Clinical trial NCT04285684
Conditions: Ketamine Lactation
Keywords: ketamine lactation postpartum depression breastfeeding infant exposure
Sponsor: The Ketamine Research Foundation
Start date: 2019-12-20; Completion date: 2021-01-05
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Quantification of Ketamine in Breast Milk at 3 hour Intervals up to 30 hours-- obtained from lactating women who receive 2 different Intramuscular injections of ketamine on two separate days at least 5 days apart.

Detailed description:
Quantification of Ketamine in Breast Milk at 3 hour Intervals up to 30 hours-- obtained from lactating women who receive 2 different Intramuscular injections of ketamine on two separate days at least 5 days apart: 0.5mg/kg and 1.0mg kg.

Women are required to have been breast feeding for at least 3 months and be healthy and on no medications. Support is provided for the entire time at the site and for any at home pumping. During the period of ketamine's influence, subjects are reclining and with 2 Investigators. The initial subject's data will determine the length of time for pumping--most likely 12 hours as ketamine and the active principle metabolite have half-lives of less than 3 hours. Determination of concentration of ketamine in breast milk is being done at the UCSF Clinical lab with quantification of metabolites that are inactive as well. This research is of benefit by providing lactating women information on potential exposure of infants/children to ketamine. It will serve as a guide as KRF conducts research on postpartum depression and for women at large using ketamine for psychiatric indications.

Arms: arm 1: Lactating women--4 subjects, 2 dosage format: ketamine 0;5mg/kg and 1.0mg/kg IM at least 5 days apart.
Interventions: intervention 1: ketamine in lactation
Intervention descriptions: intervention 1: 2 dose IM by weight and assessing concentrations of ketamine in expressed milk at intervals

Protocol documents:
Prot_SAP_000.pdf: 
​Ketamine Lactation Protocol 
Date: December 19, 2019 
Title: ​The Pharmacokinetics of Ketamine in the 
Breast Milk of Lactating Women: Quantification of 
Ketamine and Metabolites
Sponsor: The Ketamine Research Foundation 
Clinical Coordinator: Phil Wolfson MD, 
Principle Investigators: Rob Cole MD, Melissa Whippo, 
LCSW 
ClinicalTrials.gov ID:  NCT04285684


Ketamine Lactation Protocol 
 
Sponsor: The Ketamine Research Foundation 
 
 
Clinical Coordinator: Phil Wolfson MD, 
Principle Investigators: Rob Cole MD, Melissa Whippo, 
LCSW 
 
Title: ​The Pharmacodynamics of Ketamine in the Breast Milk 
of Lactating Women: Quantification Over 3 Half-Life Intervals of 3 
Hours Each 
 
 
Protocol: PP1 
 
 
Purpose​: There is no available data on presence and concentration of ketamine in 
breastmilk. There are statements in the literature made as to the safety of the use of 
ketamine in lactating women​,​ though these are unsupported​.​ This information is pertinent 
for the treatment of women who are lactating who may have depression, PTSD, 
postpartum depression, and other emotional difficulties and would benefit from ketamine 
treatment. The objective of this study is tto…. o measure the presence and concentration 
of ketamine in breastmilk 
 
Background 
 
Ketamine was developed as an anesthetic agent, by Parke Davis, in the search for 
analogs resulting from recognition of the anesthetic properties of phencyclidine, the first drug 
developed in the arylcyclohexylamine structure during the late 1950s​,​ 1960s​.​ This drug was 
marketed as Sernyl and in addition to anesthesia​,​ was also noted to cause significant increase 
in blood pressure and often prolonged postsurgical emergence delirium, even to the point of 
unmanageable​,​ and at times​,​ violent​,​ ‘manic behavior’​.​ Ketamine was developed clinically in 
the mid 1960s and was a successful anesthetic agent with fewer adverse effects than the 
parent compound. It was dubbed a ‘dissociative anesthetic’ by the wife of Edward Domino, the 
primary research clinician, as a solution to the descriptive puzzle offered by the drugs novel 
effects. Ketalar, ketamine’s brand name, was approved by the FDA in 1970 for use in children, 
adults, the elderly and animals as an anesthetic agent. During the Vietnam War, ketamine 
became widely used as a field anesthetic administered to wounded soldiers because of its fast 
onset and quick recovery period and its property of maintaining or elevating blood pressure in 
trauma situations. 


