GMHC Treatment Issues 1994 Mar 1; 8(1): 3
Results from the first controlled, phase II trial of Peptide T
show that the widely used underground drug is not effective in
controlling pain associated with HIV-related peripheral
Background of Peptide T
Peptide T, created in 1986 at the National Institute of Mental
Health (NIMH), was one of the first drugs to be designed
specifically as an AIDS therapy. The basic concept of the drug
- the small molecule occupies cellular receptor sites in the
brain and the immune system that might otherwise be used by
gp120 - the outer (envelope) protein of HIV, is both simple
and elegant. The drug's developers suggest that Peptide T can
slow or reverse neurological (nerve system) and cognitive
(mental or thinking abilities) effects of HIV, including AIDS
dementia, fatigue and pain.
Peptide T has been the subject of many anecdotal accounts from
underground users regarding its effects on cognition,
constitutional symptoms and neuropathy. However, the Phase II
peripheral neuropathy trial is the first peptide T study to
provide rigorous evidence of either the drug's efficacy or
lack of it.
What is Peptide T?
Peptides, the general class of compounds to which Peptide T
belongs, are small strings of amino acids. Because some
peptides function as the active portion of many hormones,
growth factors, and neurotransmitters, they play important
roles in digestion, immunity and emotion. These peptide
components interact with key cells in the responsive organs by
means of receptor molecules located on the cells' surfaces.
The same receptors may exist in more than one organ system. At
least 30 are common to the brain and immune system.
One common receptor site is "CD4." This is the molecule that
the HIV envelope protein gp120 attaches to as the first step
in infecting several different types of immune cells. CD4
receptor sites also exist on glial cells, which excrete
various substances necessary for maintaining the metabolism of
nerve cells (neurons). One theory is that the neurocognitive
effects of HIV, such as dementia, are due to the linkage of
gp120 to CD4 molecules on glial cells. Some scientists believe
that this improper "connection" impedes glial cell performance
and damages neurons. Peptide T is designed to mimic the
attachment sequence in gp120. According to Candice Pert, a
former NIMH researcher who is Peptide T's inventor and chief
promoter, introducing Peptide T into the brain allows the drug
to compete with HIV and free-floating gp120. By occupying CD4
receptor sites, it prevents HIV from interfering with brain
Other experts point out, though, that the process leading to
HIV-associated nerve tissue damage is extremely varied from
one individual to another. The inflammatory process that
arises in response to the presence of HIV in the brain can
disrupt the operation of neurons and their support cells,
which form a complex and delicate interactive network. Another
important factor is the opening up of the calcium channels on
neuron membranes. Too much calcium can poison cells. In
addition, other HIV proteins, besides gp120, seem to be toxic
to cells in neural tissue.
Pert makes a number of other claims for Peptide T, which she
calls a "selective antidote" to gp120. In the first place,
Peptide T may also compete with HIV and free gp120 in binding
to the CD4 on immune cells. A growing number of researchers
suspect that when gp120 links up with the CD4 sites on the
immune system's T-helper cells it leads to a cascade of events
fatal to these cells (a process known as "apoptosis").
However, at this time, there is no evidence to substantiate
Peptide T's benefits in this area.
Peptide T has been found to reduce levels of tumor necrosis
factor-alpha (TNF-alpha). Release of this cytokine has been
associated with HIV disease progression. Excess TNF-alpha is
widely alleged to contribute to wasting syndrome, increased
replication of HIV, immune cell dysfunction and death, and
nerve cell damage as well.
Finally, Peptide T is very similar to the active section of
vasoactive intestinal peptide (VIP), a naturally occurring
regulator of digestion that may have "growth promoting
functions" in the central nervous system. VIP seems to
interact with the CD4 on immune system cells, too. This has
led some researchers to suggest that Peptide T can supplement
VIP in promoting general mental and physical health.
What is Peripheral Neuropathy?
Peripheral Neuropathy is usually characterized by a sensation
of pins and needles, burning, stiffness, or numbness in the
feet or toes. It is a common, sometimes painful, condition in
HIV-positive patients, affecting up to 30 percent of people
with AIDS. It is perhaps most common in people with a
history of multiple opportunistic infections and low CD4
counts. Peripheral neuropathy in people with AIDS can range
from a minor nuisance to a disabling weakness.
