6.

03 S UBS TAN C E A BUS E AN D D IS ORD E RS

DR. LYNN RODRIGO, May 7, 2021
Elysian Trans by shocky
CLINPHARMA
Outline All drugs of abuse
 are unnatural rewards
I. Neurobiology of addiction  cause the nucleus accumbens to receive a flood of dopamine
II. All drugs of abuse and dopamine-mimicking signals
III. Drug of abuse
 Drugs that activate G protein coupled receptors
 Drugs that mediate their effects via inotropic receptors
 Drugs that bind transporters of biogenic amines

Source: Doc Rodrigo’s ppt and Elysian MD2 trans (2019)

Neurobiology of Addiction
 Tolerance
o State of adaptation to a drug that results in reduced
effects at a given dosage
o Continued need for dose escalation to maintain
same level of pain relief
 Psychological Dependence (DEPENDENCE)
o State of response to a drug whereby removal of the drug
evokes unpleasant symptoms, usually
the opposite of the drug’s effects
o Abrupt cessation of opioid use or drugs with addictive
potential
o Administration of an opioid antagonist

 Psychological Dependence (ADDICTION)

o The state of response to a drug whereby the drug taker
feels compelled to use the drug and suffers anxiety when
separated from the drug
o Self-administered
o Drug use controls the user’s behavior
o Relatively rare in cancer patients

 Pseudoaddiction
o Borderline abnormal drug seeking behavior
o Undertreatment of pain
o Return to proper normal behavior after adequate pain
management

1 of 7
 6.03 SUBSTANCE ABUSE AND DISORDERS

o Oxycodone
o Meperidine – common among health professionals
 Withdrawal Syndrome
o Lacrimation, Intense dysphoria, Muscle aches
o Sweating, Nausea and Vomiting, Diarrhea,
o Mydriasis, Yawning, Fever, Piloerection

2. Cannabinoids
 Relative risk for addiction: 2
 ENDOgenous cannabinoids (known as RETROGRADE
MESSENGERS) act as neurotransmitters.
o 2-arachindonyl glycerol (2-AG) CB1
o Anandimide - Binds to CB1 receptors inhibiting release of
glutamate or GABA

 EXOgenous cannabinoids - acts by DISinhibition of dopamine

in neurons by PREsynaptic inhibition of GABA neurons in the
VTA (Ventral Tegmental Area)
o Marijuana
Ø Institute of Medicine (IOM) of the National Academy
of Sciences
- Justification of medicinal use of marijuana is
controversial
- Fear-gateway to the consumption of “hard”
drugs or schizophrenia (predisposed)
o Delta-9-Tetrahydrocanabinol (THC) – powerful
 4 Cs of Addiction psychoactive substance
o Impaired Control over drug use Ø Half-life: 4 hrs
o Compulsive drug use Ø Onset: within minutes
o Consequences: Continued use despite harm Ø Peak effect: (Maximum) 1-2hrs
o Craving Ø THC effects:
- euphoria and relaxation (most prominent)
-dysphoria
- feelings of well-being, grandiosity, and altered
perception of passage of time
- dose-dependent perceptual changes (visual
distortions)
-drowsiness
- diminished coordination
- memory impairment
- visual hallucination, depersonalization, frank
psychotic episodes are rare; very high doses
(e.g. hashish)
Ø Medical uses
- appetite stimulant
- attenuation of nausea
- decreases intraocular pressure
- relief of chronic pain
 Synthetic cannabinoid
Drugs of abuse o DRONABINOL – synthetic THC analog; FDA approved;
A. Drugs that activate G protein coupled receptors USA and some European countries
1. Opioids o NABILONE – older commercial THC analog
 Opioids as analgesic – rarely develop addiction Ø Recently reintroduced in USA for adjunctive therapy
 Opioids for recreational use – highly addictive in chronic pain management
 Relative risk ratio = 4/5  Chronic exposure – dependence, mild and short-lived
o 1 = nonaddictive while 5 = highly addictive  Withdrawal Syndrome
 Most commonly abused Mu opioids o Mild agitation
o Morphine o Nausea
o Heroin (diacetylmorphine) -> Morphine o Insomnia, irritability, restlessness
o Codeine o Cramping