Ketamine’s potential to treat different psychological or psychiatric problems 
commenced in 1974 in Argentina as an adjunct for antidepressant psychotherapy (Fontana 
1974)​.​ In Mexico​,​ the psychiatrist Salvador Roquet introduced ketamine to patients in group 
settings as a component of his approach to psychedelic psychotherapy (Kolp et al.​,​ 2007)​.​ And 
then he brought ketamine to the attention of investigators at the Maryland Psychiatric 
Research Center, Stan Grof and Bill Richards among them. Ketamine’s versatility extends to 
analgesia and, for example, was used to treat patients who were at the scene of the 2005 
London underground bombings​.​ Following this awful act of terrorism, paramedics in the UK 
were authorized to possess and administer ketamine for pain relief. 
Ketamine is currently listed as one of the two injectable medicines under general 
anesthetics in the WHO Model List of Essential Medicines. The Model List designates 
medications determined “satisfy the health care needs of the majority of the population; they 
should therefore be available at all times in adequate amounts and in the appropriate dosage 
forms, and at a price that individuals and the community can afford” (WHO Technical Report 
Series 2000). 
 
Pharmacology 
Ketamine is available in two enantiomers: the S (+) and the R (−) configurations​. 
Most pharmacological preparations include an equimolar racemic mixture of the two 
enantiomers. 
Although racemic ketamine has the broadest worldwide use, S(+)-ketamine is available 
in some European countries like Denmark, Finland, Germany and the Netherlands and will 
come to market as a patented nasal preparation for psychiatric use in latte 2018. 
Ketamine’s putative action is as an N-methyl-D-aspartic acid (NMDA) glutamate 
receptor antagonist​.​ Multiple routes of administration are utilized by practitioners treating 
depression and other psychiatric conditions, each with its own unique pharmacokinetics, have 
been investigated in the treatment of depression, including intravenous, intramuscular, 
intranasal, sublingual, anal, and oral delivery. Ketamine’s antidepressant activity is believed to 
stem from its antagonism of NMDA receptors, which are widely expressed in the brain. When 
NMDA receptors on gamma-aminobutyric acid (GABA)-ergic neurons are antagonized, 
downstream glutamatergic neurons are disinhibited. This increased glutamatergic activity 
impacts neural signaling, synaptic plasticity, and connectivity.  It is posited based on animal 
models that ketamine-induced synaptic potentiation and proliferation may play a key role in 
eliciting antidepressant effects​.​ Ketamine also impacts other neurotransmitter systems, 
affecting cholinergic, opioidergic, monoaminergic, and GABAergic function. 
The bioavailability of Intramuscular ketamine is similar (93 -95%) to IV ketamine 
(Clements et al​,​ 1982)​.​ Intranasal ketamine has been used in anesthesia and found to have a 
favorable pharmacokinetic and pharmacodynamic profile relative to oral and rectal 
administration (Costantino et al​,​ 2007)​.​ In a blinded, randomized, controlled trial of 20 MDD 
patients​,​ 5​0​ mg of intranasal ketamine was found to elicit only mild side effects and produced 
significant antidepressant activity within 24 hours of administration (Lapidus et al​,​ 2014). 
Estimates of intranasal absorption are variable ranging from 30-50%, with the lower figure 
seeming more the case in clinical practice. In several studies, Sublingual and Oral ketamine 
have a calculated bioavailability of about 30 % and 20 %, respectively (Lara et al, 2013; Paslakis 
et al, 2010). Again, in clinical practice, these percentages appear to be lower—20-30% for 
sublingual preparations and perhaps 10% for the oral administration. Of 27 patients with MDD 
given variable​,​ escalating doses of sublingual ketamine​,​ 20experienced antidepressant efficacy 
(Lara et al, 2013). A retrospective review of 20 hospice patients receiving a single 0.5mg/dose 
of ketamine, given orally for 22 found significant antidepressant efficacy (Iglewicz, 2015). 


