13 - Stimulants Part I (6.29.26)

PBSI 336:

Drugs & Behavior

Summer 2026

6.1. Cocaine & amphetamines:History and basic pharmacology

Professor: Morgan Paladinomsp@tamu.eduDepartment of Psychological & Brain Sciences

6.1.2026

Summary

• Cocaine
• Forms: raw leaves  coca paste  cocaine HCl (powder)  cocaine free base OR crack cocaine
• History of use, pharmacokinetics
• Amphetamines
• Forms: naturally-occurring amphetamines, bath salts, amphetamine, methamphetamine, amphetamine-related synthetics
• History of use, pharmacokinetics
• Acute effects of stimulants
• Effects of repeated use of stimulants: Withdrawal, tolerance, sensitization
• MDMA and related drugs
• Forms: MDMA, MDA, MDE
• History of use

Summary

• Cocaine
• Forms: raw leaves  coca paste  cocaine HCl (powder)  cocaine free base OR crack cocaine
• History of use, pharmacokinetics
• Amphetamines
• Forms: naturally-occurring amphetamines, bath salts, amphetamine, methamphetamine, amphetamine-related synthetics
• History of use, pharmacokinetics
• Acute effects of stimulants
• Effects of repeated use of stimulants: Withdrawal, tolerance, sensitization
• MDMA and related drugs
• Forms: MDMA, MDA, MDE
• History of use

Psychostimulant drugs

Cocaine and amphetamines are part of a larger class of drugs known as stimulants, psychomotor stimulants, psychostimulants, or “uppers.” Major behavioral properties of psychomotor stimulants:

• Stimulate alertness and arousal (“psycho-”)
• Stimulate motor activity (“-motor”)

Stimulants include:

• Cocaine
• Amphetamines
• Nicotine
• Caffeine

Cocaine

Cocaine is a psychoactive alkaloid found in coca leaves (Erythoxylon coca) in South America (natural). Cocaine is a weak base.

• Reports of coca use for ~8000 years
• 1499: First reported use by Europeans
• 1859: Active agent isolated by German chemists
• 1800s and early 1900s: Widely used; doctors and scientists lauded its properties

Forms of cocaine: Raw leaves

• Route of administration: Raw coca leaves are chewed with lime powder or ash to increase saliva pH, which enhances absorption by decreasing the ionization of cocaine (weak base). Absorption in mouth.
• Cocaine concentration: < 2% cocaine

Forms of cocaine: Coca paste

• Coca paste is a crude extraction from leaves by mixing with sulfuric acid.
• Cocaine concentration: ~80% cocaine sulfate (salt)
• Route of administration: Can only be smoked (often with tobacco or marijuana) -- too caustic for other routes.
• “Paco” or “basuco” is very cheap, low-grade cocaine, abused in low-income areas of South America.

Forms of cocaine: Cocaine HCl

• Cocaine HCl (hydrochloride, salt) is a crystalline powder extracted and purified from coca paste.
• Cocaine concentration: Very high but usually cut with other powders.
• Route of administration: Water soluble (due to HCl) and can be taken
• Orally (e.g. Coca-Cola)
• Intranasally (20-30% enters bloodstream)
• Intravenously (IV injection).
• Cannot be smoked because vaporization temperature is close to burn temperature…

Forms of cocaine: Cocaine free base

• Cocaine free base is the pure form of cocaine with HCl removed.
• Made from cocaine HCl + water + base (e.g. ammonia) → extraction with ether (flammable solvent).
• Route of administration: Lower melting point, so can be vaporized and smoked (“freebasing”). But, residual ether can be dangerous and explode with flame.

June 10, 1980

Forms of cocaine: Crack cocaine

• “Crack” or “rock” cocaine is also free base cocaine without HCl.
• A cruder preparation of free base made from cocaine HCl. Safer to make because baking soda used instead of solvent.
• Cocaine concentration: 75-90%
• Route of administration: Smoked
• Crack led to a new epidemic of cocaine use in 1980s-90s, particularly in poor US neighborhoods; stiff criminal sentences:

The federal Anti-Drug Abuse Act, passed in 1986, imposed mandatory-minimum sentences that were far harsher on users of crack cocaine than on those found with the drug in powdered form. The Fair Sentencing Act of 2010 reduced that disparity in sentencing from 100:1 to 18:1.

History of cocaine use: Cocaine products

10

Coca/cocaine was widely used in many products by late 1800s. Until 1903, Coca-Cola had ~60 mg per 8 oz serving.

