CDC Report on Findings from the U.S. Public Health Service Sexually Transmitted 

Disease Inoculation Study of 1946–1948, Based on Review of Archived Papers of 

John Cutler, MD, at the University of Pittsburgh 

29 September, 2010 
1

Executive Summary 

From 1946–1948, the U.S. Public Health Service (USPHS) Venereal Disease Research 

Laboratory (VDRL) and the Pan-American Sanitary Bureau collaborated with several 

government agencies in Guatemala on U.S. National Institutes of Health-funded studies 

involving deliberate exposure of human subjects with bacteria that cause sexually 

transmitted diseases (STD). Guatemalan partners included the Guatemalan Ministry of 

Health, the National Army of the Revolution, the National Mental Health Hospital, and 

the Ministry of Justice. Studies were conducted under the on-site direction of John C. 

Cutler, MD, in Guatemala City, who worked under the supervision of R.C. Arnold, MD, 

and John F. Mahoney, MD, of the USPHS VDRL in Staten Island, New York. The 

primary local collaborator was Dr. Juan Funes, chief of the VD control division of the 

Guatemalan Sanidad Publica. 

The work by Dr. Cutler and VDRL colleagues was recently brought to light by Professor 

Susan Reverby of Wellesley College, as a result of archival work conducted as part of 

the research of her 2009 book on PHS syphilis studies, Examining Tuskegee. Her 

article on the STD Inoculation studies is scheduled to be published in the Journal of 

Policy Studies in January 2011 and will be available on her departmental homepage in 

October 2010 (www.wellesley.edu/WomenSt/fac_reverby.html). 

Upon learning of Professor Reverby’s work, staff from the Centers for Disease Control 

and Prevention (CDC) conducted a review of materials in the papers of Dr. Cutler, 

archived at the University of Pittsburgh. These papers included several summary 

reports, experimental logs, correspondence between Dr. Cutler and professional 

colleagues, and subject-specific records. The findings from this review are consistent 

with the observations to be published in Dr. Reverby’s paper and are summarized as 

follows. 

According to materials in the archives, the primary purpose of the studies was to develop 

human models of transmission of Treponema pallidum—the bacteria that causes 

syphilis—by sexual transmission and cutaneous and mucous membrane inoculation in 

order to assess the effectiveness of potential chemoprophylactic regimens. Additional 

studies were conducted to: assess the potential for re-infection of persons with 
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untreated, latent syphilis or of those with recent treatment of syphilis with penicillin; 

compare performance of various serologic tests for syphilis; and develop human models 

of transmission and chemoprophylaxis of the agents of gonorrhea (Neisseria 

gonorrhoeae) and chancroid (Hemophilus ducreyi). 

 Subjects for the transmission studies included female commercial sex workers (CSWs), 

prisoners in the national penitentiary, patients in the national mental hospital, and 

soldiers. These subjects were also involved in comparative serologic studies. 

Transmission studies initially included sexual exposure of prisoners to female CSWs, 

experimentally infected with either syphilis or gonorrhea. Later, subjects underwent 

direct inoculation—primarily of skin and mucous membranes—by viable T. pallidum, N. 

gonorrhoeae, and H. ducreyi. The design and conduct of the studies was unethical in 

many repects, including deliberate exposure of subjects to known, serious health 

threats; lack of knowledge of, and consent for, experimental procedures by study 

subjects; and the use of highly vulnerable populations. 

According to a “Syphilis Summary Report” and experimental logs in the archives, syphilis 

studies included CSWs, prisoners, and patients in the mental hospital. In the series of 

syphilis studies, a total of 696 subjects of individual experiments (some representing the 

same patients involved in several experiments) were exposed to infection (by sexual 

contact or inoculation). Of these, 427 (61%) were judged to be infected, of whom 369 

(86%) received what was considered to be “adequate treatment” with injections of 

penicillin (defined by the investigators as ≥3.4 million units). 

Gonorrhea studies included CSWs, prisoners, soldiers, and mental hospital patients. In 

the series of gonorrhea studies, a total of 772 subjects of individual experiments (some 

apparently representing the same patients involved in several experiments) were 

exposed to infection (by sexual contact or inoculation). Of these, a summary report and 

experimental logs indicate that 234 (30%) were infected, 233 (99.5%) of whom were 

stated to have received treatment with injections of penicillin (300,000 units). 

Chancroid studies included soldiers and mental hospital patients. A total of 142 subjects 

were exposed to infection by inoculation. Of these, a summary report and experimental 
3

logs indicate that 138 (97%) were infected, 129 (93%) of whom were stated to have 

received treatment with sulfathiazole (1 gram PO per day for 5 days). 

To supplement findings in the “Syphilis Summary Report” and experimental logs, a 

detailed review of subject-specific records for the syphilis inoculation studies was carried 

out for persons involved in the majority of the syphilis experiments. This allowed for the 

unduplication of subjects involved in multiple experiments and included some subjects 

who may not have been included in the “Syphilis Summary Report”. This review 

included subject-specific records from 532 persons, 497 (93%) of whom were inoculated 

with infectious syphilis. Of these 497, prescription of adequate therapy with penicillin 

(≥3.4 million units) could be documented for 332 (67%). Based on laboratory 

assessment, 433 (87%) could be considered to have evidence of syphilis. Of these 433, 

adequate penicillin therapy was prescribed for 331 (76%), although completion of 

therapy was documented for only 85 (26%). Over the course of observation, 71 subjects 

were noted to have died, including one who developed fatal status epilepticus during 

penicillin therapy, although the records do not allow determination of the relationship of 

the deaths to study procedures. There was no systematic description of other adverse 

events arising during the study or follow-up observation period. 

The study appears to have ended in 1948, although some follow-up laboratory testing 

and patient observation continued until the early 1950s. There is no indication that 

results of the STD inoculation experiments were ever published in the scientific literature 

or other forums. 
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Outline of the Cutler files 

As outlined in the Appendix, the Cutler files at the University of Pittsburgh consist 

entirely of files from the PHS-funded STD Inoculation Study of 1946–1948. The files 

include the following: 

a. a long 7-part summary report of the rationale, methods, and results of the 

syphilis studies (designated as the “Syphilis Summary Report”); 

b. shorter summary reports of the studies of gonorrhea (“Experimental 

Studies in Gonorrhea”) and chancroid (“Chancroidal prophylaxis”); 

c. correspondence between Dr. Cutler and USPHS colleagues; 

d. experimental records, logbooks, and summaries; and 

e. short, subject-specific records of subjects involved in the syphilis 

inoculation studies that included records of baseline history, physical 

exams, and syphilis serologic results; experiment number(s) and T. 

pallidum inoculation(s); follow-up syphilis serologic results and periodic 

clinical examination findings; and dates and doses of penicillin treatment. 