Ketamine is water and lipid soluble​.​ It is absorbable by IV, intramuscular, intranasal, 
subcutaneous, epidural, oral, and rectal routes of administration. Differences in the effects of 
ketamine are entirely determined by the degree and rapidity of absorption. Ketamine’s 
relatively low binding capacity to plasma proteins leads to rapid brain uptake and distribution 
(Weber et al​.​ 2004)​.​ The differences in bioavailability are due to gastrointestinal absorption 
and first-pass metabolism​.​ Th​e α​ -elimination phase half-life is only 11 minutes, while ​the β​ - 
elimination phase is about 2​.​5 hours (Wieber et al.,1975). 
Ketamine undergoes extensive hepatic metabolism. It is N-demethylated by 
cytochrome P45​0​ enzymes in liver microsomes into NK and other metabolites (Hijazi and 
Boulieu 2002)​.​ The principal isoform responsible for demethylation is CYP3A4, with minor 
contributions by CYP2B6 and CYP2C9 (Hijazi and Boulieu 2002). NK plasma levels are about 
three times higher after oral administration than after IV administration​.​ The metabolites of 
nor-ketamine primarily undergo renal excretion; about 91 % of ketamine is excreted in the 
urine as metabolites, and 1–3 % is found in the feces (Chang and Glazko 1974)​.​ Parenteral 
ketamine (as hydrochloride) is rapidly distributed throughout the body into widely perfused 
tissues, including the brain. It is likely 
excreted into breast milk and does cross the placenta​.​ However​,​ it was posited to have 
no clinically relevant or adverse effects on neonates (Little et al., 1972). As this was early work 
and related to anesthesia, this remains an open issue for often repeated psychiatric use by 
pregnant or lactating mothers. 
Ketamine’s tolerability and safety have been demonstrated over almost 5 decades. It 
has been used as an anesthetic for adults and children since the 1960s and has been used in 
neuropsychiatric research for more than two decades. Anesthetic doses from 1 to 3 mg/kg are 
considered to be very safe (Wan et al​.​ 2015)​.​ Subanesthetic doses of ketamine (from 0.1 to 2 
mg/kg) have been associated with transient side effects including neurocognitive, sensory- 
motor, and hemodynamic changes​.​ A pooled data study from three different clinical trials of 
subanesthetic IV ketamine administration in MDD patients found that adverse effects 
common within the first four hours of administration included dizziness​,​ derealization​,​ and 
drowsiness. Whether these are truly to be considered ‘adverse’ or are part and parcel of 
ketamine’s actual effects that result in the antidepressant and/or therapeutic benefits is the 
subject of much debate. One third of all patients experienced transient hemodynamic 
changes, particularly elevated blood pressure. There have been no cases of persistent 
neuropsychiatric sequelae, medical effects, or increased substance abuse in clinical practice. 
Route of administration and dose provided will also affect tolerability. While there have been 
multiple reports of dissociative and psychotomimetic effects of ketamine with IV and IM 
preparations, a trial of sublingual ketamine in 27 MDD patients reported no such side effects 
(Lara et al.​,​ 2013)​.​ A trial of intranasal ketamine also found only small increases in dissociative 
symptoms (Lapidus et al., 2014)​. 
A cautionary here in that increasing dosages of ketamine through any route of 
administration will result in an increase in dissociative effects. 
Ketamine has been approved by regulatory bodies worldwide for use as an 
anesthetic and an analgesic in both human and veterinary medicine. Ketamine was classified 
in 1999 as a Schedule 3 substance. Off label use has been a constant in ketamine’s history. 
 
 
Summary of Research Design: ​This study will be conducted with 4 lactating women 
who agree to postpone breastfeeding and provide samples of their milk. Ketamine’s half-life 
is variously placed at 2 and a half to 3 hours. The most reliable data puts ketamine’s half-life 


at 2.1 hours and for the metabolite—norketamine at 1.2 hours—this from a ketamine study 
in children indicating the safety of this medicine (Herd et al 2002). Samples will be collected 
prior to injection for baseline measurement, and timed at 3, 6, and 9 hour 
intervals--choosing the maximum half-life  duration. Two dosages will be administered: 
0.5ml/kg and 1.0ml/kg. administered Intramuscularly (IM). Each administration will be 
separated by a minimum of 3 days and preferably one week. 
 
