levo- L-tetrahydropalmatine tetrahydropalmatine attenuates heroin self- administration and heroin-induced reinstatement in  Reduces heroin consumption in animal rats.Yue K, Ma B, Ru Q, Chen L, et al models of addiction. Zhongguo Zhong Yao Za Zhi. 2012 Nov;37(22):3457- 61. Study on acting mechanism of anti-morphine conditioned place preference between aqueous  Prevents heroin-driven changes in the NA extract of Corydalis yanhusuo and L-THP and and VA comparison of their effects. Luo SY Physiol Behav. 2013 Jun 13;118:195-200. Roles of  Diminishes reward pathway activation of the levo-tetrahydropalmatine in modulating methamphetamine reward behavior. Su HL, Zhu J, reward pathway activation, suggesting Chen YJ, et al. balancing effects on the limbic system. J Integr Neurosci. 2013 Dec;12(4):513-28. Effects of tetrahydropalmatine on post-traumatic stress  Protects the limbic system from stress- disorder-induced changes in rat brain gene expression. Ceremuga TE, Shellabarger P, Persson T, induced changes in gene expression. et al. AANA J. 2011 Aug;79(4 Suppl):S75-80. Evaluation of the anxiolytic properties of tetrahydropalmatine, a Corydalis yanhusuo compound, in the male Sprague-Dawley rat. Henkes H, Franz M, Kendall O OTHER PROTOBERBERINE ALKALOIDS

Drug Alcohol Depend. 2013  L-isocorypalmine is a partial agonist at D1 Dec 1;133(2):693-703. L- isocorypalmine reduces and antagonist at D2 receptors, shown to behavioral sensitization and rewarding effects of cocaine mitigate cocaine withdrawal symptoms. in mice by acting on dopamine receptors. Xu W, Neuropharmacology. 2013 Aug 21. pii: S0028-  3908(13)00364-X. Acetylchorynoline prevent dopaminergic Acetylcorynoline attenuates degeneration in Parkinson’s disease models. dopaminergic neuron degeneration and α- synuclein aggregation in animal models of Parkinson's disease. Fu RH,  Tetrahydroberberine may help correct J Pharmacol Exp Ther. 2011 Sep;338(3):917-24. opiate-induced digestive suppression by Tetrahydroberberine, an upregulating GI motility via D2 serotonergic isoquinoline alkaloid isolated from corydalis tuber, receptor agonism. enhances gastrointestinal motor function. Lee TH, Eschscholtzia californica

 Eschscholtzia poppies contain small amounts of natural opiates. Arzneimittel- forschung. 1995 Feb;45(2):127-31.  Eschscholtzia is a gentle nervine and may ease opiate Modulation of withdrawal symptoms, and possibly reduce the cravings for key reactions of the opiate when used long-term. catecholamine metabolism by extracts from  Eschscholtzia may inhibit catecholamine breakdown by Eschscholtzia californica and MAO. Corydalis cava. Kleber E, Schneider W,  Eschscholtzia inhibits adrenaline production and affects Schäfer HL, et al. HPA tone. Eschscholtzia californica Harpagophytum procumbens Phytother Res. 2007 Dec;21(12):1228-33.  Devil’s Claw reduces arthritic pain and Effectiveness and safety of need for pain medications. Devil's Claw tablets in patients with general rheumatic disorders. Warnock M,  The plant has anti-inflammatory effects Planta Med. 2008 Apr 10 Dermal and orally and topically. Transcutaneous Delivery of the Major Glycoside Constituents of Harpagophytum  Harpagophytum may be pain relieving via procumbens (Devil's Claw) opiate pathways. in vitro.Abdelouahab N, Biol Pharm Bull. 2008 Feb;31(2):240- 5.Antinociceptive effects of St. John's wort,  Harpagophytum may help wean from Harpagophytum procumbens extract and opiate pain meds and other opiates. Grape seed proanthocyanidins extract in mice. Uchida S,

 St. Johnswort has broad neurotransmitter Phytother Res. 2009 effects on serotonin, GABA, and dopamine. Nov;23(11):1549-52. The inhibitory effect of Hypericum perforatum extract on morphine withdrawal syndrome in rat and comparison with  Hypericum may ease the symptoms of clonidine. Feily A, Abbasi N. acute morphine withdrawal. Phytother Res. 2009 Apr;23(4):564-71. Adulterant profile of illicit street heroin and reduction of its precipitated physical dependence withdrawal syndrome by extracts of St John's wort (Hypericum perforatum). Subhan F, Khan N, Sewell RD. Pharm Biol. 2013 Nov 21. Nature cures nature: Hypericum perforatum attenuates physical withdrawal signs in opium dependent rats. Khan M, Subhan F, Khan AU, et al Hypericum perforatum

 Hypericum was shown to be as effective as clonidine for the symptoms of opiate withdrawal in animal models of addiction.

