PYB260 2024 Psychopharm of Addictive Behavior PDF

PYB260 PSYCHOPHARMACOLOGY OF ADDICTIVE BEHAVIOUR Week 7: Action & Effects of Major Stimulants: amphetamines & cocaine Melanie White  Lecture Outline What are stimulants? Amphetamines & cocaine History Administration, distribution & excretion...

PYB260 PSYCHOPHARMACOLOGY OF ADDICTIVE BEHAVIOUR Week 7: Action & Effects of Major Stimulants: amphetamines & cocaine Melanie White  Lecture Outline What are stimulants? Amphetamines & cocaine History Administration, distribution & excretion Effects of stimulants – physiological & performance Conditioning, tolerance & withdrawal Harmful effects Treatment approaches  Reflection Questions (egs, not exhaustive) Describe the differences & similarities between amphetamine & cocaine in: Route of administration, absorption & excretion profiles Neurobiological mechanisms of psychomotor effects Describe the effects of these drugs on motor behaviour, & explain how they arise (which structures & neurotransmitters responsible) Think of 2 different motivations for users to consume these substances: Now link each of those motivations to specific desired effects & the neurobiological or physiological pathways involved How might the self-administration profile differ by those 2 motivations, & are they likely to lead to different withdrawal profiles? Why/why not? How does stereotyped behaviour look in animal vs human users? What common clinical uses have you used these types of substances or know someone who has? Describe the mechanisms of the desired effects.  What are stimulants? & The history of stimulant use  What are stimulants? Drugs which stimulate transmission of: Epinephrine (E) Monoamines (MAs) Norepinephrine (NE) or biogenic amines Dopamine (DA) E, NE, and DA are aka catecholamines. These neurotransmitters have very Serotonin (5-HT) similar chemical structures Serotonin is an indolamine “sympathomimetic”  What are stimulants? Amphetamines Natural ephedrine Synthetic d-amphetamine (dex-amphetamine/ Dexedrine) l-amphetamine (levo-amphetamine) dl-amphetamine (Benzedrine; Adderall) methylamphetamine (‘meth’/’speed’; crystalized form = ‘ice’) Amphetamine-like stimulants (synthetic): methylphenidate (MPH/ Ritalin) pipradrol Ettinger (2011)  What are stimulants? Cocaine Extracted from leaf of coca plant native to Sth America Cocaine-like drugs: Cathinone (khat) Extracted from African shrub Synthetics: methcathinone (jeff, cat); buproprion (Zyban)  History of stimulants: Amphetamines Early use of amphetamines (ephedrine) in ma huang in China > 5000 yrs 1880’s: ephedrine isolated from the plant – investigated in 1924 (similar to NT epinephrine) 1887: amphetamine synthesized 1927: properties of amphetamines understood Ephedrine had been used to treat asthma – now Benzedrine inhalers became popular 1937: AMA sanctions medical use of amphetamines 1943: widely used to treat obesity & depression, alertness WWII: amphetamines used to combat fatigue & elevate mood 1950’s: speedball (amphetamines+heroin) originated by soldiers  History of stimulants: amphetamines cont. 1970’s:  use Late 1980’s/1990’s: ↑ use with emergence of crystal methamphetamines – ice Australia: 2016: “Australians now consider meth/amphetamines to be more of concern than any other drug (including alcohol) and a greater number thought of it as the drug that caused the most deaths in Australia. For the first time, meth/amphetamines was the drug most likely to be nominated as a drug problem.” (AIHW, National Drug Strategy Household Survey 2016) % episodes by specialist AOD treatment services primarily for amphetamines doubled from 2011-2016 (AIHW). 2017: Covert testing sewerage: ice is most consumed illicit drug https://www.acic.gov.au/publications/national- wastewater-drug-monitoring-program-reports 2024: National Wastewater Drug Monitoring Report (#22) found methylamphetamine use was at record high (capital cities) in Dec 2023 & regional consumption highest since April 2020 www.acic.gov.au/sites/default/files/2024- 07/National%20Wastewater%20Drug%20Monitoring%20Program%20%E2%80%93%20Report%2022_0.pdf  History of stimulants Cocaine Coca leaves chewed for centuries Considered sacred by Incas Coca used as currency – given by Spanish as payment for work in gold & silver mines 1844: active ingredient isolated (1860 Niemann publishes) Late 1800s: Endorsed by Freud as a cure for a variety of illnesses incl. morphine & alcohol addiction Koller – discovers anesthetic properties Added to various beverages (1863: wine; 1886: Coca-Cola)  History of stimulants: cocaine cont. ↑ popularity in late 1800s & early 1900s 1906: cocaine outlawed by Pure Food & Drug Act 1914: declared a narcotic under Harrison Narcotic Act 1930’s:  use 1960’s: ↑ use 1980’s: ↑ demand for crack cocaine 2022-2023: Australian survey (AIHW NDSHS, 2024) – cocaine at highest use (4.5% of adults) since 2001; 2nd most used illicit drug behind cannabis 2024: National Wastewater Drug Monitoring Report (#22) found cocaine use was at record high (both capital cities & regional) in Dec 2023 since reporting began in April 2016. 