The files cover the period primarily from mid-1946 until late-1948, with limited patient 

records regarding follow-up serologic testing for the next several years. Descriptions 

from the “Syphilis Summary Report” provide many details and are the source of the 

quotations in the following sections, unless otherwise specified. The “Syphilis Summary 

Report” is not dated, but it includes mention of the subsequent study of syphilis 

inoculation at Sing-Sing prison (in New York state) in the 1950s, as well as several other 

published references from as late as 1954 (including a 1954 report from the Tuskegee 

study). A note included with a handwritten table of “Individual patient response in each 

experiment” indicates that the table was compiled by Sacha Levitan and John Cutler in 

December, 1948, and that it was the basis for the final analysis and write-up by Henry 

Miller and John Cutler from 1951–1954. 

The subject-specific records contain information about subjects in the syphilis 

experiments, many of whom were included in multiple experiments and followed with 

frequent serologic tests over time. These records contain limited personal identifying 

information, apart from name, gender, and the institution with which they were affiliated, 
5

although some do specify age, names of parents, and city of residence. Subject record 

forms are identified with an inscription at the bottom of each page: “Centro de 

Adiestramiento e Investigaciones de las Enfermedades Venereas, Sandidad Publica, 

Guatemala, C.A.” 

Background of the research studies 

The USPHS VDRL had an active program investigating chemoprophylaxis of STDs (i.e., 

chemical agents to prevent acquisition of STD following sexual exposure) in the 1940s, 

assessing preparations that might be more effective and acceptable than the agent in 

widespread use by U.S. military services in World War II (U.S. Army Pro-kit—a topical 

preparation containing 33% calomel, 15% sulfathiazole, 40% white petrolatum, 14% light 

mineral oil, and 1% cetyl alcohol). There was interest in both alternative topical 

preparations (e.g., Orvus—an aqueous solution of 0.15% mapharsen and 1.0% alkyl aryl 

sulfate) as well as systemic penicillin. It is noted that studies in rabbits and small pilot 

studies among sailors in the U.S. Navy had been performed and provided promising 

initial results, although the role of the Departments of the Army and Navy in these 

studies was not specified. However, before these alternative prophylactic approaches 

could be widely adopted by the U.S. military, “it was felt that carefully controlled studies 

on relatively small groups of individuals exposed to a high risk of infection were required 

before the [new and presumably more effective and acceptable chemoprophylactic] 

preparation could be proposed for widespread use, particularly in the Armed Services 

(Part I, pg 7). “ Thus, the primary rationale for the studies was to develop models of 

human transmission to assess the impact of various chemoprophylactic regimens as 

well as to re-assess an understanding of syphilis immunology in the penicillin era 

(especially immunity to reinfection with latent or recently cured syphilis). 

Dr. Cutler’s report indicates that Guatemala was selected for these studies at the 

suggestion of Dr. Juan Funes, chief of the VD Control Division of the Guatemalan 

Sanidad Publica. Dr. Funes had studied for a year at the VDRL in NY as a fellow 

assigned by the Institute of Inter-American Affairs, during which time he became 

interested in the subject of chemoprophylaxis of STD. Since “prostitution was legalized 

to the extent that prostitutes were allowed to pay regular visits to men in penal 
6

institutions” and because the VD Control Division was “responsible for medical 

supervision of prostitution and of all rapid treatment centers where all VD patients could 

be hospitalized for free treatment” (Part I, pg 8), Guatemalan prisons were thought to 

represent useful settings to study the effectiveness of chemoprophylaxis after sexual 

exposure to STD. 

Dr. Funes explored these ideas with colleagues when he returned from the United 

States to Guatemala. The idea was “officially approved” and representatives of the 

VDRL continued discussions about project feasibility. The Pan-American Sanitary 

Bureau (PASB—the precursor to the Pan-American Health Organization), which was 

“actively interested in developing VD-control programs, as well as training and research 

facilities outside of the United States [Part I, pg 9],” agreed to collaborate. A research 

grant was made by the USPHS Division of Research Grants (the unit in charge of U.S. 

NIH extramural funding) to PASB. The VDRL “assumed responsibility for scientific and 

technical direction of the project and provided necessary personnel for assignment to the 

PASB to head the project (Part I, pg 9),” while the government of Guatemala “signed 

agreements with PASB permitting establishment of the research and training center and 

allowing cooperative working arrangements between the PASB staff and various units of 

the government for research and training purposes (Part I, pg 9).” There was an 

agreement that, “the laboratory and equipment set up in Guatemala for the study would 

revert to the government when the PASB relinquished interest in the training and 

research program; also, that local personnel would be trained to work in the public health 

service and to take over the unit as a governmental activity if so desired (Part I, pg 9).” 

The potential scope of envisioned activities was broad, including assessing the burden 

of disease in the country, training personnel to conduct disease control activities, 

establishing services for diagnosis and treatment, and research in diagnosis, treatment, 

and chemoprophylaxis. As summarized by Dr. Cutler, “this meant that the staff had 

authority to work with the medical and other authorities of the public health service rapid 

treatment center for venereal diseases; in the government hospitals; with medical 

installations and officers of the military; with institutions caring for orphans and the 

insane; and with the penal system (Part I, pg 10).” 
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There seems to have been relatively widespread knowledge in the scientific community 

about the proposed studies. A letter from Dr. John F. Mahoney, director of the VDRL, to 

Dr. Cutler (dated October 15, 1946) mentions that: “Your show is already attracting 

rather wide and favorable attention up here. We are frequently asked as to the progress 

of the work; Doctor T.B. Turner of Johns Hopkins wants us to check on the pathogenicity 

in man of the rabbit spirochete; Doctor Neurath of Duke would like to have us follow 

patients with his verification procedure; Doctor Parran (the Surgeon General) and 

probably Doctor Moore might drop in for a visit at the first of the year.” A subsequent 

letter from Dr. Mahoney (dated December 23, 1946) indicated continued high-level 

support, emphasizing that “The Surgeon General has become keenly interested in the 

Guatemala project.” 