The purpose of the Phase II study was to determine if Peptide
T was effective in reducing pain associated with peripheral
neuropathy in HIV-infected individuals. According to officials
of Advanced Peptides, Inc., a Pennysylvania-based company
which sponsored the Phase II study, there were "no
statistically significant differences between Peptide T at 6mg
per day and placebo in the treatment of painful peripheral
neuropathy in AIDS patients." The study, conducted in Miami,
New York and San Francisco, enrolled 108 patients, of whom 81
were considered evaluable for analysis. Advanced Peptides,
with which Dr. Pert is associated, is one of two companies
licensed to develop the U.S. government-owned drug.
In a secondary analysis of the study, company sources reported
that Peptide T also failed to show significant benefits
related to cognition. This was based on a battery of eight
neuropsychological tests which participants received at the
beginning of the trial (baseline) and at week twelve. Study
participants received either Peptide T or placebo for twelve
weeks. The drug was given by spray through the nose
(intranasally) in doses of 2mg, three times per day. All
participants had initial scores of at least 8 on the 15 point
Gracely Scale, a self reported measure of pain. During the
study, participants kept pain diaries in which they recorded a
Gracely pain score three times per day. The goal of the study
was to see if the Gracely Scores of participants receiving
active drug improved more than those receiving placebo.
Improvement was defined as a decline on the scale of at least
2.5 points. At twelve weeks, approximately 35 percent of the
patients in each group showed such improvement, demonstrating
no advantage of Peptide T over placebo. The result was the
same for patients irrespective of CD4 count or use of AZT.
Despite the negative study results, seventeen study
participants have elected to continue taking the drug which is
being supplied by Advanced Peptides without charge. In
addition, several hundred persons with HIV infection and AIDS
continue to purchase Peptide T on the underground, according
to Sally Cooper, Executive Director of the PWA Health Group, a
New York-based buyer's club which sells the drug.
Cooper speculates that one factor in the study's failure to
find a statistical benefit might have been the health of the
trial participants. Over 60 percent of the enrollees, she
says, had fewer than 50 CD4 cells. Another factor, according
to New York-based activist Anna Blume, might have been what
she describes as the "high pain level" required of study
participants. Blume says she has heard anecdotal reports of
people with lower pain levels who have had success in using
Peptide T to control it.
In addition, Candice Pert claims that blood tests showed that
up to a third of the people in the study's placebo arm
actually were taking peptide T, presumably obtained from the
underground suppliers. This alleged violation of the trial
protocol, which could not be independently confirmed by
Treatment Issues, would account for some of the apparent
improvement in the placebo arm - up to 11.5 percent out of the
35 percent to be exact.
The peripheral neuropathy study, nevertheless, is the only
double-blinded phase II (efficacy) study of Peptide T that has
been completed. The failure of the trial to show any benefit
is sobering news - particularly to advocates and users of the
Advanced Peptides told GMHC Treatment Issues that it will not
abandon the drug's development, but is exploring the
possibility of a phase II trial aimed at determining whether
the drug prevents the onset of opportunistic infections and
increases survival. A company proposal to examine the
peptide's effects on quality of life variables was recently
turned down by the Food and Drug Adminstration (FDA), which
cited the lack of an adequate quality of life scale on which
participants might be measured.
Peptide T Still Available on the Underground
Testing difficulties have not prevented the drug from becoming
one of the top sellers of the AIDS underground - despite a
pricetag of $260 a month. The drug's top-selling status has
been fueled by widely repeated anecdotal accounts of relief
from AIDS dementia and cognitive impairment, of increases in
quality of life variables, and indeed, of relief from the pain
of peripheral neuropathy. (Of course, as with all anecdotal
evidence, extreme caution must be exercised in attributing
improvements to a particular therapy.)
Additional Phase II Studies Underway
Because it has been suggested that Peptide T might be able to
reverse HIV-related neurological impairment, a phase II
multicenter study of the drug's neuropsychological effects is
nearing completion. This study, sponsored by the NIMH, was
expanded to two new sites (U.C. San Diego and the University
of Miami) after participant recruitment at the University of
Southern California failed to meet expectations. Enrollment
was closed in December 1993, and results are expected in the
Fall 1994. A negative result, says Anna Blume, would probably
sink any remaining interest in developing Peptide T as an AIDS
A smaller, phase II dose comparison study is being conducted
at Sibley Hospital in Washington, D.C. Twenty four patients
completed the initial open label phase of that study, which is
now being analyzed. In a continuation phase, ten patients are
receiving one of three doses of Peptide T.
In addition, Yale University researchers are continuing their
work on administering Peptide T to HIV-positive injection drug
users (IVDUs). They are presently seeking additional subjects
for an ongoing study.
