Health Professionals
STATEMENT OF EDGAR H. ADAMS, M.S., Sc.D.
Prepared for the HHS Public Meeting on the
Safety
of Dietary Supplements Containing Ephedrine Alkaloids
August
8-9, 2000
- I am
currently the Senior Vice President, Health and Public Policy
at Harris Interactive. I have been licensed to practice pharmacy
in Maryland, Connecticut, and New York. I received a Bachelor
of Science degree in Pharmacy from Fordham University, a Master
of Science degree in Pharmacology from Purdue University,
and a Doctor of Science degree from The Johns Hopkins School
of Hygiene and Public Health. For 17 years I worked at the
National Institute on Drug Abuse (NIDA) in several positions
of increasing responsibility for domestic data collection
and statistical analysis. From June 1984 through December
1990, I served as Acting Director, and then Director, of the
Division of Epidemiology and Statistical Analysis (DESA).
The DESA was reorganized as the Division of Epidemiology and
Prevention Research. I supervised several data collection
and analysis initiatives during my tenure as the head of the
Division of Epidemiology and Prevention Research, including
the Drug Abuse Warning Network (DAWN) and the National Household
Survey on Drug Abuse. In 1987, I served as an expert for the
American Delegation to the United Nations International Conference
on Drug Abuse and Illicit Trafficking. I also served on the
Interagency Committee on Drug Control. A copy of my curriculum
vitae is included as Attachment 1.
- I have
participated in numerous studies related to abuse of prescription
drugs and in studies on the effect of scheduling on the use
of these medicines. I have also lectured and published numerous
articles on the epidemiology of drug abuse and trends and
factors in drug abuse.
- In January
1999, I reviewed the Food and Drug Administrationís (FDAís)
public notice on the World Health Organization (WHO) recommendation
to add ephedrine to Schedule IV under the 1971 Convention
on Psychotropic Substances (1971 Convention), and commented
on the justification for this action from the perspective
of someone who has studied trends in substance abuse. My opinion
was based on my review of the WHO critical review and supporting
information, as well as the information provided by FDA in
support of the WHO critical review. I also conducted an in-depth
review of the DAWN data and other information on ephedrine
seizures that FDA cited as potential indicators of abuse or
misuse. Based on my review of this information, I concluded
that there was little evidence that ephedrine "was being
or was likely to be abused so as to constitute a public health
and social problem" and as such there was no basis for
WHOís recommendation that ephedrine be classified in Schedule
IV under international treaties. At that time, I strongly
urged the FDA and the U.S. government to oppose the action.
- I was
asked by the Ephedra Education Council (EEC) to review selected
adverse event reports (AERs) released by the FDA on April
3, 2000 because reviews of the reports by FDAís outside consultants,
Drs. Woosley and Benowitz, made reference to "addiction."
In addition, on FDAís list of "serious nervous system
adverse events" and on its list of "other serious
adverse events," FDA classified some as related to "addiction"
and "dependency/addiction," and the EEC asked that
I review these reports as well.
- I reviewed
reports eliminated from FDA review because they were associated
with "misuse or abuse," (AER 12876 and 13331), and
I reviewed the report cited by Dr. Benowitz as the example
of addiction (AER 11918). (Note: this case was removed by
the FDA due to insufficient data, but classified as "possible"
by Dr. Benowitz). I also reviewed several other reports identified
by members of the EEC Expert Panel. In addition, I reviewed
the most recent data from the DAWN to determine whether there
was any evidence of increasing abuse.
- Although
the term "addiction" was used by FDA and in the
reports by Drs. Woosley and Benowitz, it is not a legitimate
clinical term. The term "addiction" is not recognized
as a clinical definition by either WHO or the American Psychiatric
Associationís Diagnostic and Statistical Manual version IV
(DSM-IV™). In fact, in one case the mere presence of
possible withdrawal symptoms was used as the description of
"addiction." The appearance of withdrawal symptoms
is seen with many medications, and the presence of withdrawal
symptoms is neither necessary nor sufficient for a diagnosis
of dependence. In order to provide a scientific and consistent
basis for review, the DSM-IV™ criteria for abuse and
dependence were used wherever possible.
