Substance Use Disorders
All substance abuse drugs are NEGATIVELY REINFORCING
manipulates you to do what is even bad for you. In withdrawal punishment comes
Reinforcers vs. Punishers
Reinforcers
- Increase Probability of Behavior
Punishers
- Decrease Probability of Behavior
Who would like for me to give you something that makes you feel good?
REINFORCER
It doesn’t matter if its positive or negative.
Actually, negative is a more powerful reinforce.
Who would like for me to give you something that makes you feel good?
REINFORCER
Positive Reinforcer
Who would like for me to give you something that makes you feel BAD?
Punisher
This is NOT a NEGATIVE REINFORCER
Who would like for me to TAKE AWAY something that makes you feel good?
Punisher
Who would like for me to TAKE AWAY something that makes you feel BAD?
Reinforcer
NEGATIVE REINFORCER – All drugs are negative reinforcers
|
TYPE
|
GIVE
|
TAKE AWAY
|
|
GOOD
|
Positive Reinforcer
|
Punisher
|
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BAD
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Punisher Negative
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Reinforcer
|
Self-Reinforcing Properties
Drugs that take away pain:
Self-Reinforcing
Negatively Reinforcing e.g. Religion, Movies, Disney (takes away the pain)
Increase probability of repeated abuse to stop pain of withdrawal
Withdrawal
is
NEGATIVELY REINFORCING!
Increases the probability you will relapse!
Let’s create a Self-Reinforcing Drug. . .
CREATE A DRUG. . .
• “Makes me feel good”
• “Chills me out”
• “Forget my troubles”
• “Takes away my pain”
• Would you buy this drug?
CREATE A DRUG. . .
• DA Dopamine agonist
• “Makes me feel good”
• GABA agonist
• “Chills me out”
• Glutamate antagonist
• Forget my troubles”
• Mu opiate agonist
“Takes away my pain” (close to death to reach this point)
• Put it all together: Feel good, Chilled Out, No Worries, No Pain.
Would you buy this drug? – Alcohol C2HO8
Why is it Negatively Reinforcing?
Mesolimbic-Dopamine System
• 1 of 6 Dopamine Pathways
• Ventral Tegmental Area (VTA) to Amygdala and Nucleus Accumbens (NA)
• Nucleus Accumbens, reward center of brain
• Amygdala attaches positive valence to abuse
• Hippocampus, memory of drug’s effect
• Activates Glutamate
Overview
Substance Abuse
Estimate: 50% of an individual’s likelihood of having a substance abuse associated with genetic predisposition
Likely not “inheritance,” but “genetic predisposition”
Alcohol
Central Nervous System Depressant
Wernicke-Korsakoff Syndrome Thiamine deficiency
Ataxia
Confabulation
Oculogyric Problems
Zero-Order Kinetics
Binge Drinking: 5 for Men 4 for Women
Alcohol Health Benefits
Decreased: Pro-inflammatory Cytokines; Gallstones; Kidney Stones (also with Caffeine); Diabetes; Heart Disease & Platelet Aggregation
Increased:HDL & Vasodilation
Cannabis
Δ9-THC (tetrahydrocannabinol) (isolated in 1964) Unique has its own Classification System
Mechanism of Action
Lowers Adenylate cyclase (catalyzes the conversion of ATP to cAMP, regulator of stored energy); Lowers Glutamate in hippocampus; Lowers ACh, DA, NE, 5-HT ;LowersCa++; AChEse inhibitor in CNS; Facilitates K+ & μ opiate agonist
Stimulates DA firing in VTA & Increases release of DA in nucleus accumbens (self-reinforcing)
Chronic Use: lowered Testosterone; lowered Sperm Count; lowered Viability; lowered Follicle Stimulating Hormone; lowered Luteinizing; Menstrual Cycles Affected & Anovulatory Cycles
Treatment for. Nausea; Appetite; Analgesia; Decreases Inter-Ocular Pressure (IOC); Bronchodilation Seizures (Increases Seizure Threshold); Tourette’s; Multiple Sclerosis; Inflammatory & Neuropathic Pain & Menstrual Difficulties
Cannabinoid Hyperemesis Syndrome
Characterized by nausea, vomiting, & colicky abdominal pain.