2 of 7
 6.03 SUBSTANCE ABUSE AND DISORDERS

3. Gamma-Hydroxybutyric Acid
 First synthesize in 1960 – general anesthetic
 Produced during metabolism of GABA
 Function - unknown
 Pharmacology – complex
o Weak agonist (only GABA neurons inhibited)
o High doses - hyperpolarize dopamine neurons, inhbiting
dopamine release
o “anticraving” use
 2 distinct binding sites
o High affinity binding site for GHB – unclear
o Low-affinity binding site – GABA receptor
 Narrow safety margin and addictive potential
 Prescribed to treat narcolepsy
o Decreases daytime sleepiness and episodes of cataplexy
through mechanism unrelated to reward system
 Effects: 4. LSD, Mescaline, & Psilocybin
o Euphoria
 Hallucinogens
o enhanced sensory perceptions
o feeling of social closeness  Partial agonists of 5-HT2AR (Gq)
o amnesia  Neither dependence nor addiction
 Known as the DATE RAPE DRUG o Since studies show that they fail to stimulate dopamine
o Odorless release (unnatural reward in addiction)
o Readily dissolved in beverages  Repetitive exposure – rapid tolerance (tachyphylaxis)
o Rapidly absorbed after ingestion  Perceptual symptoms – shape and color distortion
o Maximum plasma conc: 20-30 minutes (10-20mg/kg  Psychosis-like manifestations (psychotomimetics)
dose) o Depersonalization
o Elimination t1/2: 30 minutes o Hallucination
 GHB Orange o Distorted time perception
- January 22, 2014 - 1st published in  Somatic symptoms
Chemical Communications o Dizziness
- March 25, 2014 -press release o Nausea
- novel fluorescent sensor to detect GHB o Paresthesias
- National University of Singapore o Blurred vision
- Prof. Chang Young-Tae- lead researcher,
Dept of Chemistry
- simple mix-and-see process, 30 sec

3 of 7
 6.03 SUBSTANCE ABUSE AND DISORDERS

2. Benzodiazepines
 Commonly prescribed as anxiolytics and sleep medications
 Moderate risk for abuse
o Euphoriant effects
o Concomitant w/ other drugs
 Dependence is common
 Diagnosis of addiction is often missed
 Withdrawal symptoms
o Varies as a function of elimination half-life
o Irritability, insomnia, depression, muscle cramps, seizures,
phonophobia, photophobia
o Taper: 1-2 week

3. Alcohol
 Used by majority in Western countries
 Minority becomes dependent and addicted
 Abuse is a very serious public health problem
 Alters the function of several receptors and cellular functions
o Kir3/GIRK channels
o Adenosine reuptake (equilibrative nucleotide transporter
LSD or lysergic acid diethylamide (ENT1)
Ø Alcohol dependence through accumulation of
 Ergot alkaloid adenosine-> stimulation of adenosine A2 receptors
 Discoverer: Swiss chemist Albert Hoffman (took the first -> ensuing CREB signaling
“trip”) o Glycine receptor
 Use burgeoned (flourished chos) in 1960s when The o NMDAR
Beatles were linked with it o 5-HT3R
 How to use: Blotted paper or sugar cubes are sprinkled with  Dependence - 6-12 hours after cessation of heavy drinking
liquid LSD  Withdrawal syndrome (effects):
 psychoactive effects - after 30 minutes; last 6-12 hours o tremor (mainly of hands)
 impaired ability to make rational judgments o nausea and vomiting
o excessive sweating
B. Drugs that Mediate their Effects via Ionotropic Receptors
o agitation
1. Nicotine o anxiety
 Used by more than 50% of all adults in some countries  Withdrawal syndrome
 Addiction to nicotine exceeds all other forms of addiction o 12-24H – visual, tactile, and auditory hallucination
 Smoking tobacco – responsible for preventable deaths o 24-48H – generalized seizure
 Selective agonist of nAChR o 48-72H – alcohol withdrawal delirium (delirium tremens)
o nAChR – important role in many cognitive process Ø Hallucinates, disoriented, autonomic instability
 enhances cognitive performance Ø 5-15% mortality
 relative risk: 4  Treatment of ethanol withdrawal
 association of Alzheimer’s dementia with loss of Ach o Supportive
releasing neurons from nucleus basalis of Meynert o Benzodiazepines
 Withdrawal syndrome – mild Ø oxazepam and lorazepam (since not dependent on
o Irritability hepatic metabolism)
o Sleep problems Ø Chlordiazepoxide (long-acting benzodiazepine) –
 Relapse after attempted cessation – very common for Px with normal liver enzymes where monitoring is
not reliable
 Treatment:
o Psychosocial approach
o Nicotine in slowly absorbed forms and other drugs
(nicotine patch)
o Nicotine in cigarettes 4. Ketamine and Phencyclidine (PCP)
o 2 partial agonists of a4B2-containing nAChRs  Developed for general anesthesia
Ø Cytisine – plant extract o Ketamine – only drug remained for general anesthesia
Ø Varenicline – synthetic derivative; impair the use
capacity to drive; associated with suicide ideation  “Club Drugs”; “Angel dust”; “Hog”; “Special K”
o Bupropion - antidepressant; approved for nicotine  use-dependent, noncompetitive antagonism of the NMDAR
cessation therapy; combine with behavioral therapies –  Patients undergoing surgery - unpleasant vivid dreams and
most effective hallucination after anesthesia
 Pure forms – WHITE crystalline powders