 Hypericum perforatum can reduce abdominal spasm and diarrhea in animal models of acute opiate withdrawal. JITAI TABLETS and JINNUI CAPSULES

 Jitai tablets are a TCM herbal-marine combo with a dozen ingredients traditionally used for acute opiate withdrawal symptoms. Journal of Chromatography B Volume 912, 1 January 2013, Pages  Jitai tablets contain amygdalin, danshensu, Datura alkaloids, 75–84 Simultaneous determination of six ferulic acid, hydroxysafflor yellow A, and salvianolic acids. hydrophilic components in rat plasma after of Jitai  The effects of Jitai tablets are similar to those of clonidine in tablet by liquid controlling the withdrawal symptoms of morphine-dependent chromatography– animals. electrospray ionization–tandem mass spectrometry: Application to a  Human Clinical studies further confirm Jitai tablets to be effective pharmacokinetic study Shu-Ping in controlling both acute and protracted opiate withdrawal Wanga et al. symptoms. JITAI TABLETS and JINNUI CAPSULES

 Jitai tablets were found to be as effective as lofexidine for acute heroin withdrawal in one Am J Drug Alcohol Abuse. . 2008;34(6):792-800. A comparative clinical study of the effects of the traditional Chinese medicine Jinniu  No significant adverse effects have been found capsules and lofexidine on acute heroin withdrawal on the and kidney function in patients. symptoms. Shi J, Xu GZ, Liu TT, Wang X, Shen LY, Li J, Hao W, Chen HX, Li SX, Lu L. Addict Behav. 2013 Oct;38(10):2596-600. The effectiveness comparison of Jitai tablets versus methadone in community-based drug treatment: a 1-year follow-up study. Hao SQ, Zhao M, Zhang RW, Zhang JC, Zhang J, Feng XS. Magnolia

Methyhonokiol may bind cannabinoid receptors and J Neuroinflammation 2012 Jun 20;9:135. Methylhonokiol contribute to its anti-inflammatory attenuates neuroinflammation: effects on neural tissue. a role for cannabinoid receptors? Gertsch J, Anavi-Goffer S.

 Kratom/Khratom, Ketum is an Asian plant use by Drug Metabol Drug Interact. 2013;28(2):95- villagers in Thailand and Malaysia. 105. Mitragyna speciosa Korth leaves extracts induced the CYP450  Mitragyna leaves contain and related catalyzed aminopyrine-N- alkaloids having both opiate and cocaine-like effects demethylase (APND) and and was banned in Malaysia in 2004. UDP-glucuronosyl transferase (UGT) activities in male  Mitragyna tea is reported to be relaxing and Sprague-Dawley rat . enjoyable, and to increase stamina and physical Azizi J, endurance, provide pain relief and improve sexual J Ethnopharmacol. 2012 May 7;141(1):446-50. performance. Mitragyna speciosa use in the northern states of  Malaysia: a cross- Many users reported difficulty in abstaining from sectional study. Ahmad K, consuming the tea so frequently. Mitragyna speciosa

Int J Drug Policy. 2010 Jul;21(4):283-8. The informal use of  Heroin addicts in Thailand and Maylasia report ketum (Mitragyna speciosa) for Mitragyna has helped them wean off heroin. in the northern states of peninsular Malaysia and implications for drug substitution therapy. Vicknasingam B,  Animal studies suggest Mitragyna induces Narayanan S, Beng GT, Mansor SM. cytochrome enzymes in the liver promoting drug Drug Metabol Drug Interact. metabolism. 2013;28(2):95-105. Mitragyna speciosa Korth leaves extracts induced the CYP450 catalyzed aminopyrine-N-demethylase (APND) and UDP-glucuronosyl transferase (UGT) activities in male Sprague-Dawley rat livers. Azizi J, Ismail S, Mansor SM Mitragyna speciosa BLACK SEED, BLACK CUMIN SEED OIL

J Ayub Med Coll  Abbottabad. 2008 Apr- Nigella sativa has been shown to ease opiate Jun;20(2):118-24. A new withdrawal symptoms without being an opiate itself. and novel treatment of opioid dependence:  Nigella sativa 500 mg. Ayruvedic clinicians report empirically that Nigella Sangi S. also reduces the and weaknesses to which most addicts suffer. Anisodamine

 Anisodamine is a naturally occurring atropine J Appl Toxicol. 2007 derivative studied in China for Opiate addiction. Mar-Apr;27(2):116- 21. The pharmacological properties of  Like atropine and scopolamine, anisodamine is a anisodamine. cholinergic antagonist and alpha adrenergic blocking Poupko JM, Baskin SI, agent. Moore E.

 Anisodamine has a weak vasodilating activity as well as anti-anxiety activity helpful in acute withdrawal, or possibly to use in small amounts for long term maintenance. Scopalamine and SDT

 Scopalamine is a tropane alkaloid found in , Hyoscyamus, and Datura.

 Isolated scopolamine has been used for decades as a topical patch to prevent acute motion sickness in susceptible individuals.