Proposed Disorder, currently unlisted
Affects of Cannabis
Age of use significantly affects biological process
Use ‹17 YOA: Smaller whole brain volumes; Less cortical gray matter; Greater amounts of cerebral blood flow
THC increases cognitive effort for simple inhibitory tasks: Slower processing speed; Memory problems & Decreased Attention
Cannabis Withdrawal
Symptoms emerge 1 day after discontinuation & Peak at about 1 week & Last up to 3 weeks
Symptoms: Cravings; Anorexia; Irritability; Restlessness & Sleep Disturbances
Epidiolex®
Liquid formulation of highly purified cannabidiol (CBD) – 1 of 85 active cannabinoids identified in cannabis
Cannabidiols, 40% of plant extract, lack psychoactivity no interference with psychomotor of psychological functioning
Investigational Drug – Not approved for use by FDA
Orphan drug designation granted for Epidiolex® for: Lennox-Gestaut Syndromes (Fast Track Designation) Dravet Syndrome (Severe Myoclonic Epilepsy of Infancy, SMEI, rare genetic epileptic encephalopathy)
6.3 children per 1000 diagnosed with epilepsy
Cannabis & Post Traumatic Stress Disorder
Possible Explanation of Cannabis’s effectiveness in treatment of PTSI
Potentiates GABA in amygdala
Concomitantly antagonizes (blocks) Glutamate in amygdala
Result: Extinguish Fear Memories
Decreases GABA at Ventral Tegmental Area (VTA) which increases DA
Result: Patient feels better!
Cannabis & Viagra®
Cannabis & Viagra® Don’t Mix!
Cannabis CYP 3A4 Inhibitor (enzyme needed to breakdown Viagra)
Viagra, metabolized by CYP 3A4
MIX = Cardiac ARREST
Cannabis
Recent Cause of Concern
Increae Heart Rate & Increase Blood Pressure
When Lying Down = May Cause Heart to Lose Rhythm
2 Recent Deaths in Colorado
Cocaine
MOA: SNDRI Serotonin, norepinephrine, dopamine, reup inhibitor
Long Lasting DA decreaser & Tyrosine hydroxylase decreaser
Damages 5-HT Serotonin fibers in neo-cortex, hippocampus, & striatum
Stereotypies (Pronounced: “Stare-e-ot-o-pees”)
Sympathomimetic
Chronic Use: Long-term deficit in frontal lobe glucose utilization; Decrease gray matter & Decreased attention, verbal memory, & motor function
Cocaine as a Negative Reinforcer
A single dose of cocaine auses up-regulation of receptors; Can last as long as a month and
Leads to craving & drug seeking behavior
Cocaine the Perfect Heart Attack Drug
Sympathomimetic Increases Aortic Stiffness; Increases Systolic Blood Pressure;Increases Thickness of Heart’s Left Ventricle
FYI: Cocaine Causes Hyperthermia: decreases Sweating – Do not feel discomfort & increase Deaths in Summer
Caffeine
Mechanism of Action: Adenosine Antagonist at A1 and weakly at A2;
1/16th tsp = 250 mg 3 Red Bulls®
1 tsp = 50 Red Bulls®
Foosh® Energy Mints = 1 Red Bull ®
Stimulant; Absorbed Rapidly, Peak Effects within 30 Minutes
>250 mg per day may interfere with deep sleep
Half Life Caffeine
• t ½ = 3-5 Hours
• t ½ = 10 Hours when mixed with contraceptives
• t ½ = Increased more than 3-5 Hours in Fetus
• t ½ = Increased when mixed with SSRIs
A1 Antagonist
• decreased Ach acetylcholine - memory
• decreased NE norepinephrine – energy, alertness
• decreased DA dopamine - sad
• decreased 5-HT serotonin - apathy
• decreased GABA - anxious
Central Nervous System Stimulant
“Zeitgeber” works on hypothalamus; Alert; Insomnia; increased Heart Rate; Diuretic; Constricts Cerebral Blood Vessels (30%); Dilates Peripheral Blood Vessels; Dilates Coronary Arteries; Constricts Cerebral Arteries & Decreases blood flow and pressure in brain by 30%; increase heart rate; increase Body Temperature; increase Blood Pressure; increase Blood flow to skin/extremities; increase Blood Sugar; increase Stomach Acid & increases Urine (diuretic)
Caffeine Suppositories - Tour de France Neurogum® “Optimize Your Body & Mind” Nootropic Chewing Gum $35 (pack of 12)
Nicotine
Perfect Nootropic (mind nourishing) – except for one pesky, little side effect!