The study subjects participants to greater than minimal risk because the protocol design 
calls for administration of IM ketamine. While the safety of IM ketamine administration 
is well established over decades of use, participants will be provided with full 
information on risks. 
 
SEE PACKAGE INSERT FOR THIS MANUFACTURER—ATTACHED. 
 
The IM route confers rapid onset—2-5 minutes for effect and a reliable 
approximate 95% absorption of ketamine​.​ The dosage range for a 50 kg woman amounts 
to 25-50mg and for a 70kg woman 35mg-70mg​,​ both quantities well within commonly 
used therapeutic administration of IM ketamine for depression and other psychiatric 
diagnoses (Dore et al, 2019)​. 
 
While psychiatric use of ketamine may well exceed 1.​0​ mg/kg​,​ blood concentrations of 
ketamine for anesthetic use have tended to follow a linear pattern of concentration, enabling 
estimates of concentration in breast milk, should there be a decision to exceed 1.0mg /kg IM in 
clinical practice. 
 
Inclusion Criteria 
Obtained by Interview/Self-Report 
• Age 21-45 
•
•
Postpartum with established lactation for a minimum of 3 months. 
•
•
Ability to pump breast milk and to provide a reservoir for infant feeding prior 
to the study; or acceptance of bottle feeding by the infant. 
•
•
In good health—normal BP/P; afebrile-temp ascertained; review of systems 
by MD; absence of diagnosed illnesses. 
•
•
Not pregnant--Pregnancy tested for before each administration by urine assay. 
 
Exclusion Criteria: 
•
•
Hypertension with a BP greater than 145/90 
•
•
Subjects must be offAbsence of all psychiatric medications specifically; 
medications and supplements, or evaluated by the PI for non-interference 
•
•
No alcohol or other substances such as marijuana for 72 hours or more. 
•
•
Weight <50kg or > 90kg​. 
•
•
Pregnancy 
 
Method of Subject Identification and Recruitment 
Two of the investigators have close connections to practicing OB/GYNs, one being one 
of these himself; and the other has a practice with postpartum women in part at a local 
university medical school. As only 4 subjects will take part, with the possibility of drop-out 


requiring further recruitment this ‘n’ is compatible with the outreach potential of the 
Investigators. Lactating patients and staff in both situations will be approached for an initial 
screening conversation. 
 
No advertising is involved. 
 
 
Procedures 
Initial screening for participation will be conducted by an investigator, via telephone. 
The IC and Intake form will be emailed/mailed  to a potential participant based on 
the suitability for admission to the study as per the screening determination.​ The intake 
form assesses current and previous illnesses, psychiatric conditions, medications, 
supplements and emergency contacts, etc. 
Review of the Intake form will occur prior to the formal Intake Interview to be 
performed at the site.  This review will again determine potential eligibility. 
The intake Interview at the site will take place with two investigators present 
and will take as long as necessary to review the protocol, the IC, the information on 
the actual Intake form, and to determine admission to the study.​ This will enable 
Investigators to screen potential subjects prior to enrollment—as is our general 
practice. The Informed Consent will be provided along with the Intake Form for 
review by the subjects prior to making a decision to proceed with the study intake 
process.  Subjects will discuss, and make a decision to sign, or not, the 
 Informed Consent. 
HIPAA confidentiality will be maintained throughout. Subjects will be given a numerical 
designation for all materials, other than the written forms discussed herein. All written and 
confidential materials will be stored in a locked file on premises available only to the 
Investigators. 
 
Preliminary lab tests, BP and PR and an initial pregnancy test will be performed​.  
 BP and PR will be performed at 1 hour post-administration to assess peak impact on 
cardiovascular status. 
 