- The generally
accepted meaning of the terms misuse, harmful use/abuse, dependence,
and withdrawal along with their underlying focus follow. Misuse
is defined as repeatedly using the drug for non-therapeutic
purposes but with no resultant problems (e.g., use
of a stop smoking medication to avoid smoking restrictions).
Harmful use/abuse refers to repeated misuse that causes
damage to health or problems in social or occupational activities
or legal obligations. Dependence refers to the International
Classification of Diseases (ICD-10™) or DSM-IV™
definitions that focus on evidence of loss of control over
drug use and include tolerance and withdrawal. Withdrawal
refers to a time-limited syndrome that occurs upon cessation
of use and which has symptoms that are clinically or functionally
significant. The diagnostic criteria for abuse and dependence
as listed below.
- Abuse:
- A maladaptive
pattern of substance use leading to clinically significant
impairment or distress, as manifested by one (or more) of
the following, occurring within a 12 month period:
- recurrent
substance use resulting in a failure to fulfill major role
obligations
at work, school, or home (e.g., repeated absences
or poor work performance related to substance use; substance-related
absences, suspensions, or expulsions from school; neglect
of children or household);
(2)
recurrent substance use in situations in which it is physically
hazardous (e.g., driving an automobile or operating
a machine when impaired by substance use);
(3)
recurrent substance-related legal problems (e.g.,
arrests for substance- related disorderly conduct);
(4)
continued substance use despite having persistent or recurrent
social or interpersonal problems caused or exacerbated
by the effects of the substance (e.g., arguments
with spouse about consequences of intoxication, physical
fights),
- The
symptoms have never met the criteria for Substance Dependence
for this class of substance.
Dependence:
A maladaptive pattern of substance use, leading to clinically
significant impairment or distress, as manifested by three
(or more) of the following, occurring at any time in the
same 12-month period:
(1) tolerance,
as defined by either of the following:
(a)
a need for markedly increased amounts of the substance
to achieve intoxication or desired effect;
(b)
markedly diminished effect with continued use of the same
amount of the substance;
(2)
withdrawal as manifested by either of the following:
(a)
the characteristic withdrawal syndrome for the substance;
(b)
the same (or a closely related) substance is taken to
relieve or avoid withdrawal symptoms;
(3) the
substance is taken in larger amounts over a longer period
than was intended;
(4) there
is a persistent desire or unsuccessful efforts to cut down
or control substance use;
(5) a
great deal of time is spent in activities necessary to obtain
the
substance, use the substance, or recover from its effects;
(6) important
social, occupational, or recreational activities are given
up or reduced because of substance use;
(7)
the substance use is continued despite knowledge of
having a persistent or recurrent physical or psychological
problem that is likely to have been caused or exacerbated
by the substance (e.g., an ulcer made worse by continued
drinking) .
CASE REVIEWS
(see tables, Attachment 2):
- In reviewing
the cases, I tried to assess the following information: product
taken, product content, age, sex, weight, reason for use,
dose, duration of use, the nature of the adverse event, outcome,
and relationship to DSM-IV™ criteria.
AER 12876:
A 22-year-old, 160 lb. male took 6-7 tablets of Twin Lab Ripped
Fuel to stay awake to study. Reported to emergency room (ER)
with tachycardia and complaining that he could not sleep.
Patient given IM Valium with prescription for oral valium.
This is an obvious case of misuse (use for other than intended
effect) that was classified as unsupportable by FDA.
AER 13331:
A 16-year-old male had an argument with his mother and took
70 health food supplements. Approximately 20 Metabolife 356
were ingested. This is likely a suicide "gesture,"
which was correctly classified as "not supportable."
AER 11556:
A female was taking numerous herbal life products (up to 42
tablets a day) for 12 weeks. She complained of diarrhea, loss
of sleep and missed menstrual cycles. This case was correctly
considered as not evaluable due to insufficient information.
AER 12464: A 23-year-old, 175 lb. male was taking 6 to 12
Twin Labs Ripped Fuel per day for 2 years. Subject had hair
loss, facial twitching and was lethargic. He said that he
could not stop because he got withdrawal symptoms when he
tried. The young manís father was the complainant. He felt
that his son was addicted and would not seek treatment. He
felt his son should also be looking for work. FDA classified
this case as not supportable due to insufficient information.
