Objectives
Using Historical Case Studies of Musicians
and Artists to Review Drugs of Abuse
Testing and TDM
Larry Broussard, PhD DABCC
LSUHSC New Orleans
Dept Clinical Laboratory Sciences
List the drugs which should be included in
a panel for drugs of abuse testing
Discuss therapeutic drug monitoring and
list those drugs typically monitored.
Discuss toxicology tests which would aid
in detecting drugs causing death in rock
and roll musicians or in diagnosing or
treating Vincent van Gogh.
Mentioned in Song: Died of
Drug Overdose
Testing for Drugs of Abuse
(Illegal and Prescription)
Case Studies of Rock and Roll
Musicians Dead of Drug Overdose
Jimi Hendrix
Janis Joplin
Jim Morrison
Mentioned in Song: Died of Causes
Other Than Drug Overdose
Otis Redding – plane crash Lake Monona
near Madison, WI (12-10-67; 26 y/o)
Jim Croce – plane crash Natchitoches, LA
(9-30-73; 30 y/o)
Bobby Darin – heart operation sepsis
damage to artificial heart valves
(12-20-73; 37 y/o)
Brief Review of Clinical
Toxicology
1
General Principles of
Emergency Toxicology
Screen in urine except ethanol
Quantitate in blood,serum,plasma
Physicians treat symptoms
Typical Drug Panel
in Emergency Departments
Ethanol (blood)
Acetaminophen (serum possibly urine first)
Salicylates (serum possibly urine first)
Drugs detected using immunoassays (urine):
amphetamines, opiates, cannabinoids,
cocaine, PCP, barbiturates,
benzodiazepines, propoxyphene,
methadone, methaqualone, tricyclic
antidepressants (serum)
Comments Concerning
Drug Testing
Confirmation by a second method not typically
performed for clinical testing; required (by
regulations) for workplace (forensic) testing
and postmortem testing (by consensus)
Know parameters of analytical techniques used:
accuracy, precision, specificity, sensitivity,
dynamic or linear range, interferences
Scope of Drugs Tested
Varies with institution
Determined by availability of equipment
and personnel or access to reference
or specialty laboratory
Simple screen: blood alcohol + urine
POCT kit screen
Complex screen: blood alcohol + multiple
drugs using screening and
confirmation
Negative Results Doesn’t Mean
Drugs Not Present
1. Screen performed may not include drug
ingested —need a list of drugs that are included in the
drug screen
2. Method may not detect drug ingested
Immunoassays (most common method) test for certain
drugs or classes of drugs (specificity of test)—drug
ingested may be in that class but not detected by that
immunoassay. Ex. Ecstasy is chemically an
amphetamine but the immunoassays for amphetamine
may not detect Ecstasy
3. Drug may be present at levels below cutoff
level for the test used to determine positive/negative
(sensitivity of test)
Common Methods for Detecting
Drugs in Biological Fluids
Immunoassay: reagent has antibody to drug; easily
automated
Gas Chromatography Mass Spectrometry (GCMS):
more sensitive & specific; reference method
Liquid Chromatography Tandem Mass Spectrometry
(LCMSMS): very sensitive; less sample prep; ID
many drugs with 1 injection
Thin Layer Chromatography (TLC): detects many
drugs at one time; least sensitive but can detect
overdose levels of most drugs
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Case Study 1: September 18, 1970
27 year old black male who played at
Monterrey Festival
Samarkand Hotel, London
Circumstances of Death: night before took 1
amphetamine; that evening took 9
Vesperax (German; secobarbital,
brallobarbital, hydroxyzine HCl)
Experimental drug use history: marijuna,
LSD, alcohol
Jimi Hendrix
Born: November 27, 1942
Guitar genius: left-handed, known to have
played right-handed and could play righthanded guitar
Hits: Hey Joe, Purple Haze, Foxy Lady