Most Addictive Psychoactive Substance - Central Nervous System Stimulant
Approximately 90% absorbed = very toxic drug
Mimics Acetylcholine - Biphasic: Stimulates then Blocks
T 1/2 = 90 Minutes
First Cigarette in the Morning the Best (Withdrawal); Lowers Dose, Left Hemisphere = Mental Stimulation; increases Dose, Right Hemisphere = Sedation
Casual vs. Chain Smokers: CYP 1A2 Inducer & 2A6 Inducer; decreases Oxygen to heart Thereby increasing amount of work heart must do: increase Heart Rate; increases Blood Pressure; increases Atherosclerosis (artery wall thickens); Risk of Thrombosis (narrowing & clotting); increases Cognitive Performance (nootropic); increases Arousal & increases Muscle Tone
OPIATES
Introduction of Hypodermic Needle 1856
Analgesic – Relieve pain without producing unconsciousness
94% of World Opiate Supply from Afghanistan
Most US Opiates from Columbia & Mexico
Harrison Act, 1914, required physicians to report prescriptions for opiates
Indicators of Opiate Poisoning - The Opioid overdose Triad: Coma, Pinpoint Pupils & Depressed Respiration
OPIATE Receptors
ORL-1, Opiate Receptor Like-1; Mu (μ) (Endorphins) when hit get pain relief, pleasure, hero affect; Found Throughout Brain
High doses act on regulation of respiration in ventral medulla, inhibiting respiratory responses triggered by carbon dioxide – result, respiratory depression
Delta (δ) (Enkephalins) Found in striatum and nucleus accumbens for pleasure; Kappa (_) (Dynorphins); Contributes more to dysphoria & thermoregulation Amygdala, hippocampus, & pituitary; Tolerance; Analgesic effects, rapid tolerance; Constipation & Pinpoint Pupils, limited tolerance
Chronic Use: decrease Testosterone & decrease Estrogen (as much as 50%); decrease Melatonin, Interferes with REM and Δ Delta Sleep; decrease Adenosine; Ataxic/Biot’s Respiration (quick, irregular apnea); Adrenergic Rebound (when come off the drug) and decreaseNorepinephrine in Locus Coeruleus
Natural Narcotics: Morphine & Codeine (prototype Pro drug)
Semisynthetic Narcotics
Heroin; Hydromorphone (Dilaudid®); Oxycodone (OxyContin®; Percodan®; Oxecta®, breaks into chunks, not powder,turns to gel if mixed with H2O, contains sodium laurel sulfate, irritant to nose if snorted)
Totally Synthetic Narcotics
Meperidine (Demerol®); Fentanyl (Sublimaze®) (Lazanda®, fentanyl nasal) (marijuana became legal the Mexican cartels lost money and looked for a drug easy to make which works fast)
Methadone (Dolophine®) (Nazi drug, in WWII, using heroine as drug to kill people with dignity got if from Afghanistan, but when allies cut the path to get opiates from Afghanistan, they created a synthetic opiate and named in his honor Adolf Hitler) (rosh drug offered Christ on cross – head of poppy plant- opiate wine and myhrr)
New Opiate Partial Agonist
Belbuca® (bel-BYOO-kuh) Twice-daily film – hydrophilic polymer that rapidly dissolves on tongue.Joins Butrans® once-weekly patch as another buprenorphine product approved for chronic pain
C-III, lower abuse potential than other opiods; Fewer withdrawal if stopped; Less risky in overdose; Possible analgesic ceiling & Can be abused!
• NOTE: OxyContin® (oxycodone ER) - generic!
