. Addiction Circle (Abuse, Dependence, Addiction) 2. Pathophysiology of Addiction and Reward or pleasure pathway 3. Mechanism of addictive Drugs on Reward System 4. Signs and Symptoms of intoxication and Withdrawal of different Drugs 5. Table List of most common Addictive drugs classified according to action 6. treatment of intoxication 7. Treatment of Withdrawal Syndrome

1. Pharmacotherapy of
Drug Abuse
Prof. Sawsan Aboul-Fotouh
Department of pharmacology, faculty of Medicine, Ain shams University

2. 1. Distinguish between drug Abuse, drug misuse and drug dependence.
2. Identify the anatomical areas of the brain involved in the reward
(pleasure) pathway
3. Outline the neurotransmitter systems which activate the reward
pathway
4. Specify the anatomical areas and receptors involved in activation from
psychoactive drugs
5. Predict the anatomical areas and receptors involved in the withdrawal
from psychoactive drugs
6. Understand concepts relating to the development of drug addiction.
7. Apply the pharmacological basis for proper selection of the drugs used
in the management of intoxication and withdrawal symptoms of
substances abuse

3. Important Terminologies and Concepts
• Drug abuse:
Intentional and inappropriate use of a drug
resulting in physical, emotional, financial,
social & intellectual harmful consequences.
e.g. seeking for euphoria or alter perception.
• Drug misuse:
unintentional or inappropriate use of the
prescribed OTC (or using drugs without a
prescription). Misuse can include taking a
drug in a manner or at a dose that was not
recommended by the physician.

4. • Drug dependence:
A drug is needed to function normally.
A. Physical dependence
indicates an altered physiological state due to repeated
administration of a drug, the cessation of which results
in a specific syndrome (Withdrawal Syndrome).
Important Terminologies and Concepts

5. B. Drug addiction: “Psychological dependence”
- Compulsive repeated use of a substance, despite its
negative, harmful or dangerous effects. Loss control on
taking a Drug. e.g. CVS diseases, cancers with tobacco smoke,
-There is Craving.
Important Terminologies and Concepts
Intense desire to take the drug
Craving

6. • It is possible to be dependent on a drug without
being addicted.
e.g. A terminal cancer patient being treated with
morphine for pain will experience withdrawal if the
drug is stopped, but they are not a compulsive user of
the drug therefore they are not addicted.

7. Tolerance:
 Drug response after continuous use  Need larger dose to
produce the same initial effect  loss of control of addict over
amount of drug used.

8. Abuse
Dependence
Addiction

10. Drug Group Most Common Other Examples
I. CNS Depressants
A.Opioids
B. Sedative hypnotics
• Heroin
• Morphine
• Codeine
• Meperidine
• Hydromorphone
• Ethanol or Alcohols
• Benzodiazepines
• Rohypnol© (Flunitrazepam)
• Barbiturates
• Nonbarbiturate sedatives (Lyrica)
II. CNS Stimulants
• Cocaine
• Methamphetamine (Ice)
• MDMA or Ecstasy (Hallucinogen)
• Amphetamines
• Methylphenidate
• Nicotine, Khat (Cathinone)
III. Hallucinogens
psychedelics
• Lysergic acid diethylamide (LSD)
• Dimethyltryptamine (DMT)
• Phencyclidine (PCP)
• Ketamine
• Psilocybin, Ayahuasca
• Mescaline (peyote cactus),
IV. Cannabinoids • Hashish, cannabis, Marijuana
• Bhango, Weed
• Synthetic (Voodoo and Strox)
V. Inhalants
(hallucination &euphoria)
VI. Others
• (solvents glue & Paint)
• OTC Cough/Cold Medicines
(Dextromethorphan )
• Steroids (Anabolic)
• Nitrous oxide, Ether
• Anticholinergics
-Benztropine & Trihexyphenidyl tablets -
Cyclopentolate & Tropicamide eye drops

11. Pathophysiology of Drug
Addiction

12. Reward (Pleasure) Pathway
(plays a key role in addiction)
1. Nucleus accumbens (NAc) = Pleasure center
2. Ventral tegmental area (VTA)
3. Prefrontal cortex (PFC)
Pleasure center
↑ ↑Dopamine in
NAc →Euphoria
NAc

13. TYPES OF REWARD SYSTEMS
A. NATURAL reward stimulus
(e.g., food, water, sex, ….)
B. ARTIFICIAL reward stimulus
(e.g., drugs as heroin, Hashish ……),
information travels from VTA to NAc & then to PFC.
VTA contains dopamine (DA) neurons which release DA in the nucleus
accumbens →Euphoria and in the prefrontal cortex (Behavior)