Earlier Peptide T Studies
To date, the Phase II peripheral neuropathy study is the only
placebo-controlled, double blinded (efficacy) study of Peptide
T to have been completed. Such studies are, of course, the
only studies considered by scientists to provide conclusive
evidence of whether a drug is useful. However, a series of
small phase I safety studies have been reported. Several of
them, according to advocates of Peptide T, suggest a possible
lessening of HIV-related symptoms in the areas of
neuropsychology and general well being.
A very early phase I study was conducted at Sweden's
Karolinska Institute in 1987. Four near-terminal men with AIDS
were treated with intravenous Peptide T (1mg twice daily) for
one week, followed by 2mg twice daily for three weeks.
Significant decreases in serum levels of p24 antigen,
decreased levels of beta-2 microglobulin and significant
improvement in abnormal MRI (magnetic resonance imaging) scans
and lymphocyte counts were reported. One patient's
psoriasis was reported to have improved. No toxicities were
No toxicity was again observed in a second uncontrolled phase
I study conducted by Bridge and Heseltine et. al. at the
University of Southern California (USC). Six AIDS patients
with moderate neuropsychiatric impairment and a mean CD4 cell
count of 42 received intravenous Peptide T for 30 days
followed by intranasal administration (sprayed into the
nostrils) for three to seven days. According to a letter
published in The Lancet, "where HIV-associated [neurocognitive]
deficits were present, function returned to normal during drug
testing. Similarly, where HIV constitutional symptoms had been
present at baseline (weight loss, watery diarrhea, fatigue,
anergy, HIV-associated dermatitis), improvement or resolution
was observed." Two p24 antigen positive subjects became
negative; CD4 cell counts remained stable and CD8 counts
increased 50 percent.
In a separate USC study, fourteen volunteers with HIV-related
cognitive impairment were given intravenous Peptide T (.1mg to
3.2mg/kg/day) for twelve weeks. After a four-week washout
period, six of the participants were given 25mg intranasal
Peptide T daily for another eight weeks. According to the
investigators, toxicity was minimal. They reported a reduction
in neurological symptoms and improvements on a repeated
battery of neuropsychological tests compared to a group of 18
HIV-negative gay male controls who took the same tests but
were given neither drug nor placebo. There were no significant
immunologic or antiviral changes.
At Boston's Fenway Community Health Center, 32 patients not
using antiretrovirals were randomized to receive one of three
dose levels of intranansal Peptide T (1.2mg per day, 6mg per
day, 30mg per day) in a 24 week on-off-on trial (12 weeks on
drug, four weeks on placebo, eight weeks on drug).
Researchers noted a stabilization of CD4 cells, reduction in
p24 antigenemia, and significant improvements in memory loss
and malaise. On a battery of five neuropsychological tests,
statistically significant clinical benefits were suggested by
the researchers. In their abstract for the Seventh
International AIDS Conference in Florence in 1991, the
researchers noted that the lowest dosage group (1.2mg per day)
showed the greatest improvement.
Another phase I study was conducted at Yale University, where
five HIV-positive cognitively-impaired intravenous drug users
(IVDUs) with HIV were treated intranasally with Peptide T
(5mg, three times a day for four weeks, followed by four weeks
of placebo). Subjects, who were maintained on methadone,
showed an improvement on neuropsychological tests on which
they had previously been impaired, compared to those given
The most recent clinical work has come from a trio of
researchers in Toronto who presented several papers at the
Ninth International AIDS Conference in Berlin and at an HIV
neuroscience conference held in Vienna. One study of fifteen
patients was designed to assess whether or not Peptide T was
immunosuppressive. According to the authors' paper, the
subjects' immune capacity was "enhanced" and not decreased
following two weeks of Peptide T treatment thereby
"confirm[ing] that Peptide T is not immunosuppressive." In
addition, the researchers found that levels of TNF were
decreased in five of eight patients.