This study will assess if the rapid elimination of ketamine facilitates a short and 
tolerable suspension of breastfeeding. If the study determines that significant amounts of 
ketamine remain in breast milk after 9 hours and 3 intervals, a decision will be made to add 
further intervals for assessment. The collection at 3 hour intervals will continue until 
ketamine levels are undetectable. 
 
No hazardous substances or procedures are involved 
 
 
Pumping of breast milk will be performed by the subjects, collected, and preserved as 
per the lab’s criteria. Every attempt will be made to collect milk in volume. The study will 
provide a pump for collection to each participant 


 
Subjects may stay at the clinic for the duration of the collection ​, or may be provided
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
with instructions and collection materials for at home pumping if the duration is prolonged
 
 
 
 
 
 
 
 
  
 
  
 
beyond 9 hours​.​ As much as possible, tThe samples will be collected by the next day. 
 
Subjects will refrain from eating and drinking 3-4 hours before receiving ketamine, 
this to prevent stomach contents that may contribute to nausea, and reduce any risk of 
aspiration. Subjects are permitted one cup of coffee if they are caffeine dependent​,​ or juice 
or water at 3-4 hours prior. Subjects will provide consent for fasting prior to its initiation 
verbally and later fully in person at the clinic. 
 
A urine pregnancy test will be conducted prior to each administration of ketamine. 
 
A first subject in the study will have milk collected at ​0,​ 3, 6, 9, 12 and 15 hours to 
determine if these intervals are sufficient to characterize a basic pharmacodynamic profile. 
If there is a negligible quantity in the samples as the time frame proceeds, the lab will not 
analyze subsequent samples. Once determined, the study will proceed with the remaining 3 
subjects at the intervals projected from the first subject 
 
Two dosages will be administered: 0.5ml/kg and 1.0ml/kg. Intramuscularly (IM)​. 
Each administration will be separated by a minimum of 3 days and preferably one week. 
Each session will follow the same process and procedure as described herein and ocur at 
the study site. 
 
 
 
 
PROCEDURE TIMING CHART 
HOUR
PROCEDURE 
-30 minutes
Arrives at Study Site 
Pregnancy Test 
Review of IC and Fasting with Consent 
 
-!5
BP, HR, Review of Systems 
 
0 Hour
Zero Time Pump 
 
15
IM 0.5mg/kg; or Second Session 1.0mg/kg 
 
15-60
Support for Subject who is reclining on sofa 
with eyeshades and ambient music 
 


1 hour
BP, HR 
 
1-3 hours
Support for subject and integration of 
experience 
 
3 hours
BP, HR, Second Pump 
 
3-6 hours
Subject relaxing at Study Site 
 
6 hours
Third Pump 
 
9 hours
Fourth Pump 
 
12 hours
Fifth Pump if necessary (as per procedure) 
 
Home
Milk has been quantified for volume at each 
pump and an aliquot labelled, saved and 
refrigerated. 
If subject has gone home earlier—at 6 hours 
or later, subject will be contacted to pump at 
the assigned intervals and an aliquot 
refrigerated for pickup and delivery to the 
clinical lab for analysis.
 
 
 
Safety​: Administration of ketamine will occur in office premises and with standard of 
care safety equipment available. This includes CPR trained personnel, ambu bag, defibrillator 
and a suction device. MDs will be present on site throughout and will administer the injections. 
 
Injections are provided with a 25 gauge, 1 inch needle using ketamine in a sterile 
100mg/ml concentration​.​ Total volume of ketamine fluid will be less than 1 cc. Occasionally, 
there may be a slight bleed from the injection site. There may be mild ache at the injection site 
for up to a few hours​.​ Injections are intra-muscular and into the deltoid or buttocks regions. 
 
Subjects will be provided in advance for preliminary screening with our standard 
intake form to assess current and previous illnesses, psychiatric conditions, and emergency 
contacts, etc. This will enable Investigators to screen potential subjects prior to 
enrollment—as is our general practice. The Informed Consent will be provided along with the 
Intake Form for review by the subjects prior to making a decision to proceed with the study 
intake process. 
At Intake, subjects will discuss, and make a decision to sign, or , the Informed 
Consent. 