Current medical use for cocaine

11

Cocaine has local anesthetic effects (therefore, DEA schedule II)

• Primary mechanism of cocaine: blocks monoamine transporters (like DAT).
• High doses: also inhibits voltage-gated Na+ channels (involved in action potentials).
• Topical/local anesthetics developed from cocaine: procaine (Novocain), lidocaine (Xylocaine), benzocaine, tetracaine…

Cocaine absorption and distribution

12

Extremely rapid absorption of cocaine with smoking or IV; lipophilic enough to easily cross BBB within seconds

Fowler et al. 2001

Cocaine absorption and distribution

12

Peak subjective effect for crack cocaine is ~1-2 min; over within 5-15 minutes.

Fowler et al. 2001

Cocaine metabolism and elimination

13

Rapid metabolism (via enzymes in blood and liver) and elimination; half-life of cocaine is 0.5-1.5 hrs. Inactive major metabolite benzoylecgonine is detectable in urine for several days (weeks in heavy users). Active metabolite cocaethylene is formed when cocaine and ethanol are ingested simultaneously; longer half-life than cocaine.

cocaine

+ ethanol

benzoylecgonine

cocaethylene

Amphetamines and related compounds

14

Amphetamines: chemical family of synthetic and natural psychostimulants that act as sympathomimetic amines (mimic catecholamines like DA).

Forms of amphetamines (natural): Ephedrine

15

• Ephedrine comes from Ephedra or “Mormon tea” plant (natural); traditional Chinese medicine for asthma, colds.
• Active components are ephedrine and pseudoephedrine:
• Decongestants: Pseudoephedrine has long been a major cold treatment, but since 2006, purchases are more restricted (behind the counter).
• Pseudoephedrine is easily reduced into methamphetamine or oxidized into methcathinone (bath salts).
• Phenylephrine substitute in OTC forms (over the counter).

Forms of amphetamines (natural): Cathinone

16

• Cathinone comes from “khat” or “qat” shrub leaves (natural).
• Commonly chewed in East Africa and Yemen (~80% of men in Yemen use khat; spend about 17% of income).
• Increases heart rate, excitement, euphoria, more talkative; oral route produces slow onset, relatively mild effects.

Catha edulis

Forms of amphetamines (synthetic): Bath salts

17

Methcathinone (“cat”) and mephedrone (“meow meow”) are synthetic variants of cathinone. These designer drugs were disguised as household products, such as bath salts. Placed on DEA Schedule I.

Forms of amphetamines (synthetic): Amphetamine and methamphetamine

18

• Amphetamine synthesized 1887
• Methamphetamine synthesized ~1919

History of use

• 1920-30s: Medical use developed
• Benzedrine inhaler (for congestion) - 1932
• First use for narcolepsy - 1935
• 1940s: Widespread adoption during WWII
• Early 1970s: Peak use of “speed,” 10 billion tablets sold

Forms of amphetamines (synthetic): Amphetamine

19

D-Amphetamine (dextroamphetamine)

• Vyvanse® (prodrug)
• Dexedrine®, dexies

L-amphetamine (levoamphetamine)

• Less potent

Amphetamine (racemic) - mixture of enantiomers (D&L)

• Adderall® (25% levo, 75% dextro)
• Benzedrine® (50/50), bennies, speed

Route of administration: Taken orally or by injection (IV, SC).

Forms of amphetamines (synthetic): Methamphetamine

20

Methamphetamine (dl-methylamphetamine)

• Methedrine®
• meth, crystal, crank, speed, ice, glass
• most potent of amphetamines

Route of administration: Oral, snorted, injected IV, or smoked.

Amphetamine-related synthetics

21

“Amphetamine-like” stimulants differ in chemical structure: Methylphenidate

• Ritalin®, Concerta®
• Attention deficit disorder

Modafinil

• Narcolepsy; sleep apnea

For comparison

amphetamine

phenethylamine

History of amphetamine use: Congestion

22

Wide acceptance of amphetamines in medical community (e.g., Benzedrine inhaler for congestion) when initially introduced in 1932, but stimulant and mood effects were noticed.

History of amphetamine use: Mood and weight control

23

Amphetamines used for narcolepsy (starting in 1935) due to wake-promoting effects. Because it could elevate mood and suppress appetite, also was used for mild depression and as a diet pill (NOT a current medical use though).

History of amphetamine use: Military

24

• Amphetamines used widely by military during WWII and subsequent conflicts.
• Used to increase attention and reduce fatigue (increase wakefulness).
• Still standard in US Air Force

History of amphetamine use: General use for fatigue

25

1970: >10% of population were regular users (truckers, housewives); 10 billion tablets legally made in US 1971: control began

(1956)

(1952)

Current methamphetamine use: Meth epidemic

26

• As crack wave diminished in mid-late 90s, meth use increased.
• High purity, can be smoked. As with other drugs, faster route of administration = more abuse potential.
• Easily prepared from common household ingredients (with pseudoephedrine).