Dr. Benowitz classified it as possible. More information is
needed to make a determination.
AER 12544:
A 65-year-old female was taking Fit America for weight loss.
She took the product for three and a half weeks and complained
of headache initially and tremors of her right hand and tingling
in her head. She was taking the product as directed-approximately
12 tablets three times a day. Patient discontinued use and
her symptoms diminished. Upon evaluation there was no evidence
of stroke. There is no relationship to abuse or dependence.
AER 12837:
This complaint consisted of a letter and a completed questionnaire
from a 31-year-old male taking ephedra/ma huang as a workout
enhancer. Patient reported that he was taking one tablet one
hour before workouts and eventually was taking 20-25 tablets
daily. He reported extreme tension, feelings of mania and
rage, and he snapped at his family. He stated that he relapsed
to cocaine use and felt that the ephedra product triggered
the relapse. Because ephedra has stimulant properties, this
possibility has to be considered.
AER 12906:
A 36-year-old female taking up to 30 drops per day of AMP
II Pro Drops and Liqua Thin for weight loss for a period of
10 weeks reported severe nasal hemorrhaging. FDA classified
this case as not supportable due to insufficient information,
and Dr. Benowitz classified it as unrelated. This case has
nothing to do with abuse or dependence.
AER 13332:
This patient was taking a variety of Herbal Life products
for weight loss. He took 32 pills from 9 different bottles
plus 2 replacement drinks per day. He initially complained
of diarrhea, which lasted for a few days, but after approximately
2 weeks, the patient complained of constipation. FDA classified
this case as non-supportable due to insufficient evidence,
and Dr. Benowitz classified it as unrelated. This case has
nothing to do with abuse or dependence.
AER 12572:
This obese adult female was taking Stackers for weight loss.
She took 12 Stackers and was admitted to a hospital for tachycardia.
FDA classified this case as not supportable due to insufficient
information. This case has nothing to do with abuse or dependence.
AER 13344:
This patient is a 21-year-old male weighing 170 lb. who was
taking Hydroxycut for purposes of muscle building. He was
taking 12 capsules a day for at least several weeks. There
is a notation that the event abated after dose stopped or
reduced and did not reappear after reintroduction. However,
the patient reported that he took 4 capsules in the morning
and 4 in the afternoon for about 6 months and that just prior
to the event he took Theraflu. (Note the maximum recommended
daily dose is 8 capsules in divided doses.) His girlfriend
reported that prior to a ski trip, he was not himself, and
was somewhat short-tempered. He began screaming and was "frothing"
at the mouth. He became combative and was sweating. He was
taken to an emergency room where he was kept under sedation
for 2.5 days. The physician reported that he was taking the
equivalent of 32 cups of coffee per day. The ER physician
reported the patient as combative, flailing his extremities
and not responsive to commands. His lab tests were negative
for drugs of abuse. Low levels of alcohol and acetaminophen
were noted. The patient was sedated using lorazepam. He suffered
some short-term memory loss, which was attributed to the residual
effects of lorazepam and Hydroxycut. The patient was reported
to be very sensitive to anesthetics during previous surgery
in that it took him 3 times as long to recover as normal.
The discharge diagnosis was a possible overdose. This may
be a case of unintentional overdose or a reaction to prolonged
use, but it is not related to abuse or dependence.
AER 11918:
In this case, a female, 38 years old, took Be Thin Again to
lose weight for a wedding. She was told that up to 5 tablets
a day (the maximum recommended dose) would be safe. She began
taking 3 tablets daily and increased the dose, upon recommendation,
to 5 tablets per day when the rate of her weight loss slowed.
She took the product for 19 months. She began experiencing
some of the long term effects of sympathomimetic use. She
began experiencing mood changes and began having fights and
abusive arguments with her fiancée (note: he was taking
the same product at the same dose). She initially thought
that her behavioral changes might be due to the medication
but continued taking it. Then she thought that she might be
"addicted" and discontinued use. There is no indication
of any withdrawal symptoms.
This
woman does not appear to meet the criteria for dependence,
especially since her use of the product was quite well-controlled.
However, since she took the product for a while after she
believed that it was contributing to her behavioral changes,
she may meet the criteria for abuse.