Review of Summary Reports and Experimental Logs: Study Populations 

Study Populations. 

According to the “Syphilis Summary Report”, the initially targeted population of research 

subjects were prisoners in the Central Penitentiary, housing about 1,500 male inmates 

ranging from short-term offenders to those with life sentences, and female CSWs 

engaged to provide services to prisoners. Medical care in the prison included an entry 

physical exam to “assure freedom from venereal disease, ecto-parasitic infestations, and 

gross physical deformity...”; quality and quantity of care was noted as being, “better than 

that available to most of the inmates when they were free (Part I, pg 13).” 

Several problems arose with the prison studies. First, initial studies indicated problems 

with specificity of syphilis serologic tests. Tests previously considered to have good 

performance characteristics in North America and Europe (e.g., Mazzini and Kahn tests) 

appeared to perform non-specifically as screening tests in the prisoners and other 

Guatemalan populations studied, in spite of what was believed to be the rarity of 

endemic, non-venereal treponematoses such as yaws or pinta in Guatemala. Resolving 

this issue required studies comparing a battery of serologic tests in several populations. 

Second, while it was ultimately determined that more newly developed serologic tests 

(i.e., VDRL slide test and Kolmer test) performed more accurately with far fewer false 
8

positive tests. Attempts to collect sequential serum samples revealed that most inmates 

were unwilling to submit to frequent blood sampling. “Most of them believed that they 

were being weakened by weekly or biweekly withdrawals of 10cc of blood,” and this fear 

“could not be countered by promises of or actual administration of penicillin for syphilis 

and iron tablets to replace blood (Part I, pg 16).” 

Finally, while a primary stated rationale for conducting studies in Guatemala was the 

legal environment allowing prisoners to have sexual contact with CSWs, initial studies 

indicated that sexual transmission of syphilis was relatively inefficient. For the studies of 

sexual transmission, two CSWs were inoculated by intra-cervical injection of infected 

rabbit tissue. Both developed serologic evidence of infection without visible lesions and 

subsequently became seronegative “after specific therapy” of unstated type. A total of 

12 male “volunteers” from the penitentiary had a single sexual exposure to one of these 

women. Despite the absence of condoms or chemoprophylaxis, none developed clinical 

infection, and based on incomplete serologic follow-up (due to reluctance to undergo 

repeated bleedings), it was estimated that at most, one or two (8-16%) were 

asymptomatically infected. There is no description of specific knowledge of 

experimental details (e.g., risk of infection), nor consent by the subjects. 

The issues noted above led the investigators to consider several changes: a change in 

design from studies of sexual transmission to human inoculation studies and a change in 

population from prisoners to a primary focus on patients in the National Mental Health 

Hospital. This facility was the only one of its kind in Guatemala, was estimated to serve 

patients derived from a population base of 3.5 million people, and had a daily census of 

800–1,000 men and women. The asylum was described as “desperately and 

pathetically poor, both financially and in terms of personnel and medical attention,” 

although it was noted that “the standards of housing and feeding and medical care of the 

inmates were, with but few exceptions, superior to that of normal members of the 

families from which they came.” Specifically, there were limited supplies of anticonvulsants (although many patients had epilepsy), antibiotics, refrigeration space, and 

tableware, and no funds to support cigarettes or recreational items such as a motion 

picture projector for the patients. It is noted that the director of the hospital, “was 

anxious to institute serologic screening of the inmates (Part 1, pg 17).” Also of note is 

that one of the authors (who appears to have worked in the hospital) suggested “that 
9

since we had available a certain and sure cure for syphilis, it should be possible to set 

up experiments with his patients which could give conclusive answers to a number of 

questions (Part 1, pg 21).” These included questions about the effectiveness of 

chemoprophylactic regimens, performance of serologic tests, and issues about 

reinfection following treatment. There is a lengthy description of the process involved in 

deciding to conduct the studies, the background of the investigators in performing 

human challenge studies, and the need to avoid widespread knowledge of their 

occurrence (Part I, pg 23): 

 “Responsible medical officials representing all groups concerned decided to 

undertake studies involving inoculation with syphilis at the insane asylum. 

Members representing the VDRL had previous experience in inoculation of 

volunteers both with gonorrhea and syphilis and the organizations concerned had 

been involved with inoculation studies with other types of diseases, such as 

malaria and infectious hepatitis, so that there was a large background of 

experience in the methods of working in human inoculation and with safeguards 

for the individuals concerned. But as a result of experience elsewhere, it was 

deemed advisable, from the point of view of public and personal relations, to 

work so that as few people as possible knew the experimental procedure. As will 

be appreciated, this necessitated certain compromises in experimental design 

and patient management which were believed necessary in the interests of the 

total experiment.” 

Although there seems to have been institutional support for the studies and even 

participation by institutional staff in some study elements such as subject tracking for 

follow-up, the question of subject consent is not addressed. It is noted, that although 

funds had originally been “allocated in the budget for payment of volunteers (Part I, pg 

25),” with the shift of primary focus to patients in the asylum rather than the prison, “it 

was decided to use these funds for the benefit of the institution rather than for the 

individual (Part I, pg 25).” Such institutional support included provision of items noted as 

lacking, such as anti-convulsant medications, a refrigerator, a motion picture projector, 

and tableware. Subjects were offered cigarettes as an incentive: a pack for involvement 

in an experiment or if blood or cerebrospinal fluid (CSF) was collected, or a single 

cigarette for a clinical observation. It is noted that “patients would often attempt to make 
10

numerous trips past the physician, for bloodletting, cisternal puncture or examination, 

just to augment their supply of tobacco (Part I, pg 33).” 

Studies of syphilis. 

A compilation of subjects involved in studies of syphilis, gonorrhea, and chancroid is 

outlined in Table 1. 