Antagonists
Naloxone (Narcan®, Evzio®)
Naltrexone (ReVia®, Vivitrol®)
Mixed Agonist-Antagonist
Buprenorphine (Buprenex®, Subtex®)
Opiate Partial Agonist combined with naloxone (antagonist)
FYI: Contrave® = Naltrexone + Bupropion Weight Loss
PCP & Ketamine
Entheogenics (allow you see the face of God) “To be one with the Universe”
Along with Ecstasy (MDMA), LSD, mushrooms, ketamine and phencyclidine fall broadly under “hallucinogens”
MOA: NMDA Antagonists (Glutamate) Closely Related Compounds; Dissociative Amnesia – “Down the K Hole”; Highly Reinforcing; Paranoia; Catatonia; Convulsions ;Vertical Nystagmus & Coma with Eyes Open
Overdose
Positive (Delusions & Hallucinations) & Negative (Affect, Anhedonia, inAttention, Alogia, Avolition) Psychotic Symptoms
MDMA - Ecstasy
Entacogenic (Latin. “tactus,” to touch)
1914 – Appetite Suppressant
1950s – Tested for “Brainwashing”
1970s – Therapeutic EST (Erhard Seminars Training)
1970s CIA Ultra
MOA: SRI, Stimulates DA, 5-HT > DA (could be used to treat autism-missing mirror neurons)
Damages 5-HT pathways in forebrain; Axons pruned (will regrow, but not same); lowers 5-HT Function
Side Effects: Water toxicity; Trismus – tightening of jaw muscles & Bruxism, teeth grinding
MDMA Side Effects
Mouth (biting inside of mouth)
Death (“Suicide Tuesday,” affinity for 5-HT-2B receptor in heart)
Memory (can last up to 40 days)
Aqua (Hypotonic, water intoxication)
UNIQUE ACTION
Has the ability to uncouple the energy-producing capacity of mitochondria in the body
Mitochondria loses its ability to generate ATP, body’s principal energy currency
Can’t generate ATP, mitochondria waste their energy as heat
Seen mostly in muscles
Males have more muscles; they are more sensitive to this phenomena than females
Inhalants
MOA: Not clearly known; Enhances inhibitory GABAA; Inhibits NMDA (Glutamate antagonist); Increases DA in VTA; More brain abnormalities than cocaine, amphetamine, marijuana, opiates & alcohol; Methemoglobinemia
Damage: Highly perfused areas Liver, Kidney, Lungs, Brain (Highly vulnerable), Cognitive Abnormalities & White matter (myelin) abnormalities; “Sudden Sniffing Death Syndrome” FATAL: 1 whiff = heart arrhythmias
Inhalant ABUSE
Hearing Loss, Peripheral Neuritis, Paresthesia, Cerebellar Signs, Motor impairment, Rhabdomyolysis, Irreversible Hepatic & Renal Damage, GI Distress – Vomiting & Hematemesis, Nausea & Vomiting; Headache, Appetite Decrease, Light Sensitivity, Aches Muscle, Neurons Decreased, Tachycardia (arrhythmias) & Tinnitus, Skin Rash, Sneezing, Sniffling, Slurred Speech
Unsuspecting Parents & Inhalants
Helium & Gasoline 46% of Acute Fatalities
Energy vs. Chill Drinks
Energy Drinks:
• Red Bull®
• NOS®
• Monster®
• Anti-Energy Drinks (“Relaxation Drinks”)
• Bliss®
• Just Chill®
• Dream Water®
• iChill®
• Marley’s Mellow Mood®
• “Drank® – To Slow Your Roll”
Energy Drinks
Ingredients: Ephedrine (in ADHD medicines), Taurine – amino acid regulates heart beats & muscle *, Ginseng – root believed to reduce stress & boost energy, B-Vitamins – Group of vitamins that can convert sugar to energy & improve muscle tone
Side Effects
Cardiac Arrest, Headaches & Migraine, Insomnia, Type 2 Diabetes
Drug Interactions
Addiction, Risky Behavior, Vomiting, Jitteriness & Nervousness, Allergic Reactions
Relaxation Drinks
“Anti-Energy”, Ingredients (usually not listed; combination of): GABA, Melatonin, L-theanine – amino acid in green tea shows some evidence for relaxation, L-threonine, amino acid in proteins, no evidence it facilitates relaxation, 5-HTP – 5-hydroxytryptophan, raises serotonin, Botanicals: Chamomile, passion flower, and valerian, KAVA – GABAA agonist, NDRI, CB1 agonist, MAO-B reversible inhibitor, Na+ &,Ca++ channel inhibitors
Side Effects
Consumer Reports: “Little evidence these products have been associated with harmful reactions.” But: Drowsiness, Should be avoided by pregnant or nursing women, Not for children, Avoid with alcohol, Sugar Content: 0 to 54 grams
Over-the-Counter & Herbal
Psychopharmacology Natural, not necessarily safe!
Anxiety & Tension
B-Complex
5-HTP
St. John’s Wort
Sage
Valerian
L-theanine
N-Acetyl cysteine (overly promoted prodrug, free radical scavenger)
Depression
St. John’s Wort
5-HTP & tyrosine
Pumpkin Seeds
B-Complex
Vitamin D
Folic Acid
N-Acetyl cysteine
SAMe
Memory
Choline – Aricept
Huperzine-A (HUP-A) work similarly to aricept
Gingko
Ginseng
Sleep
GABA
Melatonin
Valerian
Lavender Oil (Aroma Therapy)
Lemon Balm
Chamomile