AER13408:
A 26-year-old man who had been taking Ripped Fuel on and off
for three years had a seizure on February 20,1999 and had
recurring seizures over the next few days. His wife and mother
stated that they were unclear how often he took the products
three at a time when he needed energy for exercise or at work.
He was stressed and tired and complained of a headache for
three days before the incident. On the day of the seizure,
he had 4 hours sleep and did not eat at all. This case was
reported as a possible abuse case because a third party said
that he took Ripped fuel, Wastraw, Creatine, XTC and GHB.
The neurologist thought that it might be related to poly-substance
drug abuse. There was some reference made to past cocaine
use. However, there is no objective evidence to support this
contention. It appears to simply have been carried over in
the medical records.
AER 13651:
Someone called the emergency room to say that a friend tool
Thermadrine because he was bored. He experienced nausea and
induced vomiting. He never came to the ER. This case cannot
be evaluated based upon the information given.
AER 13764:
A 23-year-old woman purchased Midnight Ecstasy on April 26,
1999 to enhance sex with her boyfriend. They both took 4 tablets
at around 8 PM. Her heart started racing, her head was pounding
and she induced vomiting which became involuntary. She was
admitted to the ICU on life support for a collapsed lung and
heart attack. She reportedly had no previous experience with
this product or similar products. She has a previous history
of cocaine and alcohol use and her urine toxicology was positive
for marijuana and amphetamines. This case is not related to
the abuse of or dependence on ephedrine containing products.
It is unclear whether other drugs may have contributed.
AER 13905:
This 36-year-old woman was taking Metabolife for one month.
She took 2 to 3 caplets daily. The maximum daily dose is 8
caplets. She had coffee in the morning and a salad and cola
at lunch. She collapsed 20 minutes after drinking the soda.
She was admitted to the CCU for respiratory arrest and a stroke.
She had used the product in 1997 but had stopped after an
automobile accident. She resumed use in April 1999 upon her
return to work. Her urine toxicology was positive for amphetamines.
This case is not related to abuse or dependence.
AER 13946:
A 17-year-old male was taking Ripped Fuel, Thermotek and Metabolic
Thyrolene and suffered a mini-stroke. He had been using the
products for about 3 months. In one part of the report, it
states that on the day of the min-stroke, he did not take
Thermotek and in another section it states that he did. The
young man has a history of remote seizures and a cyst around
the brain. He was supposed to have the cyst checked every
6 months but has not been evaluated for 2 years. The report
says that he has a history of substance abuse. This case is
not related to abuse or dependence.
Summary
Part 1
Before
commenting on the cases, I want to note that the reviewers
were given cases to review that had already been classified
as not supportable by FDA. Second, the use of the word "addiction"
is inappropriate in a document that purportedly contains clinical
reviews. Third, the typical case of "addiction"
in Dr. Benowitzís report does not, in my opinion, meet the
DSM-IV™ criteria for dependence and ironically is taken
from the "not supportable" cases. Fourth, Dr. Woosley
seems to equate "addiction" with physical withdrawal.
On page 3 of his report, he noted, "reports of addiction
in which patients reported that they could not stop taking
the product because of the development of extreme fatigue
and symptoms of depression when they tried." Withdrawal
is common with many medications such as steroids and tricyclic
antidepressants, and as noted previously, withdrawal is neither
necessary nor sufficient for a diagnosis of dependence.
In reviewing
the cases in which abuse or dependence might be suspected,
I found one case of a reported relapse to cocaine use and
a possible case of abuse. Both of these cases were in the
"not supportable" group due to insufficient information,
so these are conservative, worst-case estimates.