HIPAA confidentiality will be maintained throughout. Subjects will be given a 
numerical designation for all materials, other than the written forms discussed herein. All 
written and confidential materials will be stored in a locked file on premises available only to 
the Investigators. 
No hazardous substances or procedures are involved 
 
Methods 
Quantitative analysis of ketamine will be performed by Alan Wu PhD​,​ Professor of 
Laboratory Medicine at UCSF School of Medicine and Kara Lynch at UCSF. 
 
1.
1)
Lab will prepare a standard for analysis of ketamine and its principle 
metabolite norketamine In breast milk. The half-life of ketamine is 2.1 hours​,​ and 
that of norketamine 1.2 hours (Herd et al 2007). The study will view the half-life as 
being a conservative 3 hours. 
Subjects will refrain from eating and drinking 3-4 hours before receiving ketamine, 
this to 
prevent stomach contents that may contribute to nausea, and reduce any risk of 
aspiration. Subjects are permitted one cup of coffee, juice or water at 3-4 hours prior if they 
are caffeine dependent. PROVIDED IN LAST VERSION 
1.
1)
A urine pregnancy test will be conducted prior to each administration of 
ketamine. 
2.
1)
 
3.
2)
A first subject in the study will have milk collected at ​0,​ 3, 6, 9, 12 and 15 hours to 
determine if these intervals are sufficient to characterize a basic pharmacodynamic 
profile. If there is a negligible quantity in the samples as the time frame proceeds, the 
lab will not analyze subsequent samples. Once determined, the study will proceed with 
the remaining 3 subjects at the intervals projected from the first subject​.​ The lab will 
process the samples from the first subject as rapidly as possible to enable continuation 
of the study. Breast milk will be collected until ketamine levels are undetectable. If 
significant amounts of ketamine are found in samples from the 3 subsequent subjects 
at the last interval determined by the profile of the first subject, additional time frames 
for collection will be added. If necessary, the process will be repeated to fully document 
pharmacokinetics. 
As real time testing of ketamine content in breastmilk is not possible, 
the first subject will be the exemplar for the timing of the resumption of 
breast feeding based on the data obtained, such as not detectable at 9 hours, 
hence breast feeding may resume​.​ For that first subject​,​ breast feeding may 
resume at 18 hours​,​ which corresponds to 9 half-lives for ketamine, 4 
half-lives being the accepted timing for the absence of a molecule. This will be 
confirmed by lab testing as quickly as possible for the first subject. 
 
1.
3)
Pumping of breast milk will be for a full expression so as not to influence 
concentrations in subsequent sampling intervals. The volume of breast milk will be 
quantified for each expression. 
 
1.
4)
Milk will be refrigerated in sterile containers and aliquots of one ounce will be
 
 
 
 
 
 
 
 
 
 
 
 
 
 
brought to the lab refrigerated as soon as possible. A second aliquot of each
 
 
 
 
 
 
 
 
 
 
 
 
 
 


expression will be frozen in the event of loss or spoilage of the first aliquots​, site to be
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
determined. 
 
1.
5)
Each aliquot will be labelled with coded subject designation, concentration of 
ketamine administered, date, and interval. The lab will be provided with the actual 
quantity of ketamine administered to each subject at the ​0.​5 and 1.0mg/kg levels and 
the weight of each patient in kgs. 
1)
 
1.
6)
The Lab will provide the data to KRF in formats suitable for journal publication. 
 
INTAKE FORM ATTACHED 
AS PREVIOULSY INDICATED THERE ARE NO QUESTIONNAIRES BEING 
ADMINISTERED— THIS WAS DELETED FROM THE PRIOR REVISION 
 
Inclusion Criteria 
•
Age 21-45 
Postpartum with established lactation for a minimum of 3 months. 
Ability to pump breast milk and to provide a reservoir for infant feeding prior to the 
study; or acceptance of bottle feeding by the infant. 
In good health—normal BP/P; afebrile-temp ascertained; review of systems by MD; 
absence of diagnosed illnesses. 
Not pregnant--Pregnancy tested for before each administration by urine assay. 
 