“Rainbow Bridge” film of concert 2 months
before death
Elected to Rock and Roll Hall of Fame in 1992
Pathologist’s testimony
Drugs detected:
ethanol (estimated 100 mg/dL)
large amount of seconol (secobarbital)
20 mg amphetamine
THC (marijuana)
Cause of Death: inhalation of vomit after
barbiturate intoxication
Barbiturates
Duration: Short (secobarbital), Intermediate,
Long acting
Sedative-hypnotics (short-intermediate acting)
Induction of anesthesia (ultrashort acting)
Anti-convulsant (Phenobarbital)
Migrane therapy (Butalbital)
Reduction of cerebral edema from head trauma
(Pentobarbital)
3
Toxicity of Barbiturates
Due to progressive CNS depression
Respiratory depression greater problem
than cardiovascular depression
Death usually due to respiratory arrest or
cardiovascular insufficiency
Prolonged coma; complication:
pneumonia
Testing for Barbiturates
Screening: cross-reactivity varies with
immunoassays; comprehensive
panel using MS (GCMS or LCMSMS)
Confirmation: GCMS; LCMSMS
Barbiturate Overdose
Case Study 2
Judy Garland
Seconal ® (secobarbital)-for
sleeping problems caused by
Benzedrine ® (amphetamine),
used for weight control
Marilyn Monroe
Nembutal® (pentobarbital)
Case Study: October 4, 1970
27 yr old white female
Landmark Hotel, Hollywood
Found face down; fresh puncture marks
History: heroin addict; heavy alcohol use
(codeine-containing cough syrup in
Southern Comfort bottles)
Janis Joplin
Born: January 19, 1943
Band: Big Brother and the Holding
Company
Hits: Piece of My Heart; Me and Bobby
McGee (after her death)
Movie “The Rose” (1979) based on her
life
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Back to the Case Study
Dead when Emergency Personnel
arrived: Death Certificate
If patient alive and brought to ER or if
patient dead autopsy performed drug
testing results would be:
Positive
opiates by immunoassay
positive morphine and 6-acetyl morphine
by GCMS
Heroin
Semi-synthetic; Di-acetyl morphine (Acetylation of
opium extract from poppies)
Crosses blood-brain barrier easier than
morphine; 2.5 times as potent
Metabolites: 6-acetyl morphine; morphine;
codeine
Heroin acts mostly on MU opioid receptors
causing euphoria, analgesia, and respiratory
depression.
Antidote: Narcan (naloxone)
Heroin Overdose:
Narcotic/Opiates Toxidrome
Presentation:
Miosis (pinpoint pupils)
Bradycardia
Hypotension
Hypoventilation
Coma
Heroin
Heroin is rapidly converted to
monoactylmorphine (MAM) and
morphine. MAM also called 6acetylmorphine (6-AM or 6-MAM)
Heroin is more potent and euphoric than
morphine.
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Heroin
Derived from the dried
“milk” of the opium
poppy which contains
morphine and codeine
Opiates Immunoassay
Detects primarily codeine and morphine
Detection of other opiates: depends on
antibody specificity
Does assay detect conjugated drugs
(glucuronide)?
Cutoffs: 2000 and 300 mg/L
Poppy seeds contain morphine
Confirmation of Heroin Use
Summary: Janis Joplin
6-Acetyl morphine and morphine present
in urine
Death due to heroin overdose
Heroin metabolized to 6-AM and
morphine
Morphine concentrated in bile (and liver)
Farewell Party for Janis:
Other Heroin-Related
Deaths of Musicians
$1500 in will for party; Grateful Dead performed for 200 friends
Mike Bloomfield (Butterfield Blues Band)
Paul Butterfield (Butterfield Blues Band)
Gram Parsons (Byrds)
Brian Cole (The Association) drug overdose,
probably heroin
Tommy Brolin (Deep Purple)
Hillel Slovak (The Red Hot Chili Peppers)
Sid Vicious (Sex Pistols)
Robbie McIntosh (Average White Band)
6
Other Heroin-Related
Deaths of Musicians
Allen Woody (Allman Brothers)
Jonathan Melvoin (Smashing Pumpkins)