2022–2023 National Drug Strategy Household Survey (NDSHS) Figure 1: Summary of alcohol, tobacco, e-cigarette, and illicit drug use, people aged 14 and over, 2022–2023 https://www.aihw.gov.au/reports/illicit-use-of-drugs/national-drug-strategy-household-survey/contents/summary Figure 1: Most used illegal drugs (excluding non-medical use of pharmaceuticals and cannabis), people aged 14 and over, 2022–2023 https://www.aihw.gov.au/reports/illicit-use-of-drugs/meth-amphetamine-ndshs 15 16  Figure 16: Use of cocaine in Australia, people aged 14 and over, 2001 to 2022–2023 https://www.aihw.gov.au/reports/illicit-use-of-drugs/national-drug-strategy-household-survey/contents/use-of-illicit-drugs National Wastewater Drug Monitoring Program www.acic.gov.au/sites/default/files/2024-07/Queensland%20%E2%80%93%20Report%2022.pdf www.acic.gov.au/sites/default/files/2024-07/Queensland%20%E2%80%93%20Report%2022.pdf www.acic.gov.au/sites/default/files/2024- 07/National%20Wastewater%20Drug%20Monitoring%20Program%20%E2%80%93%20Report%2022_0.pdf www.acic.gov.au/sites/default/files/2024- 07/National%20Wastewater%20Drug%20Monitoring%20Program%20%E2%80%93%20Report%2022_0.pdf https://www.acic.gov.au/sites/default/files/2024- 07/National%20Wastewater%20Drug%20Monitoring%20Program%20%E2%80%93%20Report%2022_0.pdf https://www.acic.gov.au/publications/national- wastewater-drug-monitoring-program-reports/report- 22-national-wastewater-drug-monitoring-program Administration, absorption, distribution & excretion of stimulants  Administration Amphetamines Weak bases (pKa = 9-10) Oral administration - ionized in digestive system (slower rate of absorption) - blood levels can be kept constant - medical uses Injection & inhalation - more potent than oral - rush Crystal Meth (Ettinger, 2011)  Ionization of drug molecules pKA Theoretical curve for weak base with pKA ~9-10 (adapted from McKim & Hancock, 2013, Fig. 1-7, p.15)  Administration Cocaine pKa = 8.7 Usually injected or inhaled Oral administration Ettinger Sucking coca leaves (2011) Mix leaves with lime (wood ashes) to  ionization (↑ absorption) Inhalation (salt or base forms) ‘tooting’: Inhaling vapor from heated powder Freebasing – separates cocaine from HCl Crack (cocaine HCl + sodium bicarbonate; ‘cocaine base’) Snorting powdered salt (cocaine HCl)  Absorption Amphetamines Oral – determined by food in stomach & physical activity Peak blood levels within 30 mins – 4 hrs Inhalation (smoked)/intranasal (snorted): ~2.5 hrs I.V. – peak blood level ~ 20 mins (subjective effects sooner) Cocaine IV crack – 2-5 mins Inhalation (snorting) – 30 – 60 min (10 – 20 min subj. effects) Freebasing & crack – not studied Since un-ionized should be extremely rapid absorption Distribution Amphetamines & cocaine cross the BBB & concentrate in kidneys & lungs (>amphetamine) & brain (>cocaine) Crack Cocaine Ettinger (2011)  Excretion Amphetamines Depends on pH of urine: more basic = more reabsorption 30-50% excreted unchanged/ rest metabolized by liver ½ life = 7-14 hours if acidic urine & 16-34 hours if basic Also excreted through sweat & saliva Metabolites can also be active with long half lives, can detect in urine ~ 1 week Cocaine Excreted faster than amphetamines ½ life = 45-75 minutes, also dependent on urine pH Metabolites may be present in urine 24-36 hrs >single admin. Metabolites also deposit in hair Effects of stimulants  Neurophysiology Both classes of drugs act on the monoamine synapses, but mechanisms differ Amphetamines Effect on synapses using 5HT, E, NE, & DA (esp. DA) 3 effects: 1. Cause NT to leak into synaptic cleft 2.  NT released due to AP 3. Block reuptake (& inhibit MAO activity) Cocaine 1 effect/action only: 1. Reuptake blocker  (DAT) (VMAT) Source: Text, Fig 10-1  Neurophysiology PNS: stimulate epinephrine synapses – fight-or-flight response CNS: multiple effects 1.  dopamine (DA) in nucleus accumbens (reinf. & motivation) 2.  DA in nigrostriatal system (motor activity) 3. Cocaine also blocks APs (via Na+ ion channel blocking) local anaesthetic - Procaine (Novocaine) Ettinger (2011)  Effects of stimulants On the body  HR & BP Vasodilation Bronchodilation Side effects include: Headaches Dry mouth Upset stomach Methamphetamine has fewer PNS effects  Effects of stimulants On sleep Prevents sleep Insomnia Suppression of REM sleep On mood Improve mood (2-5hrs)  fatigue/  energy Rush (IV & smoking routes; also snorting cocaine) Followed by depression/crash Acute tolerance to pleasurable effects Cocaine has shorter-acting effects (