 Recent research suggests scopolamine detoxification technique (SDT) may be an alternative for acute heroin withdrawal symptoms. Scopalamine and SDT

 Human trials suggest that IV scopolamine with CNS Drugs. 2013 Dec;27(12):1093- chlorpromazine may reduce heroin craving, depression, 102. Scopolamine and anxiety compared with the methadone group. detoxification technique for heroin dependence: a randomized trial. Liu S, Li L, Shen W, Shen X, Yang G, Zhou W. Withania somnifera

Behav Pharmacol. 2013  Ashwaghanda mitigates morphine’s effects on the Apr;24(2):133-43. CNS and is thereby therapeutic for opiate Withania somnifera addiction. prevents acquisition and expression of morphine- elicited conditioned place preference. Ruiu  Withania has effects on GABA receptors and S, et all. MORs.

 Withania has protective and regenerative effects on neurons. Withania somnifera

Neurotox Res. 2009  Withania reduces heroin withdrawal symptoms if Nov;16(4):343-55. given chronically prior to withdrawal, but not to Withania somnifera ease the symptoms when given upon initial prevents morphine withdrawal-induced abstinence in animal models of heroin addiction. decrease in spine density in nucleus accumbens shell of rats:  Long term ingestion of Withania has been shown to a confocal laser scanning microscopy fully prevent the loss of dopaminergic density in study. Kasture S, et al. the NA upon opiate withdrawal. SAMPLE CLINICAL THERAPY FOR ACUTE WITHDRAWAL PRIOR TO WITHDRAWAL- PREPARATION  Secure an educated, compassionate support person MEDICINES TO HAVE ON HAND:  Gather all Supplies and Medicine (Right)  Herbal Tincture (Following Slide)

 Prepare a room with rags, towels, a  Herbal Tea both iced and hot (Recipe bucket or large bowel to vomit in, and Following) preferably near a bathroom, spare sheets.  Scopalamine patches?  Massage Oil, Tiger Balm  Prepare the bathroom with a large bucket for emesis, extra toilet paper, Epson salts  Heating pad or Heat Pack. and candles for the bath.  Essential Oils for Topical and Inhalant Use  Begin taking Withania, several weeks  GABA 500 mg pills ahead of time where feasible.  Calcium/Magnesium liquid or powder  Consider music, books on tape, recorded to use in water or herbal tea. nature sounds as person prefers. FORMULAS TO EASE ACUTE WITHDRAWAL SYMPTOMS Example Tincture Other Tincture Options  Hypericum 15 ml  Actae racemosa  Piper methysticum 15 ml  Withania  Corydalis 15 ml  Salvia miltiorrhiza  Eschscholtzia 15 ml  Datura stramonium  Stephania  Atropa belladonna 4 ml

SIG: 1 dropper (1/2 tsp) every 15 minutes, reducing as symptoms ease over 24 hours. TEA TO EASE ACUTE WITHDRAWAL SYMPTOMS

Tea Formula for Opiate Withdrawal  Prepare ahead of time and have several cups hot, in a thermos.  Matricaria chamomilla  Fill one ice cube tray with the tea and freeze.  Melissa citronelle When frozen, place the ice cubes in a zip lock  Hypericum perforatum back, cover with a thick towel and pound into slivers. Return to the freezer until ready for use.  Mahonia (shredded root bark)  Place remainder of the tea in a large jar and  Mentha piperita chill.  Eschscholtzia californica  Allow the patient to choose hot or cold tea. Offer ice chips by the spoonful when severe N & V are leading to dehydration. Combine equal parts of the dry herbs and prepare 6 or more cups by steeping 1 TBL per cup of hot water. Steep and strain ESSENTIAL OILS FOR ACUTE WITHDRAWAL

Mint Oil Citrus Oils

 Simply smelling mint oil can  Orange, Lemon, Tangerine, help with nausea and Mandarin, and Grapefruit essential oils has a room reduce vomiting. uplifting effect.

 Rubbing mint oil into the  Spray in the room or combine with Mint essential abdomen and covering with oil for a person to simply heat can reduce intestinal inhale through out the cramping, bloating, pain withdrawal process. and diarrhea. LONG TERM CONSIDERATIONS

 Adrenal Herbs

 Treat Underlying Pain  Consider a Change in Environment, Friends, Visual Cues

 Treat Underlying  New Music, New Art, New Routines Anxiety and  Meditation, Mindfulness, Therapy Groups, Recovery Support Depression  Exercise, Hiking, Yoga,  Devise a diet plan with regular meals  Nature Therapy and snacks  Focus on Interpersonal Relationships

 Avoid  Pets, Plants, Gardening, Hypoglycemia  Ritual and Ceremony  Ample Protein  Consider liver support, brain nutrients, detox protocols  Nutritional  Consider in Patient, Year Long Treatment programs Supplements RESOURCE GUIDES FOR PARENTS, PATIENTS, AND SIGNIFICANT OTHERS

Put together a resource guide to services  I have this information typed up into a large available in your community. booklet for patients, family members, physicians, and other clinicians,  Mental Health Crisis Lines  For Educational and Team Building Purposes  Nearest ER for Overdose  And For patients themselves  Addiction Specialists  Needle Exchange  Methadone and OMT Centers [email protected]  Clinicians offering Vivitrol  In Patient Facility  Out Patient Recovery Group  Counselors and Mental Health Services  Social Service Organizations for Food Stamps, Job Support, Skill Centers THANK YOU!!