Kristen Pfaff (Hole)
Bradley Nowell (Sublime)
Andrew Wood (Mother of Love Bone)
Billy Murcia & Johnny Thunders (NY Dolls)
Danny Whitten (the Rockets)
Tim Hardin (songwriter)
John Belushi (Blues Brothers); speedball—
cocaine and heroin
Case Study 3: July 3, 1971
27 yr old white male
Body found in Paris
Cause of Death: heart failure (possible blood
clot from respiratory illness)
Circumstances: found dead in bath tub; rumors
of drug overdose – took heroin thinking it
was cocaine; no autopsy
History: alcohol abuse (fifth/day); drug use
Buried in Paris
Wife died of heroin overdose 3 yrs later
Case Study 3
Jim Morrison
Born: December 8,1943
Songwriter, Poet
Band: the Doors (from Aldous Huxley’s
book on mescaline, the Doors of
Perception); played last concert with
Morrison in New Orleans
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Ethanol
Reporting Results
Laboratory report should include the specimen
tested and the units
Sample: blood; grey top tube (NaF)
preferred
Units:
Units:
Sample:
mg/dL (ex. 80 mg/dL)
percent or g/dL (ex. 0.080)
Methods Used For
Clinical and Forensic Ethanol
Clinical:
Enzymatic; alcohol dehydrogenase
(ADH); affected by other alcohols (methanol,
isopropanol)
Forensic:
Gas Chromatography (GC or GLC);
separates and measures ethanol and other
alcohols individually
mg/dL (ex. 80 mg/dL)
percent or g/dL (ex. 0.080)
whole blood vs serum or plasma
Be aware of any limitations of method/ sample
Ethanol Sample Relationships:
Serum/blood = 1.12 – 1.17
(Hematocrit dependent)
**Key points when comparing clinical and
forensic ethanol results:
Clinical (serum or plasma) ethanol will be
higher than forensic (whole blood)
ethanol collected at same time—law
enforcement may not understand.
Laws use BAC (blood alcohol concentration)
not serum or plasma concentration
Effects of Ethanol
0.050
0.100
0.200
0.300
0.400
Moody; Impaired judgement
Clumsy; Blurred vision
Loud; Angry; Unusual Behavior
Disoriented and confused
Unconscious; CNS depression
Alcohol-Related
Deaths of Musicians
8
Amy Winehouse
7-23-2011 (27 y/o)
Cause of Death:
alcohol intoxication
BAC: 416 mg/dL
(0.416%)
No illegal drugs
detected
Alcohol-Related Deaths of Musicians
Brian Jones – founder Rolling Stones;
drowned in pool, “Misadventure”;
ethanol and barbiturates
Ron “Pig Pen” McKernan – singer Grateful
Dead; stomach hemorrhage & liver
failure due to alcoholism; cirrhosis
Gene Clark – co-founder Byrds; bleeding
ulcer caused by alcoholism
Keith Whitley
5/9/1989 (34
y/o)
BAC: 470
mg/dL
(0.470%)
Other Alcohol-Related
Deaths of Musicians
Steve Clark – guitarist Def Leppard
Dennis Wilson – drummer Beach Boys
John Bonham – drummer Led Zeppelin
Bon Scott – singer AC/DC
Case Study: September 19, 1973
Case Study 4
Body of 26 yr old white male (1-time
member of the Byrds -- band that
performed at Monterrey Festival
before he joined)
Room 8 of Joshua Tree Inn near
Joshua Tree National Park
9
Gram Parsons
Born: November 5, 1946
Considered by many to be the first to
combine rock and country music
Gram Parsons
Autopsy:
cocaine, BAC 0.21, heroin, barbiturates
Cause of Death: “drug toxicity, days, due
to multiple drug use, weeks.”
Byrds, Flying Burrito Brothers; duets with
Emmy Lou Harris
Cocaine
Prescription:
local vasoconstrictive anesthetic
Incan Herbal tea illegal
Extracted from coca leaves
Half-life about one hour
Primary metabolite: benzoylecognine
Cocaine Overdose
CNS stimulation, convulsions
Ventricular arrhythmias
Respiratory dysfunction with eventual
depression
Increased muscular activity
Possible hyperthermia
Summary: Gram Parsons
Autopsy:
cocaine, BAC 0.21, heroin, barbiturates
Cause of Death: “drug toxicity, days, due to
multiple drug use, weeks.”
