W12 - Stimulants_Notes.pdf

STIMULANTS PSY3142 HISTORY: COCAINE • Plant based, indigenous cultural use • Pre-Columbian (2500 B.C.) • Spanish conquest 1500s introduced to Europe • Isolated concentration from plant (1860) • Medical use, Late 1800s • Freud • First Local Anesthetic • Added to Various Beverages • Vin Mariani...

STIMULANTS PSY3142 HISTORY: COCAINE • Plant based, indigenous cultural use • Pre-Columbian (2500 B.C.) • Spanish conquest 1500s introduced to Europe • Isolated concentration from plant (1860) • Medical use, Late 1800s • Freud • First Local Anesthetic • Added to Various Beverages • Vin Mariani • Coca Cola • Became commonplace and used as a health tonic in NA • Became illegal due to recognition of addiction potential and health issues and possibly racism HISTORY: AMPHETAMINES • Plant based, indigenous cultural use • Ephedrine used in China for 5,000 years and India traditional medicine and spiritual purposes • Leaves were used in teas to help with respiratory problems and as a stimulant • Amphetamine extracted from plant (1885) later synthesized (1887) • But effects not widely grasped until 1920s • Medical use sanctioned by American Medical Association (1937) • Commonly used in wartime to help soldiers stay awake and remain vigilant, ‘pep pills’ which likely popularized these • After the war, used for many purposes: weight reduction, antidepressant, stimulant, menstrual difficulties etc.. Fairly widespread use regularly prescribed • Recognition in the 70s of risk for dependence and a decline in prescription and use and later restriction • Currently used medically for narcolepsy and hyperactivity in children • Currently also illegally manufactured Weight loss Depression Bored housewife HISTORY: CATHINONE (KHAT) • Khat plant grown in Africa and other places • Leaves chewed to provide a mild stimulant effects…like coca leaves, chewing history thousands of years in some indigenous populations • Alexander the Great - Cure for melancholia • Various references by Arab physicians for many disorders historically • Early awareness in Europe (1600) but only more recent use in western nations due to transport degradation of plant • Illegal in N.America and some EU countries • Mephedrone (synthetic cathinones like active component of Khat) was synthesized in 1920s and rediscovered early 2000s (meow meow, bath salts, plant food) banned in 2012 in Canada AGENDA • Basics • Use • Neuropharmacology • Effects • Treatment 5 SOME BASICS 6 NATURAL SOURCES Cocaine (coca bush) Ephedrine (Ephedra vulgaris) Cathinone (Khat) COCAINE • coca leaf (low concentration), chewed for mild stimulant effect • exposed to chemical extraction Cocaine hydrochloride (high concentration, salt), snorted, injected • Use solvent to release cocaine from hydrochloride Freebase Cocaine (stronger/faster effect) • Smoked or inhale vapours 8 Add a base substance and heat to produce ‘rocks’ Crack Cocaine (stronger/faster effect) • Smoked or inhale vapours SYNTHETIC SOURCES • Amphetamines (treatment of ADHD and narcolepsy) • Dex-amphetamine – more potent CNS effects – treatment for ADHD and narcolepsy • Levo-amphetamine • Combination of both found in dl-amphetamine – Adderall used for ADHD and narcolepsy • Methamphetamine (uncommonly used treatment of ADHD and obesity; more commonly in illegal trade: crystal, ice, crystal meth) • Methylphenidate (Ritalin - treatment of ADHD, similar chemical structure to cocaine) • Pipradol (Meratran) – used some places to treat dementia • Many synthetic derivatives of Cathinone – e.g. buproprion – antidepressant and smoking cessation aid, bath salts used recreationally 9 USE 10 GLOBAL RATES COCAINE USE CAN 12 GLOBAL RATES OF AMPHETAMINE & METHAMPHETAMINE 13 METHAMPHETAMINE USE CAN 14 OVERDOSE AND DEATHS • 2,744 poisoning deaths (overdoses) caused by stimulants in 2020 (6provinces) • cocaine is frequently involved in overdose deaths • 63% of accidental opioid-related poisoning deaths in 2021 involved cocaine, while 53% involved methamphetamine • National Drug Driving Research Project collected data from 4,976 injured drivers treated in 15 trauma centres across Canada between January 2018 and May 2021 • cocaine, amphetamines or both were detected in 11% of drivers 15 NEUROPHARMACOLOGY 16 ADMINISTRATION, ABSORPTION, DISTRIBUTION • Cocaine • Water soluble, weak base • Easily absorbs into the body • From slowest to fastest routes: • • • • Stomach (beverage) Nasal membrane (powder, cocaine HCL) Lungs (smoke or vapor, free base, crack) Injection (powder, cocaine HCL) Cross the blood-brain barrier and are concentrated in the spleen, kidneys, and brain • Amphetamines • Oral route is typically used for medicinal delivery • When used recreationally, use other faster administration routes As with most illegal drugs from illegal markets, cocaine and other stimulants usually contains adulterants/impurities. It may also be mixed with other drugs often unknown to the user. EXCRETION • Excretion of the amphetamines depends on the pH of the urine. • Also excreted in sweat and saliva • Half-life between 16-34 hours • Cocaine • Excreted much faster than amphetamines • Half-life of about 40-75 minutes • Cathinone • Half-life of about 90 minutes STIMULATE MONOAMINES Catecholamines • Epinephrine (EA) • Norephinepherine (NE) • Dopamine (DA) Indolamine • Serotonin (5-HT) NEUROPHYSIOLOGY: EFFECT ON MONOAMINE SYNAPSE 1. Cocaine acts as a reuptake inhibitor • Binds to the receptor site of the transporter and remains there, blocking the transport of monoamine into the cell (reuptake) • Monoamine remains in the synapse NEUROPHYSIOLOGY: EFFECT ON MONOAMINE SYNAPSE 2. Amphetamines act as substrate-type releasers • Leaking of neurotransmitter from vesicles into synaptic cleft • Increase amount of transmitter released in response to action potential • Block reuptake NEUROPHYSIOLOGY Monoamine transporters: • Dopamine transporter (DAT) • Norepinephrine transporter (NET) • Serotonin transporter (SERT) • Cocaine binds similarly to all three • Amphetamine and metamphetamine are most potent at NET, less at DAT, and even less at SERT • Methcathinone and cathinone similar to amphetamines EFFECTS 23 EFFECTS IN THE CNS • Increased hindbrain activity = increased alertness, less sleep, more activity • Increased midbrain activity – more energy, more agitation • Increased forebrain activity/limbic system = positive emotions, increased motivation, and activity • Much of CNS activity is driven by DA • Epinephrine involved in SNS • Leads to sympathetic arousal (fight-flight/stress response) parasympathetic • Excites synapses that use epinephrine sympathetic Effects in the PNS ACUTE EFFECTS OF STIMULANTS Effects on Body • Dilated pupils • Dry mouth • Increase in heart rate and blood pressure • Vasodilation • Bronchodilation – useful for asthma • Indirect effect on food consumption (ꜜ) • Increased energy (adrenalin, glucose release) ACUTE SUBJECTIVE EFFECTS Improved mood Decreased fatigue Increased energy Improved concentration Rushes: intense feelings of euphoria produced by rapid absorption procedures often sexual in nature (orgasmic); shows rapid tolerance • Crash: mild depression • • • • • • Peak at 2 h amphetamine; 3 h for methylphenidate; shorter for cocaine (23-30 minutes) • Influenced by expectation • Greater when blood levels are rising than falling SENSORY EFFECTS • Increased visual acuity • Minor improvements in hearing • Passage of time is underestimated, so time is perceived to go by more slowly • Watch: rats on drugs and the passage of time – 2 min video STEREOTYPED BEHAVIOUR • First described by Gosta Rylander (1965) • • • • • Repetitive performance of an act for extended length (punding) Also observed in lab animals More ‘complex’ species, more complex and varied the stereotyped behaviour Usually same behaviour in one individual Likely related to stimulation of nigrostriatal DA system EFFECTS ON PERFORMANCE AT LOW DOSES Improved.. • reaction time • attention (but possible deficits for divided attention tasks) • vigilance • short term memory • Athletic performance – bronchodilators, banned by sports feds • ADHD – correction of inattention related to deficit in monoamine function in prefrontal cortex • Driving – 2.3 x more likely to have fatal car accident likely related to narrowing of attentional focus DISSOCIATION AND DRUG STATE DISCRIMINATION Animals trained under the influence of amphetamine cannot completely remember what they learned when the amphetamine has worn off. CHRONIC HIGH-LEVEL USE • Monoamine psychosis • Paranoid Schizophrenia • Formication: tactile hallucinations • Violence • Anxiety and depression • Dependence* TOLERANCE • Acute Tolerance • Related to subjective effects • Chronic Tolerance • Appetite suppressant • Heart and blood pressure • Lethal effects • Sensitization (increased sensitivity of mesolimbic DA system) • Stereotyped behaviour • Psychotic behaviour WITHDRAWAL • Not associated with a severe or medically serious withdrawal • Crash • Depression • Symptoms: depression, insomnia, decreased appetite AMPHETAMINE FOR ADHD • Why do stimulants work for ADHD? • Increased DA activity may help individuals pay attention to what is important among competing stimuli • Side effects: reduction in growth rate • May be given inappropriately eg may suffer from depression, anxiety, learning disabilities, conduct disorders for which other treatments would be more appropriate 35 HARMFUL EFFECTS OF STIMULANTS • Physical damage related to chronic use • Cocaine can interact with nasal mucous to produce hydrochloric acid and dissolve nasal tissues (ulcerations, loss of tissue), anesthetic properties of cocaine may encourage further use • Damage liver • Heart damage • Stroke risk • Parkinsonian-like tremors • Sleep disturbances • Psychological 36 • Anxiety • Depression • Paranoia, psychosis Shocking video shows the devastating physical toll drugs take | Daily Mail Online HARMFUL EFFECTS: INDIRECT • • • • • Hepatitis AIDS infection Prone to Violence High death rate Related to interaction of chronic effects and lifestyle FETAL EXPOSURE • Abnormalities typically observed in infants of cocaine exposure in utero • • • • • • Low birthweight Smaller head circumference Tremors Excessive crying Disturbed sleep patterns Diminished responsiveness Long term effects are difficult to study but generally show a small effect on mental and cognitive function with boys at a greater disadvantage than girls HARMFUL EFFECTS • Overdose • Those who take large doses commonly experience muscle weakness and respiratory depression. • Lethality depends on route of administration • Caine reaction (cocaine overdose) • Initial excitement followed by severe headache, nausea, vomiting, and severe convulsions • Followed by loss of consciousness, respiratory depression, and cardiac failure resulting in death TREATMENT 40 TREATMENT • Behavioral Therapies • Contingency management, CBT • Immunization • Pharmacotherapies • Modafinil • Bupropion • Methylphenidate • Oral d-amphetamine • Naltrexone SUMMARY • Basics • Use • Neuropharmacology • Effects • Treatment 42