According to the “Syphilis Summary Report”, following the initial pilot studies of sexual 

transmission of syphilis from experimentally infected female CSWs to male prisoners 

through sexual activity, which resulted in limited transmission, a series of 17 additional 

experiments involving human inoculation with syphilis were carried out from May 13, 

1947, until July 4, 1948. It was recognized quickly that exposure of subjects to infectious 

material through intact mucous membranes (cotton pledgets soaked in known quantities 

of viable T. pallidum placed under the foreskin of the penis) was also relatively inefficient 

and infection could be more reliably transmitted by intracutaneous injection or exposure 

of skin surfaces abraded with a fine needle (into the foreskin of the uncircumcised penis 

or the skin of the arm), analogous to techniques used for smallpox vaccination. These 

approaches were used in most experiments, although a few assessed transmission of 

infection by intravenous inoculation, oral ingestion, or inoculation of the CSF by cisternal 

puncture. 

The primary focus of most of the experiments was to assess various chemoprophylactic 

regimens or to assess the ability to re-infect subjects with recently treated syphilis or 

untreated latent syphilis. Subjects in these experiments largely came from the mental 

hospital, with subject selection based on baseline serologic findings and history of 

syphilis, perceived cooperativity, and the likelihood that the subject would not be 

released prior to post-inoculation observations. It appears that attempts were made to 

exclude subjects with known homosexual behavior due to concerns about potential 

sexual contact inside the hospital. 

Particular attention was given to identity of patients during follow-up because “some 

inmates did not know their names and were designated as, for example, ‘The Mute of St. 

Marcos’. Others used several names interchangeably, and some would be known by 
11

one name to one nurse and by another designation to a second nurse (Part I, pg 32).” A 

minority of subjects came from the prison. Overall, as enumerated in the “Syphilis 

Summary Report”, these 17 experiments included exposures (summed across 

experiments without unduplication of individual subjects) of 712 subjects, 682 (96%) of 

whom were exposed to infectious materials. The “Syphilis Summary Report” indicates 

that 404 (59%) of the 682 were infected, although the “Individual patient response in 

each experiment” table indicates that the number infected was as high as 423 (62%). 

As noted, one experiment assessed response to central nervous system inoculation in 

seven subjects via intracisternal puncture. The subjects were described as, 

“deteriorated and debilitated epileptics,” apparently studied in this way in part because “it 

was hoped that by shock of inoculation it might be possible to influence favorably their 

epilepsy.” It was also noted that “this experiment was undertaken at the expressed 

desire of the clinical director [of the asylum] in hopes that he might be able to do 

something for these women who had been completely resistant to all types of 

anticonvulsant therapy (Part III, pg 23).” All developed stiff neck, headache, and fever 

within several days, presumed to be due to bacterial meningitis and all of which 

responded to sulphonamides. Subsequently, the subjects developed what was thought 

to be acute syphilitic meningitis, with headache, neck stiffness, and, in one case, 

transient paralysis of the lower extremities. It is noted that “following therapy all patients 

revealed complete reversal of signs and symptoms (Part VI, pg 14).” 

Studies of gonorrhea 

For gonorrhea, initial experiments focused on sexual exposure from experimentally 

infected female CSWs to male soldiers. Although “it proved extremely difficult to obtain 

prostitutes willing to serve under experimental conditions (Experimental Studies in 

Gonorrhea, pg.3),” 12 women were recruited and inoculated with gonorrhea 5–14 days 

prior to the studies. While “none of the females thus infected showed evidence of acute 

infection such as a rich outpouring of thick yellow pus from the cervix or by signs of 

pelvic inflammatory disease..., all of them showed evidence of infection by cervical 

discharge (Experimental Studies in Gonorrhea, pg 3)” and all were culture-positive. 

However, as with experiments with syphilis, sexual exposure resulted in a low efficiency 
12

of transmission (only 5 infections in 138 exposures by 93 men). The duration of sexual 

contact was timed (average 1–2 minutes), but not directly observed by study personnel. 

These studies were followed by more extensive studies of direct inoculation, performed 

either as “superficial inoculation” (of the urethral meatus) or “deep inoculation” (in which 

the thin end of a toothpick wrapped in cotton was inserted 1⁄2 inch into the urethra)—

noted to be more painful. (The latter technique was based on observations of soldiers 

who, to secure hospitalization for treatment and avoid duty assignments, inoculated 

themselves with gonorrhea-infected pus, obtained from an infected man and inserted 

into the urethra with a matchstick.) Both techniques resulted in more efficient 

transmission and were the basis for a series of studies assessing the effectiveness of 

various chemoprophylactic regimens. The studies were primarily conducted among 

soldiers, and over the course of 41 experiments performed in soldiers between March 

1947 and July 1948, review of experimental tables indicates that 663 subjects were 

included, 214 (33%) of whom were judged to be infected. 

Study records (experimental logs) also mention gonorrhea inoculation experiments in 

four mental hospital subjects. One man, inoculated in the penis, developed a urethral 

discharge, and two men were inoculated in both penis and rectum, one of whom had a 

microscopic smear positive for gonorrhea with no information for the other. The fourth 

subject was a female described as having an unspecified “pre-terminal” illness, who was 

inoculated in the urethra, rectum, and the conjunctiva of both eyes and who developed 

bloody discharge from the urethra and bilateral conjunctivitis; she was also inoculated 

with syphilis at the same time. 

Thus, in total, 772 subjects were exposed in the gonorrhea studies, 234 (30%) of whom 

were judged to be infected. Study records for gonorrhea studies identify subjects only 

by name, gender, and study number as for the syphilis studies; no other identifying 

information is available in the archives. Likewise, there was no documentation of any 

informed consent or incentives for study enrollment, or any documentation that subjects 

understood that they were participating in research. 
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Studies of chancroid 

For chancroid, a single experiment described in the “Chancroidal Prophyaxis” summary 

report included 131 subjects (presumably from the military since they are described as a 

“company of 131 men”), each inoculated with H. ducreyi in three sites on the arms: one 

site treated with the standard U.S. Army Pro-kit, one with Orvus, and one site serving as 

an untreated control. All appear to have been infected. In addition, experimental logs 

indicate that 11 subjects from the mental hospital were inoculated in single-person 

experiments. Thus, in total, 142 subjects were exposed in the chancroid studies, 138 

(97%) of whom were judged to be infected. Again, the only identifying subject 

information is name in the study records, and there is no discussion of subject 

knowledge, consent, or incentives to participate. 

Review of Summary Reports and Experimental Logs: Subject Follow-up and 

Documentation of Treatment 

As noted above, Table 1 summarizes what is known about subject treatment from each 

set of studies. 