Exclusion Criteria: 
Hypertension with a BP greater than 145/90 
Absence of all psychiatric medications specifically; medications and supplements, or 
evaluated by the PI for non-interference 
No alcohol or other substances such as marijuana for 72 hours or more. 
Weight <50kg or > 90kg. 
Pregnancy 
 
 
 
Potential Adverse Effects 
•
•
Nausea and vomiting—a less than 5% incidence of intolerability to 
ketamine. 
 
 
•
•
Transient hypertension—BP will be monitored. In clinical practice​,​ and 
in this age group​,​ this has not occurred with any frequency. 
 
 
•
•
Ketamine is a dissociative anesthetic and subjects have a high likelihood of 
experiencing dissociative effects during the first two hours following ketamine’s 
administration. Generally, the major impact occurs in the first hour, with full 
recovery to baseline by 3 hours. The Investigators have conducted thousands of 
sessions in which dissociative effects are part of the ketamine assisted 


psychotherapy (KAP) approach, including at much higher doses than those being 
administered in this study​.​ Subjects may experience, an altered mental state in 
which there is an imaginative stream of associations, sensations and imagery. 
There can be anxiety accompanying a shift from ordinary reality. The 
Investigators have specialized in developing a transformative psychotherapy 
with utilization of this state and are fully equipped and experienced in dealing 
effectively with this state. Subjects will be prepared for the possibility of this 
•
experience. Administration will be conducted in the same 
comfortable setting in which KAP sessions are routinely provided. Investigators 
are continually present throughout the time frame of this experience, however 
long it may persist. Subjects will remain in the office until fully recovered and 
will have a ride home and will not drive themselves. 
 
 
•
•
Agitation—may occur transiently with dissociative effects. Subjects will remain 
in the clinical setting until ketamine’s influence has passed and they are safe to leave​. 
We have never had to treat agitation, as it passes, and reassurance and support have 
been sufficient to enable attainment of calmness. In the event of unusual agitation 
that is a risk to the patient, sublingual lorazepam can be administered​.​ With over 50​0 
patients and several thousand ketamine sessions, this has never occurred. 
 
 
•
•
Safety in operating machinery and driving—Subjects will have rides home when 
ready to leave. 
 
 
•
•
No long term negative effects involving administration of ketamine in these 
dosages and frequencies have been reported in vast numbers over many decades of 
use. 
A follow-up formal telephone session will occur at 4 weeks after the second 
administration. Questions will focus on any adverse effects on subjects or infants, 
difficulties in resuming breast feeding, psychological difficulties and insights not 
discussed in the prior 4 weeks of follow-up availability​.​ Throughout the study, subjects 
will be reachable by their cell phones for emergency and consultative contact with the 
Investigators--who will have developed an on-call schedule. 
 
Potential Benefits to Subjects 
Ketamine administered in this clinical environment may well contribute to a sense of 
well-being and an exploration of consciousness​.​ If emotional issues arise these will be fully 
processed. The Study Staff are skilled psychotherapists, versed in the practice of ketamine 
assisted psychotherapy. 
Subjects may well feel they are contributing to the benefit of women who have 
postpartum symptoms and disorders. 
 
Method of Subject Identification and Recruitment 
Two of the investigators have close connections to practicing OB/GYNs, one being 
one of these himself; and the other has a practice with postpartum women in part at a local 


university medical school. As only 4 subjects will take part, with the possibility of drop-out 
requiring further recruitment this ‘n’ is compatible with the outreach potential of the 
Investigators. 
No advertising is involved. 
 
