**Date:** May 15, 2000\
**To:** Corinne Moody, FDA\
**RE:** NIDA response to Federal Register Notice for Comments on 6
substances\
**From:** Stephen R. Zukin, M.D\
Associate Director for Medical Affairs, DTR&D/NIDA\
**CC:** Mr. Millstein, Dr. Delany, Dr. Vocci, Dr. Skinner

In response to the Federal Register Notice dated April 28, 2000 (Docket
No. 00N-1257), NIDA wishes to supply the following comments.

**Epidemiology:**

The following epidemiological information comes from the Proceedings of
the most recent meeting of the Community Epidemiology Work Group (CEWG)
that was held in December 1999.  The CEWG monitors patterns and trends
of drug abuse based on indirect indicators, so changes in incidence and
prevalence are not available. Of the six drugs listed in the FDA Notice,
only GHB and diazepam were mentioned in the CEWG meeting.

The Executive Summary from the meeting states that:

\"Problems associated with rave and club drugs have risen dramatically
in 1999.  Gamma-hydroxy-butyrate (GHB, a central nervous system
depressant) and two of its precursors, gamma-butyrolactone (GBL) and
1,4-BDL, also called tetramethylene), have been increasingly involved in
fatalities, poisonings, overdoses, drug rapes, and other criminal
behaviors in nearly every CEWG city and their surrounding suburban and
rural areas.

These products, obtainable over the Internet and sometimes still sold in
health food stores, are also available at gyms, nightclubs, raves, gay
male party venues, college campuses, or on the street.  Commonly mixed
with alcohol, they have a short action duration, and are not easily
detected on routine hospital toxicology screens.  GBL is available in
commercial products such as Blue Nitro, RenewTrient, and Revivarent G,
while 1,4-butanediol is sold in products such as Enliven, Weight Belt
Cleaner, and Revitalize Plus.  New esters and analogs continue to appear
as Federal and State laws progibit the sale of these drugs.\"

Concerning diazepam, the Executive Summary states that:

\"Recent deaths in Seattle have involved concomitant injection of heroin
and a depressant, typically diazepam.  Diazepam ED mentions have
declined significantly in several cities, while alprazolam (Xanax, or
\"sticks\") mentions have increased significantly.  Those two drugs are
frequently reported by crack users in Philadelphia.  In New York
diazepam now follows alprazolam as the leading psychoactive prescription
drug; in Chicago, however, diazepam remains the most readily available
and frequently used pharmaceutical depressant.\"

**Basic science studies related to abuse liability:**

**Dr. Richard Meisch**

In 1994 in JPET, the PI reported that "Diazepam-maintained responding
usually exceeded water responding as the diazepam concentration was
increased to 0.8 mg/ml" in an oral self-administration procedure with
rhesus monkeys who had a history of alcohol and pentobarbital
reinforced-behavior. The author concluded that diazepam induces "robust
reinforcing effects" when delivered by the oral route (JPET, 1994,
271:200).

Dr. Meisch has been able to demonstrate that diazepam can act as a
reinforcer when self-administered via the oral route in the monkey, but
dose/reinforcement magnitude relationships have not been established.

**Dr. Carol Paronis**

This investigator is assessing the GABAergic receptor substrates for
anxiolytic activity of benzodiazepine compounds. The dependent measures
are suppressed (by prior training with electric shock) and nonsuppressed
food delivery. Using this paradigm, the PI is able to compare drug
effects on motoric behavior (i.e., sedation or non-specific effects) to
effects on more 'psychological' variables (such as 'anxiety'). She
determined that both effects were induced by zolpidem with the same
doses in squirrel monkeys. Subsequently she reported on drugs that are
GABAergic receptor antagonists at a particular subunit of this complex.
The antagonist, B-CCt showed a differential sensitivity for disrupting
the sedative versus anxiolytic effects of zolpidem.

Some of her data with zolpidem were reported at FASEB in 1999 (FASEB
Journal vol. 13:A1106).

In a squirrel monkey model, zolpidem appears to induce sedation and
anti-anxiety effects within the same dose range; however, these two
effects may be mediated by different receptor substrates in the GABA
neurotransmitter system.

**Dr. James Rowlett**

The purpose of this preclinical research program is to "specifically
evaluate the role of benzodiazepine receptor selectivity and intrinsic
efficacy as determinants of the therapeutic versus abuse-related
effects..." using "nonhuman primate models". His data on zolpidem have
been reported in the proceeds from CPDD (NIDA Monograph) in 1999, and in
JPET (vol. 291:1233, 1999). Using drug discrimination techniques, the PI
found that diazepam only substituted for zolpidem in some of the monkeys
tested. The same result was obtained for the other 'conventional'
benzodiazepine, chlordiazepoxide when tested in zolpidem trained
monkeys. The authors conclude that binding to a benzodiazepine-I site
may be more important for zolpidem's subjective effects than is the case
with conventional benzodiazepines.

These results suggest that subjective effects between conventional
benzodiazepines, like diazepam, and zolpidem, may not completely overlap
and that this may be due to differences in the types of receptors they
bind to.

**Dr. Craig Rush**

This is probably the largest human psychopharmacology research program
on benzodiazepines in the country. His program has generated a great
deal of data on zolpidem. Most of these data are now published:

Rush CR, Baker RW, Rowlett JK

Discriminative-stimulus effects of zolpidem, triazolam, pentobarbital,
and caffeine in zolpidem-trained humans EXP CLIN PSYCHOPHARM 8: (1)
22-36 FEB 2000

Rush CR, Frey JM, Griffiths RR

Zaleplon and triazolam in humans: acute behavioral effects and abuse
potential

PSYCHOPHARMACOLOGY 145: (1) 39-51 JUL 1999

Rush CR, Baker RW, Wright K

Acute behavioral effects and abuse potential of trazodone, zolpidem and
triazolam in humans PSYCHOPHARMACOLOGY 144: (3) 220-233 JUN 1999

Rush CR

Behavioral pharmacology of zolpidem relative to benzodiazepines: A
review

PHARMACOL BIOCHEM BE 61: (3) 253-269 NOV 1998

Rush CR, Griffiths RR

> Zolpidem, triazolam, and temazepam: Behavioral and subject-rated
> effects in normal volunteers J CLIN PSYCHOPHARM 16: (2) 146-157 APR
> 1996

In his 1998 review, published in PBB, he specifically reviews the data
to date on zolpidem's reinforcing effects, discriminative-stimulus
effects, subject-rated drug effects, performance impairment, and
evidence of tolerance. Comparisons are made with other benzodiazepines.
However, at the time of publication, the PI noted a "dearth of
perspective, experimental studies" and a "paucity of published studies"
on zolpidem. More recently, in the Psychopharmacology publication of
1999, he reports on acute behavioral effects and indices of abuse
potential from subjects with a history of alcohol and drug abuse. At 45
mg, zolpidem increased subjective ratings of "like drug", "happy", "good
effects", "friendly", "elated", "carefree" and "bad effects". When
compared with triazolam on subject-rated items of the ARCI believed to
measure abuse potential, the two drugs' effects were comparable.
Dose-dependent performance impairments were also noted for zolpidem, on
a number of dependent measures.

The PI concludes from his most recent published investigations on
zolpidem in human subjects, that in spite of it's "somewhat unique
benzodiazepine-receptor-binding profile, zolpidem's acute behavioral
effects and abuse potential are generally similar to those of
triazolam."