Studies of syphilis. 

According to the “Syphilis Summary Report”, in the syphilis studies, patient assessment 

included physical exams of the site of inoculation, other skin surfaces, and lymph nodes; 

darkfield microscopy of suspected lesions; a battery of serologic tests on blood samples; 

and CSF examination after cisternal puncture. Results of a positive darkfield 

examination or positive VDRL slide and Kolmer standard tests were considered more 

specific evidence of infection, while Mazzini and Kahn test results were considered too 

non-specific for diagnostic classification (III, pg 4). It does appear that quantitative Kahn 

titers were used in assessing course of infection among those diagnosed with syphilis by 

other criteria (IV, pg 5). Blood samples were collected at weekly intervals through 

December 1948, 6–19 months after performance of the experiments. There was also an 

attempt to collect blood samples at 6-month intervals or more frequently after December 

1948. Since there was a high mortality rate among asylum inmates, primarily as a result 
14

of tuberculosis, attempts were made to perform autopsies on all experimental subjects 

who died for special spirochetal and histologic studies. 

For treatment, three preparations of penicillin were used and administered by 

intramuscular injection: aqueous solution of sodium or potassium salt of penicillin G 

(concentration 25,000 units/cc); “POB,” a calcium penicillin in beeswax peanut oil 

mixture (concentration 300,000 units of PCN per cc), and Duracillin, consisting of the 

procaine salt of penicillin in a peanut oil base (concentration 300,000 units of penicillin 

per cc). Needles and syringes were sterilized between experiments by boiling, although 

the same needle was used for administering entire contents of one syringe without 

sterilization between individual patients (Part IV, pg 3). Allergic reactions were 

monitored closely and the Summary Report describes no cases of anaphylaxis, serum 

sickness, or cutaneous reactions. Likewise, the report noted “no sign of hepatitis or 

jaundice developing in any of the experimentally treated patients (Part IV, pg 3)” 

(although specific laboratory testing for viral hepatitis could not have been conducted in 

that era). It is noted that “one patient developed status epilepticus during the course of 

therapy with aqueous penicillin for primary syphilis on the 6th day, and despite efforts to 

control the condition, died.” There is no comment about the possible relationship of the 

death to penicillin therapy, although the report states that, “he was known to have had 

constant, severe attacks and had been a problem in management of epilepsy prior to the 

experimental work (Part IV, pg 3).” 

Based on extensive studies performed by VDRL scientists elsewhere, “adequate” 

treatment was considered to be ≥3.4 million units of penicillin administered over 7–8 

days, with aqueous preparations given every 2 hours (for 85 injections) and longeracting preparations (POB and Duracillin) given at 12- or 24-hour intervals (for 20 

injections). It is noted that “scrupulous care was taken to ensure...that each 

patient...received each injection for which he was scheduled (Part I, pg 39).” The timing 

of treatment was not clearly specified other than the comment that “we attempted to treat 

patients immediately upon the finding of the first evidence of secondary lesions so as to 

prevent possible person-to-person transmission within the institution (Part VI, pg 53).” 

Response to treatment was apparently determined by clearance of lesions and serologic 

responses over time, although criteria for treatment response are not precisely stated. 
15

Although the authors were expert syphilologists with vast clinical experience, their 

assessment of treatment adequacy was limited by the nature of the serologic tests used 

and the duration of clinical and serologic follow-up after treatment. Quantitative titers 

were available only with less specific tests (e.g., Kahn test), with VDRL results available 

only qualitatively as positive or negative. 

Part IV of the “Syphilis Summary Report” outlines a “Summary of Treatment Results”. It 

notes that of 248 subjects given “adequate” treatment, only one was considered to have 

failed treatment based on persistently high serologic titers and mucocutaneous relapse 

of lesions. Following a second course of penicillin, his titers fell six-fold (from 1:512 to 

1:8 Kahn units), and the subject remained asymptomatic over approximately 8 months of 

follow-up. Additional subjects were intentionally given lower doses of penicillin 

(expected to maintain therapeutic levels for only 12–24 hours) in order to observe clinical 

and serologic patterns of relapse, and 10 of 36 (28%) such subjects were considered to 

have failed treatment. 

The most complete compilation of treatment in the archives is the “Individual patient 

response in each experiment” table, which provides a listing of the clinical response and 

treatment history of subjects involved in each inoculation experiment. Review of 

experimental logs indicates that in total, the syphilis inoculation experiments included 

638 experimental subjects, 423 (66%) of whom were judged to have been infected. Of 

the 423, the table records adequate treatment for 369 (87%) subjects, “partial treatment” 

for 10 (3%) subjects, and for 44 (10%), no prescribed treatment. For 3 of the 44, it was 

noted that subjects left the asylum before they could be treated (n = 2) or that they died 

before treatment (n = 1). Some of these “experimental subjects” represent the same 

subjects included in multiple experiments after their initial infection was treated, which 

may explain the discrepancy in the numbers from Part IV, cited above. 

Overall, combining the results from the “Individual patient response...” document with 

those from the initial studies of sexual transmission with infected CSWs (i.e., 2 infected 

CSWs of uncertain treatment status and 12 uninfected prisoners) yields the following 

totals (again, not correcting for persons involved in multiple experiments): 726 

“experimental subjects”, 696 (96%) of whom were exposed to infectious materials. Of 
16

the 696, 427 (61%) were judged to be infected, and 369 (86%) were recorded as 

receiving adequate treatment with penicillin. 

Studies of gonorrhea 

Based on statements in the “Experimental Studies in Gonorrhea” summary report, all 

232 of the infected soldiers and CSWs appear to have been treated with “adequate” 

doses of penicillin (injection of 300,000 units), although there are no subject-specific 

records to document treatment. Of the 3 mental hospital patients with documented 

infection, 2 were treated with penicillin, while the third subject—the woman with the 

unspecified “pre-terminal illness” inoculated with both gonorrhea and syphilis in her 

urethra, rectum, and eyes—died 4 days later with no recorded treatment. 

Studies of chancroid 

Based on statements in the “Chancroidal Prophylaxis” summary report, all 131 military 

subjects developed lesions at the site of chancroid inoculation. Of the 131 subjects, 129 

(98%) were treated with sulfathiazole 1 gram PO four times a day for 5 days, with rapid 

lesion healing, although there are no subject-specific records to document treatment. 