14. Drugs Act in Different Parts of
Reward pathway
• Heroin, Alcohol, Hashish (Cannabis) & nicotine (Tobacco)
act on the VTA stimulating the dopaminergic neuron cell body to
release DA in the NAc →↑ DA in NAc →Euphoria.
• Alcohol induce euphoria via release of endogenous opioids in VTA
• BZD also stimulate DA neurons in VTA & enhance euphoric effect of other substances
Heroin, Alcohol,
Hashish &nicotine

15. • Amphetamines and Cocaine act directly on NAc DA nerve
terminal to stimulate release and/or inhibit the reuptake of
DA→↑ DA in NAc→ Euphoria
Drugs Act in Different Parts of
Reward pathway
Amphetamines
Cocaine

16. Heroin, Alcohol,
Hashish &nicotine
Amphetamines
& Cocaine

17. • In all rewards, dopamine is the final
activation chemical that induce euphoria
when increased in the NAc
↑↑Dopamine

18. REWARD DEFICIENCY
• Prolonged drug use → neurodegeneration of DA
neurons in the reward pathway → chronic feelings of
anxiety, depression & an inability to feel good.
• And ↓ DA in NAc → development of craving.
• The person can only feel normal when under the influence of the
drug and developed negative and positive reinforcement.
18

19. Negative reinforcement
Escape and avoidance of negative affect is the motive for
addictive drug use
Positive reinforcement
Pleasurable sensations associated with a taking the drug
or addiction behavior, motivating the person to repeat
drug intake.

20. Withdrawal:
Corticotrophin Releasing Factor (CRF) affective & somatic symptoms
Heart rate
Blood pressure
Blood glucose
Response to stressors
Key elements CRF and NE neurons in the amygdala

21. Signs and symptoms of overdose or
Intoxication
Hypothermia
( CAT): Arrhythmia, BP. - Myocardial infarction (esp. Cocaine)

22. Signs and symptoms of Withdrawal from
selected drugs of abuse
Body aches
Sympathetic overactivity, hyperthermia
Very Strong Craving w Cocaine
Delirium Tremens

23. Alcohol
(Strong Dependence)
Mechanism : enhances GABA-A receptor action (cross tolerance with BZDs),
↓glutamate, release endogenous opioids (euphoric effect).
Acute Effects
• Euphoria - relaxation - increased self-confidence.
Withdrawal Syndrome
• Similar to barbiturates with delirium tremens:
delirium - tremors - psychosis (visual hallucinations of crawling bugs).
Chronic Abuse (Alcoholism)
1. Withdrawn, homicidal or suicidal individual - work & family problems.
2. Liver cirrhosis - peptic ulcer – cardiomyopathy.
3. Dementia - peripheral neuropathy.
4. ↓↓Thiamine (Vit. B1)  Wernicke-Korsakoff syndrome (Ophthalmoplegia,
ataxia, confusion, psychosis).

24. Ophthalmoplegia + Ataxia + Confusion
Psychosis + Amnesia
(Wernicke’s encephalopathy)
(Korsakoff’s syndrome)

25. Nicotine
(Very Strong Craving)
Mechanism : acts on central α4β2 nicotinic Ach receptors in VTA → ↑DA in
NAc reward pathway → reward upon smoking → dependence.
Acute Effects: euphoria -  anxiety -  concentration -appetite
Chronic Abuse: cancer, lung diseases, ischemic heart diseases.
Withdrawal Syndrome: Insomnia - Anxiety – aggression- Depression -
 appetite.

26. Lysergic Acid Diethylamide (LSD)
(Other hallucinogens: DMT, PCP…..)
• Taken recreationally not regularly  no dependence ??? (NIDA)
Acute Effects
• Euphoria & sensory changes: sights & sounds are distorted & fantastic.
• Hallucinations, delusions, illusions, Philosophical & creative thinking.
Risk of LSD Bad trips: frightening hallucinations  homicide or suicide.
Persistent Psychosis and flashbacks are two long-term effects of Hallucinogens.

27. Cannabis
“Hashish, Marijuana & Bhang”
• THC (Δ9-tetrahydrocannabinol) is the most psychoactive principal in cannabis.
• THC act on brain cannabinoid CB1 receptors and V1 vanilloid pain receptors.
Acute Effects (CNS ++ → -- ; sleep & relaxation)
1. Euphoria (+VTA), ↑ perceptions (sights, sounds →fantastic).
3.  Motor & mental skills (cannot drive or speak..).
4. Hallucinations & delusions (rare).
5. Philosophical & creative thinking.
Withdrawal syndrome: (usually mild) Addiction (NIDA,2015)
Irritability, Anxiety, Depression
Sweating, Confusion, Tremor, Insomnia, ↑BW
cannabis
Joint