Current medical uses for amphetamines

27

d/l - amphetamine

Current medical uses for amphetamines (DEA schedule II):

1. Narcolepsy
2. Attention deficit disorder (ADD, ADHD)
3. Almost all ADHD medications are stimulants
4. Adderall (amphetamine)
5. Desoxyn (methamphetamine)
6. Ritalin (methylphenidate)
7. Exception: Strattera (atomoxetine), but often less effective
8. 9% of U.S. population diagnosed with ADHD; 2/3 of ADHD children receive pharmacological treatment.
9. Recent formulations aim for slow release – little or no “high”.

methamphetamine

methylphenidate

Amphetamines metabolism and excretion

28

Amphetamines have a slower metabolism and elimination as compared to cocaine; half-life is 7-30 hrs. Many active and inactive metabolic products. 30-40% is excreted unchanged (can be detected in urine test).

Stimulants: Major effects

29

Behavioral and subjective effects of cocaine and amphetamines in humans

Drug discrimination: Human users and lab animals cannot discriminate between IV cocaine and amphetamine.

Autonomic effects also: increased blood pressure, hyperthermia, bronchodilation.

Cocaine vs. amphetamines

30

Effects of cocaine (as compared to amphetamines)

• Shorter duration of action
• 0.5-1.5 hours for cocaine
• 7-30 hours for amphetamines
• Worse cardiovascular effects (can be lethal)
• Higher danger of cerebrovascular accident (e.g., stroke, hemorrhage) or cardiac problems (e.g., heart failure) with cocaine, due to actions on sodium channels
• Higher convulsive/seizure properties of cocaine
• These sensitize with repeated use

Stimulants: Major effects in animals

31

Animals: hyperlocomotion Locomotor activity can appear to go down with high AMPH doses because rats perform stereotypy behavior instead. Reinforcing/rewarding effects

• Self-administration
• Conditioned place preference

Locomotor activity

Stereotypies

persistent, repetitive behaviors with no purpose

Kuczenski & Segal 1999

Effects of repeated stimulant use: Withdrawal

32

In chronic, high-dose users of stimulants (cocaine or amphetamines), withdrawal symptoms are mostly psychological (as opposed to physical) and not fatal:

• Anxiety
• Drug craving
• Depressed mood
• Fatigue
• Increased appetite
• Lack of motivation

Can last for 3-4 weeks.

Effects of repeated stimulant use: Tolerance and sensitization

33

• Tolerance to some effects of psychostimulants:
• Autonomic effects
• Anorexic effects

• Sensitization to other effects of psychostimulants:
• Rewarding effects
• Psychotomimetic effects (psychosis)
• Locomotor stimulant effects

Negative effects of chronic amphetamine use

34

• Psychosis: such as delusional parasitosis (crawling sensation on skin causes hallucination of bugs, crank bugs, meth mites)
• Anorexia (decreased eating, weight loss)
• Physical damage – “Faces of meth”
• Meth mouth: tooth decay due to neglected oral hygiene and reduced saliva
• Skin sores: due to skin dehydration, delusional parasitosis, and obsessive picking/punding (speed bumps, meth sores)

MDMA and related drugs

35

MDMA

• methylenedioxymethamphetamine
• ecstasy, E, X, XTC, adam (pills)
• M, molly (pure powder/crystal form)

MDA

• methylenedioxyamphetamine
• pre-dates more widely used MDMA

MDE or MDEA

• methylenedioxy-N-ethylamphetamine
• eve
• milder, shorter acting

History of MDMA

36

• First synthesized - early 1900s.
• Patented as cough syrup and anorectic, but never used clinically.
• Largely forgotten until 1970s when Alexander Shulgin resynthesized and tried out.
• Currently used by some psychotherapists: recent evidence that MDMA can enhance communication and openness (similar to psychedelics).
• Aug 2024: FDA rejected MDMA for PTSD therapy

MAPS (Multidisciplinary Association for Psychedelic Studies)

History of MDMA

37

• MDMA first became popular as a club drug during 1980s-90s at raves with electronic dance music.
• Schedule I classification in 1985.
• Mostly taken orally; long half-life (8 hrs).

MDMA: Major effects

38

MDMA effects at low doses

• Behavioral: Increased energy and sociability/empathy; mild euphoria
• Autonomic: Increased heart rate and temperature; decreased appetite; jaw clenching

MDMA effects at high doses

• Behavioral: Mild hallucinogenic effects, more amphetamine-like effects, “hangover”
• Autonomic: Hyperthermia & dehydration; increased H.R. and B.P. → stroke

45

Thanks for listening!

Don’t forget your Exit Ticket: tx.ag/drugsandbehavior

Next class:

3.2. The nervous system: Receptor signaling