Treatment of the other two was deferred to allow further observation, since they had 

experienced partial benefit from chemoprophylaxis, and is not documented as having 

been administered. Of the 11 subjects from the asylum, 7 developed typical lesions at 

the site of inoculation, 3 had no findings, and one had no follow-up. Treatment was not 

documented for any of the 11. 

Detailed Review of Subject-Specific Records for the Syphilis Inoculation Studies 

To enhance the archives review process, a detailed review of the short, subject-specific 

records of subjects involved in the syphilis inoculation studies was conducted by a 

record review team of medical epidemiologists, physicians, and analysts at the CDC in 

consultation with an internal Institutional Review Board chair. The purpose of the review 

was to provide greater detail about experimental exposures and treatment outcomes of 

individual patients, thus allowing an opportunity to supplement findings from the “Syphilis 

Summary Report” and experimental logs. Given the many unethical aspects of the 
17

design and conduct of the study, there was explicitly no attempt to use the record review 

findings to assess the experimental hypotheses of the study investigators, nor to create 

generalizable scientific information. 

The dates of documented, experimental activities ranged from 1947–1953. 

Experimental inoculations were conducted from 1947–1948 with follow-up clinical 

examinations, including blood tests and CSF analysis obtained through blood draws and 

cisternal punctures, continuing through 1953 for some subjects. Of the 17 experiments, 

protocols from experiment numbers 1–15 were available for review, listing 580 named 

persons who had been subjects in any of the experiments, 532 (92%) of whom had 

subject-specific records that could be reviewed. Experiment numbers 16 and 17 

included 74 and 48 unnamed subjects, respectively, potentially up to 122 different 

subjects, and because no records could be reviewed for these subjects, it cannot be 

determined whether they participated in prior experiments or whether they represent 

specific subjects in addition to the 580. Overall, of the 532 subjects in experiment 

numbers 1–15 with reviewable records, 416 (78%) were from the mental hospital, 

including 242 males and 174 females, while 116 (22%) were from the prison, 113 men 

and 3 women (noted to be “staff”). Apart from name, institution, and gender, other 

identifying information was available only in a limited number of subjects: age for 113 

(21%), city or state of residence for 63 (12%), and names of family members for 43 

(8%). For the 113 subjects with recorded ages, they ranged from 15–58 years, with 6 

subjects under 18 years of age. Though most of the subjects with stated residence were 

from Guatemalan states, other named countries of residence included Mexico, El 

Salvador, Nicaragua, and Honduras, though citizenship status was not recorded. 

Over the course of the 15 experiments, a total of 530 (99.6%) subjects received 

inoculations with experimental material; the other 2 subjects were followed with repeated 

serologic tests but had no documentation of inoculation. Of the 530 inoculated, 497 

(94%) subjects were inoculated with live T. pallidum (derived from either chancres from 

other infected humans or from ground testicles of infected rabbits), while 33 (6%) were 

inoculated with what was thought to be uninfected material (e.g., suspensions of bacteria 

that had been heat-killed, or ground testicles of uninfected rabbits). Live bacterial 

inoculations occurred among 414 (99.5%) of the subjects from the mental hospital and 

83 (72%) of the subjects from the prison. Overall, at least 184 subjects were involved in 
18

more than one experiment, ranging from two to five experiments. Over the 15 

experiments, a total of 771 inoculations with experimental material were administered. 

These 771 inoculations occurred most commonly by subcutaneous injection into the skin 

of the arms (438, 57%), with other methods including scarification or abrasion of the skin 

of the penis before applying cotton pledgets soaked in infectious material (205; 27%) or 

soaked cotton pledgets applied topically under the intact foreskin of the penis (63; 8%); 

subcutaneous injection into the coronal sulcus of the penis (38; 5%); intravenous 

inoculation into the antecubital fossa (13; 2%); oral ingestion (7; 0.9%); and central 

nervous system injection by cisternal puncture (7; 0.9%).

The records contained no documentation of informed consent for study enrollment, any 

indication that subjects understood they were participating in research, or enumeration 

of incentives received by specific subjects for participation. 

The subject record review revealed a variety of problems in assessing subjects after 

inoculation. There was variable documentation of serologic follow-up, because of either 

insufficient sample quantity, samples not being collected (due to patient refusal or 

unavailable staff), or patients having left the institution. Overall, 104 (21%) of 497 

subjects inoculated with infectious organisms were noted to have been “freed”, 

“transferred”, or otherwise discharged at some point following inoculation. In addition, 

dates of some serologic results were the dates of the report of the test result in some 

cases conducted at the VDRL in the United States, not the collection of the sample. 

There were also concerns that serologic results may have been recorded for the wrong 

patient, either due to mislabeling at the time of collection or errors in transcription of 

results. 

Table 2 summarizes findings from the record review about likely infection status postinoculation and subject treatment. Of the 497 individual subjects exposed to infection by 

inoculation, 433 (87%) were considered to have evidence of syphilis by a series of 

hierarchical laboratory criteria: 49 (10%) by identification of the organism using darkfield 

microscopy, 303 (61%) by post-inoculation seroconversion of the VDRL test, 62 (14%) 

by a positive VDRL test pre-inoculation, and 19 (4%) by post-inoculation seroconversion 

by the less-specific Kahn test. Of the remaining 64, 17 (27%) were considered to have 

“possible” syphilis based on physical examination findings in the absence of positive 
19

laboratory tests, while 47 (73%) had neither laboratory nor physical examination 

evidence of syphilis, but had variable periods of serologic follow-up, limiting the ability to 

completely rule out syphilis. 

Regarding subject treatment, since completion of all doses of penicillin injections was 

documented in only 85 subjects, treatment is noted as being “prescribed” if initiation of a 

specified course of therapy is documented in the records. Of the 497 subjects exposed 

to infection, what were considered to be adequate doses of penicillin (>3.4 mu) were 

prescribed to 332 (67%), with partial doses prescribed for 45 (9%), and no doses 

prescribed at all for 120 (24%). Of the 433 subjects with laboratory evidence of syphilis, 

adequate doses of penicillin were prescribed for 331 (76%), partial doses for 39 (9%), 

and no doses for 64 (15%). Of the 64 patients with possible syphilis or in whom syphilis 

could not be ruled out, 12 (3%) were prescribed adequate doses of penicillin, 7 (11%) 

partial doses, and 55 (85%) no doses. Of the 104 subjects who left the institution after 

inoculation with infectious material, 61 (59%) were prescribed adequate doses of 

penicillin, 2 (2%) partial doses, and 41 (39%) no doses. Of note, among the subjects not 

prescribed treatment was one of the 7 with CNS inoculation. 