The Rest of the Story:
Grand Theft Parsons
10
Garden of Memories
plot R-12-11-2
Case Study 5
Case Study 5: August 16, 1977
42 yr old white male
Found dead in home
August 15: visited dentist; played
raquetball in early am with friends,
played piano and sang; bedroom to
rest
2:30 pm August 16, 1977 Jerry Esposito, road manager, discovered body in
bathroom of this home in Memphis
Elvis Presley
Born: January 8, 1935
Died: August 16, 1977
Cause of Death: Heart Failure (probably
due to abuse of prescription
medication)
Toxicology report: 11 drugs detected
“only drugs prescribed for perfectly
normal, rational medical reasons”
11
Autopsy report sealed for 50
years on request of Elvis’s
father
Medical Examiner
investigation report public
information
Medical Examiner Investigation Report, page 2
Toxicology Report:
11 drugs detected
4 in significant quantities:
Ethinamate (sedative)
Methaqualone (sedative)
codeine (opiate)
barbiturates (sedative)
4 others in insignificant amounts:
chlorpheniramine (antihistamine)
meperidine (opiate)
morphine (opiate; metabolite of codeine)
Valium (benzodiazepine; sedative)
Therapeutic Drug Monitoring
Principles Using van Gogh
Case Study
Did Vincent van Gogh suffer from
Digitalis Overmedication?
Summary
5 Case Studies of Rock and Roll Musicians
who died unexpectedly after drug use
or suspected drug use were presented
Principles of clinical toxicology were
discussed
Many other drug-related deaths of
musicians could have been presented
Vincent van Gogh
1853 Born in Grost-Zundert, Holland
1857 Brother Theo born
1880 Returns to painting; supported
by Theo
1886 Formal art training—beginners class
1888 Rents Yellow House; Gaugin arrives
Attacks Gaugin; Depression and
Self-mutilation
12
Vincent van Gogh 1889
Mental state fluctuates; increased breakdowns
Enters mental asylum at St. Remy-de-Provence
Tries to kill himself by swallowing paints
Physician: Dr. Gachet
Portrait of Doctor Gachet
Vincent van Gogh 1890
July
Theo’s health worsens—worried about finances
and son’s health
July 27
Shoots himself ?? in chest
July 29
Dies in Theo’s arms
Vincent van Gogh
Song:
Paintings:
Vincent by Don McClean
By Vincent van Gogh (except
Van Gogh and
for 1 portrait by Martin Schwartz)
Presentation prepared by:
Larry Broussard, PhD, DABCC
LSU Health Sciences Center
New Orleans, LA 70112
copyrighted 2000
Therapeutic Drug Monitoring
(TDM)
Larry Broussard
13
Van Gogh and Classes of
Drugs Routinely Monitored
Anticonvulsant – documented seizures
Bronchodilator
Antibiotic
Psychotropic -- bipolar
Antineoplastic
Immunosuppresant
Cardiac – digitalis (for seizures)
Therapeutic Drug Monitoring
TDM
Principles of TDM
 Steady
State
 Trough
Levels
 Narrow
Therapeutic Range
 Toxicity
TDM
It takes 5.5 half-lives to reach
steady state and it takes 5.5
half-lives to clear the drug when
you stop taking the medication.
TDM
Most Reference Ranges are for
trough values
Best time to draw trough specimen is
immediately before next dose
Antibiotics should have peak and
trough levels monitored
Did Vincent van Gogh
Suffer Digitalis
Overmedication?
14
Digitalis Overmedication
Treatment for seizures:
Portrait of Doctor Gachet
digitalis
Source of digitalis: foxglove (digitalis
purpurea)
Dr. Gachet’s portrait
Portrait of Doctor Gachet
Signs of Digitalis
Overmedication
Most expensive painting ever
Yellow vision:
Bought by Japanese company (Ryoie
Saito) in 1990 for $82.5 million
Sold to Christie’s for a private collection in
1998 for approximately $10 million
lived in yellow house
later paintings--yellow prominence
15
Signs of Digitalis
Overmedication
Anisocoria:
inequality of size of pupils
Self-Portraits
Signs of Digitalis
Overmedication
Corona effect:
The Starry Night
16
Starry Night
1889
Summary of Digoxin
Toxicity Symptoms
Yellow Vision
Anisocoria
Corona Effect
Questions
Thank you for your attention
17