DRUG STUDIES ARE QUESTIONED

Psychiatric researchers over the past several years have given about 100
healthy individuals across the nation a powerful hallucinogen, known to
drug abusers as ''Special K,'' to study psychosis, often without fully
disclosing the nature of the drug or the experiments.

The studies using ketamine have involved both mentally ill and healthy
subjects, placing them both at potential risk of psychotic episodes,
according to documents reviewed by the Globe.

Using ketamine on healthy volunteers especially troubles some medical
ethicists, because there is no possibility that healthy people as a class
will achieve any benefit to offset the risk of harm. The mentally ill, at
least in theory, would be aided by any knowledge gained about the biology
of psychosis.

Most of the ketamine experiments have been conducted at the National
Institute of Mental Health in Bethesda, Md., or at NIMH-funded facilities
such as the medical schools of Yale and New York University.

A Globe review of their research and some of the consent forms that
participants are asked to sign indicates that subjects are often not being
told that the drug is being given to specifically induce symptoms such as
hallucinations or memory loss, or that it is abused as a psychedelic drug.

On the streets and on drug-subculture Internet sites, ketamine is known for
being able to create near-death experiences, feelings of floating, and
other hallucinations. It has recently been used as a date-rape drug and at
all-night parties known as ''raves,'' prompting several states to make
illegal possession a felony.

Some critics see these experiments as an echo of 1950s and 1960s research
in which psychiatrists gave people LSD without fully informing them of the
risk.

''It's just like shades of LSD research as far as I'm concerned,'' said
Carl Tishler, an Ohio State University psychologist who has written on the
ethics of ketamine experiments.

LSD, or lysergic acid diethylamide, was made illegal across the nation in
the 1960s.

Ketamine is primarily used as an animal tranquilizer, particularly for cats
and nonhuman primates. It had once been commonly used as a human
anesthetic, until its hallucinogenic properties were discovered. Ketamine,
also known on the streets as ''KitKat'' or, simply, ''K,'' is a chemical
cousin of PCP, or ''angel dust.''

In a series on psychiatric research last month, the Globe documented the
harm done by the use of ketamine and other ''challenge'' agents to induce
psychotic symptoms in people with schizophrenia, as well as from other
research approaches. An additional review has revealed studies involving
ketamine in more than 100 healthy people since 1994 - and the growing
illicit use of the drug. Such studies do not appear to have been done in
Massachusetts, although a bill has been filed by a private citizen to
strengthen research protections here.

''If this is what they are doing to normal [people], God help us with the
cognitively impaired,'' said Adil Shamoo, a University of Maryland
bioethicist and editor of the journal Accountability in Research.

As a result of the Globe's review, Shamoo said the New York-based advocacy
group he co-founded with Vera Hassner Sharav, Citizens for Responsible Care
in Psychiatry and Research, will expand its call for a moratorium on
challenge studies, to include those involving healthy people.

Among some of the results of ketamine in healthy subjects reported in the
literature: Feelings of floating and of having a transistor radio implanted
in the ear; acute psychotic states; ''psychedelic effects''; ''tearfulness,
a sad mood''; and feelings of ''life and death at the same time.''

While the possibility of experiencing long-term harm from a drug-induced
psychosis is less likely among healthy people, there is still the risk that
some normal subjects will have flashbacks months afterward, even if they
apparently have no history of substance abuse or mental illness that would
make them vulnerable, according to the Globe's review of LSD and ketamine
research, and ethicists familiar with the research.

There is also a possibility that healthy subjects would refuse to disclose
elements of their medical history to researchers for fear it would mean
they would be unable to participate. (Some of the ketamine studies paid
$100 per subject.)

''That is something to worry about,'' said Jonathan Moreno, director of the
University of Virginia's Center for Biomedical Ethics and a specialist on
the history of LSD research.

A top NIMH official and a Yale psychiatrist who has conducted some of the
studies said they do not believe that ketamine's illict use needs to be
spelled out in informed consent forms, since the drug is still approved by
the Food and Drug Administration as an anesthetic. Above all, the careful
use of ketamine in research may help yield answers for some of the most
devastating mental illnesses, they say.

''This is a medicine which is given under close scrutiny for a short-term
basis. There is no repeat long-term exposure,'' said Dr. Trey Sunderland,
chairman of NIMH's institutional review board, which has approved ketamine
studies involving both healthy subjects and those with schizophrenia. As a
result, ketamine's street use is ''not an issue in these studies'' and not
brought up with subjects.

''I don't think there's a direct comparison between the ketamine research
and the LSD research,'' Sunderland said, since ketamine is FDA-approved and
shorter acting. In addition, ''I know of no such long-term effects with
this kind of study,'' like flashbacks, although he said it is not a matter
of routine for researchers to check up with subjects months later.

Dr. John H. Krystal, a Yale professor of psychiatry who has conducted
studies in both healthy people and people with mental illness, said that
his group began using ketamine ''based on a reading of the old PCP
literature. There might be symptoms or cognitive deficits or emotional
problems associated with schizophrenia that might be modeled by ketamine.''

''The hope ... is that we might gain new insights into treatment of these
symptoms,'' Krystal said. Ketamine is thought to provide a better model of
schizophrenia than LSD or other psychostimulants, because it appears to
induce both hallucinations and bizarre thoughts, or so-called positive
symptoms, as well as the social withdrawal and other negative symptoms of
the disease.

Krystal said he is certain that during his early studies, first published
in 1994, subjects were not told of ketamine's use as a street drug, but he
did not have available the most recent consent forms to verify what
subjects are now told.

However, he said, ''People who participate are made aware that it has
effects on mood that may make some people want to use it.''

But James Childress, a member of the National Bioethics Advisory
Commission, which is calling for special research protections for the
mentally ill, said the illicit use of ketamine is ''exactly the sort of
thing that should be disclosed'' to study participants.

Arthur Caplan, a bioethicist at the University of Pennsylvania, said such
disclosure is particularly important because ''There's always the danger of
hooking someone, getting someone down a road they don't even want to travel.''

One legislator in Florida, a state that has considered making possession of
ketamine a felony, agreed.

''If government is going to do studies on people, I think they need to tell
people what they're ingesting. It seems government should have learned that
lesson a long time ago,'' said Florida state Representative Tracy Stafford,
a Democrat who has filed a bill to make ketamine a controlled substance.

Some ethicists who reviewed an NIMH consent form obtained by the Globe said
they were most worried about its failure to fully explain the effects of
ketamine.

''If in fact the purpose of the NIMH study was to produce a psychotic
state, or if they knew it would produce a psychotic state, then they should
tell their subjects that,'' said Leonard Glantz, a medical ethicist and
professor of health law at Boston University School of Public Health.
''It's not a side effect or a hazard. It's a desired outcome.''

NIMH's Sunderland defended the form. ''It does mention you might get an
altered mood, hallucinations... The main side effects of the medication are
listed in black and white.''

But he acknowledged that challenge studies are under ''intense review'' at
NIMH and elsewhere, because of the questions that have been raised.

In February, an advisory council to NIMH is set to take up challenge
studies. NIMH director Steven Hyman has publicly stated that the research
community has ''to get its house in order'' to fend off restrictive
regulation and legislation.

Checked-by: Richard Lake