4 of 7
 6.03 SUBSTANCE ABUSE AND DISORDERS

 Street: liquids, capsules, or pills - Snorted, Ingested, Injected,

Smoked
 Effects:
o Psychodelic effects for 1 hour
o INCREASED BP
o Impaired memory function
o Visual Alteration
o Unpleasant out of body and near death experience (high
doses)
o Chronic exposure: long-lasting psychosis –
schizophrenia; May persist beyond drug use
 Do not cause dependence or addiction (relative risk: 1)

5. Inhalants
 Inhalant abuse – recreational exposure to these chemical
vapors such as nitrates, ketones, aliphatic and aromatic
hydrocarbons
 Inhaled by:
o Sniffing – inhalation from an open container
o Huffing – soaking of cloth in a volatile substance
o Bagging – breathing in and out of a paper or plastic bag  Cocaine exposure
filled with fumes o Risk for intracranial hemorrhage
 Prevalent in children and young adults o Ischemic stroke
 Exact mechanism: unknown o Myocardial infarction
 Altered function of ionotropic receptors and ion channels o Seizures
throughout the CNS  Cocaine overdose
 Effects: o Hyperthermia
o Most inhalants – euphoria o Coma
o Toluene – increased excitability of VTA (addiction risk) o Death
o Amyl nitrite “poppers” – smooth muscle relaxation and  Susceptible individual
enhanced erection (not addictive) o Dependent and addicted after only a few exposure
o Chronic exposure to aromatic hydrocarbons (benzene  Withdrawal syndrome
and toluene) – toxic effects on many organs esp WHITE o Not as severe as opioids
mater lesions in CNS  Tolerance and reverse tolerance
 Management of overdose: supportive  Very strong cravings – very high addiction liability
 Management of intoxication
C. Drugs that bind transporters of biogenic amines o No antagonist available
1. Cocaine o Supportive
 Major public health problem worldwide o Developing pharmacologic treatment – TOP PRIORITY
 Relative risk = 5 -> highly addictive
 Leaves of eythroxylon coca 2. Amphetamines
 Cocaine hydrochloride  Synthetic
o Water-soluble salt – injected or absorbed by any mucosal  Indirect-acting sympathomimetic drugs – release of
membranes endogenous biogenic amines (dopamine and noradrenaline)
o Heated in alkaline solution – free base

5 of 7
 6.03 SUBSTANCE ABUSE AND DISORDERS

3. Ecstacy (MDMA)
 Class of drugs include derivatives of
methylenedioxymethamphetamine (amphetamine-related
compound)
 Originally used in psychotherapy but no medical effects
documented
 Foster feelings of intimacy and empathy without impairing
intellectual capacities

 Differ from ecstasy (context of use) – IV administration

o “hard core” addiction is more common (esp
methamphetamine)
 Neurotoxic
o exact mechanism: unknown
o depends on the NMDA receptor and serotonin and
dopamine neurons
 pill (initially), smoke or injection
 short term effects
o feelings of euphoria and excitement
o inc. strength and confidence
o sense of power and superiority
o repetitive acts and talkativeness
o abrupt shift in thought and speech
o nervousness, anxiety and panic
o inc. libido
o paranoia and hallucinations
o irritability, hostility and aggression
o headaches & dizziness
o hypervigilance & difficulty sleeping
o enlarged (dilated) pupils
o palpitations and shortness of breath
o chest pain
o reduced appetite
o stomach cramps (if swallowed)
o itching, picking, and scratching
 long term effects
o malnutrition and rapid weight loss
o chronic sleeping problems
o cracked teeth and dental problems
o high BP
o rapid irreg heartbeat
o depression, anxiety and tension
o paranoia and violence
o psychological problems
o panic and confusion
o muscle rigidity
o reduced immunity
o increased susceptibility to infections
o damage to the heart muscle
o heart attack and heart failure
o kidney failure
o death
 HIV and hepatitis – needle sharing
 Chronic use – tolerance leading to dose escalation
 Withdrawal syndrome
o Dysphoria
o Drowsiness/insomnia
o General irritability

6 of 7
 6.03 S UBS TAN C E A BUS E AN D D IS ORD E RS
DR. LYNN RODRIGO, May 7, 2021
Elysian Trans by shocky
CLINPHARMA

Appendix:

Clerks by August 1, MDs by 2022

7 of 7