There were no clear indications in the records about timing of initiating penicillin. Many 

subjects had progressed to and even resolved signs of primary or secondary syphilis 

before treatment was initiated. In several subjects, CSF abnormalities were noted, and 

in one, symptoms of neurosyphilis (loss of leg function following inoculation by cisternal 

puncture—a syndrome compatible with transverse myelitis) were documented after 

inoculation. Some subjects received penicillin for other reasons, including “political 

reasons”, “security reasons before departure”, “for reasons of fear of not having been 

completely treated”, or “because of pronounced homosexual tendencies”. 

While there is no evidence that medical or psychiatric complications during and following 

the experiments were routinely elicited or recorded, a number were documented in the 

records, although relationship to study procedures is unclear. Nonfatal complications 

included many Jarisch Herxheimer reactions, one allergic reaction attributed to rabbit 

tissue, one skin abscess, and five seizures. One subject required an arm amputation as 

a result of gangrene; this was described as following injection of the anti-seizure 

medication, pentothal, and it occurred in the same arm as an experimental inoculation 
20

two months earlier. In addition, one subject was noted to have findings consistent with 

neurosyphilis (i.e., tabes dorsalis, as evidenced by absent lower extremity reflexes and 

Argyll Robertson pupils) prior to inoculation. 

Patient death during the months of prospective observation was documented for 71 

subjects: 71 of 416 (17%) from the mental hospital, and none of the 116 from the prison. 

Records did not indicate likelihood of relationship of death to study procedures. 

However, subjects who were already suffering from other illnesses were not excluded 

from the study: at least one patient had a “pre-terminal” disease documented at the time 

of inoculation and died within days. One person with a seizure disorder died of status 

epilepticus on the last day of penicillin treatment, although, again, whether treatment 

precipitated the uncontrollable seizures is not clear. In many cases, “date of death” 

could be approximated only by the date at which it was recorded that the subject had 

recently died, an assessment that appears to have been recorded several months later 

in some cases. For most subjects, no cause of death was noted. Although an attempt 

was made to perform autopsies on patients who died, only 12 patients were noted to 

have had an autopsy. Results of autopsies that did occur were not routinely 

documented in the subject records, and the only findings described were tuberculosis in 

three subjects. In addition, clinical notes indicate that one subject died following thyroid 

surgery; one died of barbiturate (a treatment for epilepsy) intoxication; and two who died 

were noted to have had epilepsy. Temporally, the interval from the date of first 

experimental inoculation to the “date of death” for the 71 subjects who died was within 

90 days for 13 (18%), from 91–180 days later for 8 (11%), from 181–365 days later for 9 

(13%), from 1–2 years later for 15 (21%), and >2 years later for 26 (37%). 

In summary, the greater detail provided by data from the “Review of subject-specific 

records for the syphilis inoculation studies” supplements information provided by the 

“Review of the summary reports and experimental logs”, especially regarding 

involvement of patients in multiple experiments, problems with patient follow-up after 

inoculation that hindered accurate assessment of how many exposed subjects were 

actually infected, and precise determination of adequacy of treatment. A direct 

comparison of results between the two sources of data has several limitations. These 

include the uncertainty regarding how determination of “infected subjects” was made by 

the USPHS investigators, as well as reasons for higher estimates of those with infection 
21

who received adequate treatment according to the USPHS investigators (369 of 427; 

86%) than could be confirmed by subject record review (332 of 497; 67%, of all exposed, 

and 331 of 433; 76%, of those with laboratory evidence of infection). Among the 

potential explanations for these differences, are possible missing documentation in the 

subject-specific records available for review of treatments actually administered, 

possible errors in tabulating outcomes by the USPHS investigators, or the possibility that 

the “Syphilis Summary Report” was not considered to be final and ready for public 

dissemination. In addition, there was indication in the subject record review that some 

subjects were excluded from analysis for unknown reasons. Regardless of the 

differences, by either estimate, while the majority of exposed and infected subjects 

appear to have eventually been prescribed what was considered to be adequate doses 

of penicillin, treatment was routinely delayed for several months after exposure and a 

substantial number of subjects were not treated. 

The Conclusion of the Study 

A series of letters in early-to-mid 1948 offers some insight as to the conclusion of the 

study. A letter from Dr. Cutler’s supervisor, Dr. R.C. Arnold, on April 19, 1948 raises 

questions about comfort of the VDRL with the use of the asylum patients as subjects: 

“I am a bit, in fact more than a bit, leary [sic] of the experiment with the insane 

people. They can not give consent, do not know what is going on, and if some 

goody organization got wind of the work, they would raise a lot of smoke. I think 

the soldiers would be the best or the prisoners for they can give consent... In the 

report, I see no reason to say where the work was done and the type of 

volunteer.” 

Two months later (June 21, 1948), a letter from Dr. J.F. Mahoney notes that, “we are 

making the necessary arrangements for financing the terminal phases of the Guatemala 

study,” and that, “it will be recalled that two local physicians were to be maintained on 

duty for the purpose of continuing the observation of certain of the patient groups...with 

Doctors Salvado and Funes ...to be considered for these appointments,” with 

arrangement of this phase of work to “be carried out directly with the Pan-American 
22

Sanitary Bureau.” A subsequent letter from Dr. Cutler to Dr. Mahoney (August 26, 1948) 

notes that Dr. Cutler and several others “discussed thoroughly the matter of the 

continuation of our experimental studies” and lists the need to support “Juan M. Funes, 

MD, physician in charge of carrying on the present research program” and “Julio 

Salvado, MD, physician at Insane Asylum”. 

As per the understanding at the inception of the study, laboratory equipment was to be 

turned over to the Sanidad Publica of Guatemala for use in training in collaboration with 

PASB, and Guatemalan physicians and scientists whose names are mentioned in this 

regard, in correspondence from Drs. Cutler and Mahoney over the summer of 1948, 

include a Dr. Bianchi, the Minister of Health and Public Welfare, who is noted as having 

signed an agreement for the Government of Guatemala with Dr. Cumming of PASB; Dr. 