28. Risks of Cannabis Abuse
1. Academic failure & ↓achievement& life outcomes
2. Psychosis (Hallucination, delusions “Schizophrenia”)
3. Motor Deficits:↓ Cerebellar Metabolism
4. Amotivational syndrome.
5. The immune system impaired.
6. Sexual & reproductive Dysfunction:
-Male: ↓ testosterone, sperm count& ability, libido
-Female: inhibition of ovulation.
In Pregnancy: miscarriage
and ectopic pregnancy

29. Management of Acute Intoxication
in substance Abuse

30. Management of Acute Intoxication in
substance Abuse
1. Correction of life-threatening symptoms: (ABC)
2. Prevention absorption:
3. Facilitate removal
-Alkalinization (Na Hco3) of urine with Barbiturates (acidic PKa)
-Acidification (As. a, NH4Cl) , of urine with Amphetamine (basic PKa)
-Forced diuresis ,Peritoneal dialysis, hemodialysis

31. 4. Antidote (if present):
-Naloxone in Heroin intoxication
-Flumazenil in Benzodiazepine intoxication
-In Alcohol Intoxication:
▪ IV glucose to correct hypoglycemia (acute pancreatitis).
▪ Thiamine 100 mg IV or IM (to prevent neurologic injury)
5.Haloperidol and /or Midazolam injection for Agitation
and psychosis (e.g. in stimulants, Hallucinogens, Alcohols…)
Management of Acute Intoxication in
substance Abuse

32. LSD (DMT, PCP…) Abuse
• Calm the patient during bad trips.
1-long-lasting benzodiazepines, e.g. diazepam, clonazepam
2-Anticonvulsants valproate & carbamazepine (Mainly anti-impulsivity)
3-Antipsychotic agents for hallucinogen-induced psychosis,
Management of Acute Intoxication in
substance Abuse

33. Management of Withdrawal Syndrome
in substance Abuse

34. Short-acting agents have More abuse &
More Withdrawal syndrome than that
following longer-acting agents.

35. I. symptomatic treatments:
e.g. Ibuprofen for Body aches,
-promethazine for nausea & vomiting,
-diphenhydramine for sleep.
-Mirtazepine as antidepressant and hypnotic. Ramelteon hypnotic
- Haloperidol injection for Agitation and psychosis
II. Anti-impulsivity Drugs:
SSRIs e.g. Fluoxetine & antiepileptics e.g. valproate, carbamazepine
Management of Withdrawal Syndrome in
substance Abuse

36. III. α2 Agonists if sympathetic overactivity
e.g. Clonidine especially in Heroin withdrawal.
IV. Specific strategies in:
A- Heroin abuse: (see Opioids)
Detoxification (by Methadone or Buprenorphine) and
then Maintenance (on Naltrexone).
B- Barbiturates and BZDs abuse:
Replace short-acting agent by a longer-acting one  less severe withdrawal:
Phenobarbital for pentobarbital. Diazepam for clonazepam, alprazolam, flunitrazepam.
Management of Withdrawal Syndrome in
substance Abuse (cont.)

37. C- Tobacco (Nicotine) abuse:
1.Nicotine replacement : nicotine gum - transdermal patch -
inhaler – nasal spray.
2. Bupropion: ↑DA →↓ craving & Blocks α4β2 nAch R→ ↓ Relapse.
3.Varenicline : partial agonist at CNS α4β2 nicotinic Ach receptors →
partial stimulation while competitively inhibiting nicotine binding → blocks ability
of nicotine to stimulate VTA DA system→ ↓ craving & withdrawal syndrome.
Management of Withdrawal Syndrome in
substance Abuse (cont.)

39. D- Alcohol Withdrawal: (Delirium Tremens)
1. Diazepam Replaces alcohol and Anticonvulsant
2. Thiamine (V.B1) supplements.
3. Drugs ↓Relapse:
a. Disulfiram (Antabuse)
b. Naltrexone (Block opioid receptors)
c. Acamprosate (↓craving)
Management of Withdrawal Syndrome in
substance Abuse (cont.)

40. Inhibits metabolism step II
aldehyde dehydrogenase
 accumulation of
acetaldehyde  nausea
& vomiting & flushing
(disulfiram -like reaction).
→ patients stop drinking.
↓↓
✓ ++ GABA-A
✓ Opioid antagonist
✓ ↑ 5-HT

41. E- Cocaine and Amphetamine abuse
Bupropion ( craving & TTT depressive symptoms of withdrawal).
N.B. chemical structure of bupropion is similar to amphetamine.
F- Hashish (Marijuana or Cannabis) Abuse
▪ Naltrexone
▪ Dronabinol (synthetic cannabinoid used as antiemetic)
NIDA 2019: PCP can be addictive (cravings, headaches, and sweating are
withdrawal symptoms) & No specific ttt till Now
Management of Withdrawal Syndrome in
substance Abuse (cont.)