Consequences
of Use as Measured by the DAWN
- DAWN
was established as a measure of the consequences associated
with the abuse of drugs. One of DAWNís primary objectives
is to assess health hazards associated with drug abuse. The
definition of drug abuse in DAWN is quite broad. The DAWN
definition of abuse includes the "use of prescription
drugs in a manner inconsistent with acceptable medical practice,
and the use of over-the-counter drugs contrary to approved
labeling." Also included in the definition is "the
use of any other substance for psychic effect, dependence
or suicide." From the standpoint of assessing abuse or
dependence, the inclusion of suicide or intentional overdose
is totally inappropriate. It is inappropriate because (1)
the diagnostic definitions of abuse and dependence rely on
recurrent use; (2) suicide attempts and gestures are typically
single use not persistent use; and (3) generally drug-related
suicide attempts and gestures are more a function of what
medication is available (e.g., in the medicine cabinet) rather
than seeking out a particular drug. Accordingly, suicide attempts
and gestures should be removed from the DAWN estimate prior
to analysis. The impact of including suicide attempts and
gestures on the number of DAWN episodes is exemplified by
the fact that six of the top 25 drugs reported in DAWN representing
more than 15 percent of all DAWN episodes are over-the-counter
(OTC) drug products. For example, in 1998, there were 32,257
DAWN episodes associated with acetaminophen, 17,146 associated
with ibuprofen, 15,457 associated with aspirin, and 5,750
associated with OTC sleep aids. Suicide attempts and gestures
account for more than 75 percent of the cases. Similarly,
many of the episodes (more than 50 percent) associated with
ephedrine are related to suicide attempts and gestures. If
the DAWN data were corrected to remove the suicide attempts
the already small number of ephedrine episodes would be halved.
- The
methodology used to report DAWN data has changed since 1989.
The shift to reporting estimated DAWN episodes based on weighted
data has caused fluctuations in the data that in the case
of ephedrine, and all other substances, should be considered.
In 1989 there were only 66 actual reported episodes involving
ephedrine. The weighted episodes for that year were 441. Generally
the weights for ephedrine episodes ranged from 7 to 10. The
weights for other more widely abused drugs such as cocaine
are less variable and tend to be less than 2. The weighting
schemes have been corrected several times since 1989, but
the purpose is to estimate the total cases in the approximately
4,800 to 5,000 hospitals in the United States.
- The estimated
ephedrine-related episodes reported via DAWN for the years
1989 to 1998 are shown in Table 1. These data show that over
the past two years, the number of DAWN episodes associated
with ephedrine has decreased by approximately 50 percent.
In 1998 the total number of episodes, including suicide attempts
and gestures, is 1119. This is a materially small number that
represents approximately one DAWN ephedrine episode per year
for every 5 hospitals in the U.S.
.
|
TABLE 1
TRENDS IN DAWN EPHEDRINE
EPISODES BY SELECTED VARIABLES (1989-1998)
|
|
1989
|
1990*
|
1991
|
1992
|
1993
|
1994
|
1995
|
1996
|
1997
|
1998
|
Reported Episodes
|
66
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
NA
|
Weighted Episodes
|
441
|
907
|
991
|
902
|
1310
|
2363
|
1880
|
2420
|
764
|
1119
|
Percent of all Episodes
|
0.10%
|
0.24%
|
0.24%
|
0.21%
|
0.28%
|
0.46%
|
0.36%
|
0.50%
|
0.14%
|
0.21%
|
Episodes Combined with Alcohol
|
NA
|
386
|
308
|
NA
|
409
|
726
|
NA
|
NA
|
NA
|
451
|
.
- Total
shift to weighting procedure
Summary
Part 2
- The data
are consistent with my previous findings in which I reviewed
data on purported abuse of ephedrine for an FDA public meeting
considering the WHO scheduling recommendations on ephedrine
and other substances held in February 1999. In preparation
for that meeting I reviewed data from DAWN, the state of Texas,
FDAís Spontaneous Reporting System, the Drug Enforcement Administrationís
System to Retrieve Information from Drug Evidence (STRIDE)
database, the WHO Critical Review, and the response from the
50 countries that responded to the WHO questionnaire. I concluded,
"there is no evidence in either the U.S. or in other
countries of significant abuse of ephedrine and no evidence
of abuse of dietary supplements containing ephedrine alkaloids."
- The current
review supports the previous conclusion. There has actually
been almost a 50 percent decrease in the number of ephedrine-related
episodes reported in DAWN. At this point in time, DAWN ephedrine-related
cases, even including suicide attempts, represent approximately
one episode per year for every 5 hospitals in the United States.
Similarly,
my review of cases included in the AER system (see paragraph
10 above) suggests that neither abuse nor dependence is a significant
problem worthy of regulatory attention. Considering the millions
of Americans who use these products, it is my opinion that the
rate of abuse and dependence is extremely low.
Edgar
H. Adams, Sc.D.
September
26, 2000
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