Abel Paredes Luna, who was to be trained at the VDRL in serology and the clinical 

aspects of venereal diseases; Rolando Funes, who was to serve as interim director of 

the serology lab in Guatemala; Dr. Galich, Director of the Sanidad Publica of Guatemala; 

and Dr. Carlos Tejeda, chief of the Medical Service of Military Hospital and involved in 

arranging training of American physicians in tropical medicine. 

There was also strong interest in providing capacity-building efforts for serologic testing 

and venereal disease control more broadly in Central America. A letter (July 26, 1948) 

on which Dr. Cutler was copied from the Assistant Director of PASB, John Murdock, to 

the Chief of the Caribbean Sector of PASB, Dr. William McAnally, notes that a Dr. Mario 

Mollari of Georgetown University would be visiting El Salvador, Honduras, Nicaragua, 

Costa Rica, and Panama to promote training of lab technicians and standardization of 

laboratory practices. 

Although syphilis serologic results and follow-up clinical observations were recorded on 

some subjects until 1953, there is no record of what activities occurred after patient 

follow-up was taken over by PASB and the two local physicians, nor whether further 

human inoculation studies were performed in Guatemala or other Central American 

countries. The only studies known to have been published from the Guatemalan work 

addressed comparisons of serologic tests. There is no evidence, either in the Cutler 

archives or by PubMed literature review, that the results of the STD inoculation 

experiments were ever published in the scientific literature or in any other forum. 
23

As of this writing, of the individuals cited in the archives, Drs. Cutler, Levitan, Arnold, 

Mahoney, and Parran are known to be deceased. The status of the Guatemalan 

physicians—Drs. Funes, Bianchi, Gallich, Tejeda, and Salvado—is unknown. 
24

 Table 1: Overview of the USPHS STD Inoculation Study, 1946–1948, Based on 

Review of Summary Reports and Experimental Logs in the Archived Papers of 

John Cutler, MD 

Study characteristic Syphilis Gonorrhea Chancroid 

 

Source of subjects Commercial 

sex workers, 

mental 

hospital 

patients, 

prisoners 

Commercial sex 

workers, 

prisoners, 

soldiers, mental 

hospital 

patients 

Soldiers 

(presumed), 

mental hospital 

patients 

Type of exposure* 

--sexual contact with 

commercial sex workers** 

12 93 0 

--cutaneous or mucous 

membrane inoculation** 

656 679 142 

--intravenous inoculation 13 0 0 

--intra-CSF inoculation (via 

cisternal puncture) 

7 0 0 

--oral ingestion 6 0 0 

 

Total number of subjects 

exposed** 

696 772 142 

Number of subjects judged to 

be infected** 

427 (61%) 234 (30%) 138 (97%) 

Type of treatment considered 

to be adequate 

Penicillin 

(≥3.4 million 

units) 

Penicillin 

300,000 units 

Sulfathiazole (1 

g PO qid X 5 

days) 

Number (%) of subjects with 

indication of adequate 

treatment** 

369 (86%) 233 (99.5%) 129 (93%) 

*Numbers include exposure to both infected and uninfected experimental materials (e.g., 

heat-killed bacteria, uninfected rabbit tissue) 

**Numbers are totals summed from numbers of subjects in specific experiments. 

Their total is greater than the number of individual subjects overall since some subjects 

were included in multiple experiments. 
25

Table 2: Infection Outcomes and Treatment of Experimental Subjects Involved in 

USPHS Syphilis Inoculation Studies, 1946–1948, Based on Review of Subjectspecific Records from Archived Papers of John Cutler, MD 

Outcomes of patients exposed 

to infectious Treponema 

pallidum 

Total 

no. 

(%) 

Treatment prescribed1

 No. (%) ≥3. 4 

million units 

penicillin 

(PCN) G 

No. (%) 

≤3.4 million 

units PCN 

G 

No. (%) no 

PCN G 

TOTAL 497 332 (66.8%) 45 (9.1%) 120 (24.1%) 

 

Hierachical laboratory evidence of 

syphilis 

433 331 (76.3%) 39 (9.0%) 64 (14.7%) 

--Positive darkfield microscopy 49 46 (93.9%) 1 (2.0%) 2 (4.1%) 

--Seroconversion by VDRL test 303 247 (81.5%) 15 (5.0%) 41 (13.5%) 

--VDRL-positive pre-inoculation 62 31 (50.0%) 21 (33.9%) 10 (16.1%) 

--Serologic evidence by Kahn 

test)2

 

19 6 (31.6%) 2 (10.5%) 11 (57.9%) 

 

No laboratory evidence of syphilis 64 2 (3.1%) 7 (10.9%) 55 (85.0%) 

---Possible syphilis by physical 

examination3 

17 2 (11.8%) 1 (5.9%) 14 (82.4%) 

---Others (exposed, but no 

laboratory or physical examination 

evidence) 

47 0 (0%) 6 (12.8%) 41 (87.2%) 

 --<3 m serologic follow-up 12 0 (0%) 4 (33.3%) 8 (66.7%) 

 --3–6 m serologic follow-up 6 0 (0%) 1 (16.7%) 5 (83.3%) 

 -->6 m serologic follow-up 29 0 (0%) 1 (3.4%) 28 (96.6%) 

1

Based on documentation of initiation of a prescribed course of multiple injections 

of penicillin therapy. In most cases, there was no documentation in the records that 

therapy was completed. 

2 A ≥4-fold rise Kahn titer at any point 3 weeks or more after exposure to 

infection. 

3 Physical findings included ulcer, papule, nodule, or other cutaneous abnormality 

at the site of inoculation; lymphadenopathy; maculopapular rash; or new focal neurologic 

deficit 
26

Acknowledgements 

We gratefully acknowledge assistance in preparation of this report from the following: 

Donald Burke, MD, Dean of the Graduate School of Public Health, University of 

Pittsburgh, for permission to review the Cutler papers; Marianne Kasica, at the 

University of Pittsburgh Archives, for assistance in accessing and reviewing archival 

papers; and Professor Susan Reverby, PhD, Wellesley College, for permission to review 

her unpublished manuscript.