The Canadian investigators also presented results of an
ongoing open label study that they have been conducting for
over three years, in which 50 symptomatic HIV-positive
patients with CD4 cell counts below 200 (median 15) have
self-administered 8.5mg of Peptide T daily by subcutaneous
injection. In a subgroup of this study that began with 24
patients and ended after sixteen weeks with fourteen patients
still participating, statistically significant improvements
were observed in the "areas of energy-fatigue, physical
function, and overall health status." In addition, there was
statistically significant improvement on several
neuropsychological exams, and a reduction of nighttime
awakenings. Said the researchers: "preliminary results support
previous findings of neurocognitive improvement in patients
given Peptide T and our findings that Peptide T can have a
beneficial impact on health related quality of life by
improving constitutional symptoms, particularly HIV-related
Reported Side Effects of Peptide T
Reported side effects related to Peptide T administration have
been relatively minor. One patient in the Swedish phase I
study had a transitory blood pressure drop when his infusion
rate was increased. One patient in the USC phase I had a rash
that recurred upon rechallenge with Peptide T. Participants in
intranasal trials report occasional nasal congestion and
related symptoms, and these have, on occasion, required either
decongestants or antibiotics. According to a letter in AIDS
Patient Care, participants in a study of Peptide T sponsored
by the AIDS Clinical Research Center of Washington, D.C.
experienced symptoms of a "second puberty," including
increased hirsutism (excessive hair growth), acne, increased
libido, wet dreams and an increase in serum testosterone
levels. The author of the letter concluded that "Peptide T
may cause masculination and a rise in low or low normal serum
testosterone levels in some HIV-positive patients. Further
investigation into hormonal changes induced by Peptide T is
Another potentially troubling side effect has emerged in
anecdotal accounts of underground users and in the NIMH phase
II study. Several Peptide T users reported bouts of extreme
anger, which they attribute to the effect of the drug. Some of
these individuals have discontinued use of Peptide T.
How to Get Peptide T
Peptide T can be accessed in one of two ways: either
participation in a clinical trial, or by purchase through the
underground (buyers clubs). A vial of intranasal Peptide T
costs $65, according to Sally Cooper of the PWA Health Group
(212/255-0520). The vial, lasts a week when taken at a dose of
2mg three times a day. Pending completion of quality control
tests, drug from a new supplier should reduce the price by
approximately one third of its present cost. HIV- positive
IVDUs are eligible to enroll in the Yale New Haven trial. Call
Dr. Kosten at 203/781-4770. A pediatric trial will also soon
be enrolling 40 children. Call Anna Blume at 718/363-1194.
Data from the Phase II study suggest that Peptide T is
probably not of significant benefit in the treatment of
peripheral neuropathy in HIV-positive individuals. These
results conflict with a number of earlier phase I studies and
anecdotal reports of benefits from the use of Peptide T in
some HIV-positive individuals. Reported side effects
associated with Peptide T appear limited. A Phase II trial of
the drug in the treatment of HIV-related neuropsychological
conditions is near completion. It is likely that the results
of this trial will determine the future development of Peptide
T as a treatment for HIV-related conditions. In the meantime,
while positive anecdotal reports can never be completely
discarded, those who are currently considering the use of
Peptide T are advised: caveat emptor (let the buyer beware).
1 Candice B. Pert, Modern Medicine. January 1989. 57:44.
2 D.J. Phipps, et. al. Abstract PO A13 0232. Eighth
International Conference on AIDS, Berlin, Germany. June 1993.
3 Pert, et. al. AIDS as a neuropeptide disorder: Peptide
T, VIP and the HIV receptor. Psychopharmacology Bulletin.
4 Parry GJ. Ann Neurol.1988; 23 (suppl):S49-S53.
5 Cornblath ER, et al. Neurology. 1988; 38:794-796.
6 Personal Communication. Candice Pert. February 8, 1994.
7 Wetterburg L, et. al. The Lancet. 1987; 329:8525:159.
8 Bridge, TP, et al. The Lancet, 1989; 334:8656:226-227.
9 Bridge TP, Heseltine et. al. Psychopharmacology
Bulletin. 1991; 27:3:237-245.
10 K. Mayer et. al. Phase I study of intranasal Peptide T:
clinical and lab results, Fenway Community Health Center 4th
Annual Public Forum, July 10, 1990.
11 Bridge et. al., Neuropsychologic Results of Control
HIV-1 Trial of Peptide T, Abstract for the 7th International
Conference on AIDS, Florence, Italy, June 16-21, 1991.
12 Rosen et. al. American Journal of Addiction, 1992;
13 MacFadden, Phipps and Doob. Abstract PO-B28-2164. Ninth
International Conference on AIDS, Berlin, Germany, June 1993.
14 Doob, Phipps and MacFadden, Paper presented at
Neuroscience of HIV Infection: Basic and Clinical Frontiers
Conference, Vienna, Austria, June 1993. Abstract published in
Clinical Neuropathology 1993; 12(Sup. 1): S30.
15 Harris PJ. AIDS Patient Care. February 1992. 6:1.
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