Screening Script: ​The Ketamine Research Foundation is conducting a study of the 
presence and concentration of ketamine in breast milk following two administrations of 
ketamine by injection intramuscularly. This study is in preparation for use of ketamine as an 
assisted psychotherapy for women suffering with postpartum depression. If you agree to 
participate, ketamine will be 
administered to you on two separate occasions based on your body weight. You would spend at 
least 10 hours at our comfortable offices in San Anselmo under the supervision of MDs and 
psychotherapists. You would need to pump breast milk on at least 3- 4 occasions at 3 hour 
intervals. You will be asked to fast for 3-4 hours prior to administration of ketamine to reduce the 
possibility of nausea which may occur and does occur in a small percentage of patients who 
receive ketamine.​ ​ The effects of ketamine may would last for up to 2 hours, one hour of which 
can be expected to be a significant altered state and you would be lying down for the experience. 
Payment for participation includes cost of transportation and an initial stipend on acceptance 
into the study of $100, and on completion a second $100 stipend. Ketamine is known for its 
safety and positive effects on depression and other emotional difficulties. This is not about 
psychotherapy, but you will receive full attention for any emotional experiences you may 
encounter. You will be able to have a person of support present and your child as well. You will 
not be able to breast feed during the study session. To qualify, you need to be in good health, 
between the ages of 21 and 45, have been lactating for at least 3 months, not be on medication, 
and have normal blood pressure.  
To be interviewed for the study, please email to ​ke​tamine.research@gmail.com. 
Thanks for your consideration! 
Phil Wolfson MD—Director 
 
Informed Consent 
All study subjects will have full capacity to consent. The Informed Consent will be mailed 
to subjects for their review prior to enrollment. The IC will be presented to subjects by the staff​, 
reviewed for subjects understanding of the IC and what is involved in the study, for discussion 
and questions and clarification​.​ Subjects may elect to withdraw from the study prior to 
receiving the first and second injections—without consequence. The IC is attached. 
Study subjects will be fully aware that they will not breast feed infants for the period of 
the study so as not to expose infants to ketamine in breast milk. 
 
Costs to the Subject and Reimbursement for Participation 
Subjects will not bear any costs and will be reimbursed for travel expenses to the Study 
Site. Subjects will receive a stipend of $200 for participation--$10​0​ paid on enrollment and $100 
paid at conclusion of the second event. 
 
Data Analysis 
As data is accumulated by the laboratory​,​ it will be presented as both absolute 
quantities and graphed. Subject data will be correlated with concentration in breast milk 


according to age, body weight, dosage, volume of milk collected, length of breast feeding to 
the time of the study—months. 
 
Data Storage and Confidentiality 
Data will be inputted at the site into an Excel digital format with a matrix with subjects 
as specified above​.  ​No identifying data will be inputted and the study will be fully HIPPA 
compliant​.​ Subjects will be coded as follows: 1A​,​ 2B, 3C, 4D, and so on if more than 4 subjects 
are included in the Study. Access to this data will be restricted to Investigators and stored on a 
limited access backup disc. ADDED Written materials will be stored at the study site in a locked 
file cabinet, with access controlled by the Clinical Coordinator. 
 
Potential Treatment for a Research Related Injury 
Should a research related injury occur, subjects will have full support of the 
Investigators for treatment based in depth, frequency and duration on the nature of that 
injury.  Subjects have full access to the investigators by phone and email and will be 
contacted in follow-up directly at 4 weeks after the last ketamine session. 
The study will secure insurance specific to the possibilities arising to subjects as a result 
of their participation in the study--which will include medical coverage. 
The IC includes language pertinent to arbitration should that be necessary to determine 
the responsibility of the study for an injury should it occur and there be a dispute. 
 
 
 
References 
Carr DB, Goudas LC, Denman WT, Brookoff D, Staats PS, Brennen L, et al. Safety and 
efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic 
pain: a randomized​,​ double-blind​,​ placebo-controlled​,​ crossover study​.​ Pain​.​ 2004; 
108(1–2):17–27. 
 
Chang T, Glazko AJ (1974) Biotransformation and disposition of ketamine​.​ Int 
Anesthesiol Clin 12(2):157–178 
 
Clements J, Nimmo W, Grant I (1982) Bioavailability, pharmacokinetics, and analgesic 
activity of ketamine in humans. J Pharm Sci 71(5):539–542 
 
Costantino HR​,​ Illum L​,​ Brandt G​,​ Johnson PH, Quay SC (2007) Intranasal delivery: 
physicochemical 
and therapeutic aspects. Int J Pharm 337(1):1–24 
Dore J, Turnipseed B, Dwyer S, Turnipseed A, Andries J, Ascani G, Monnette C, 
Huidekoper A, Strauss N​,​ Wolfson P​.​ ​Ketamine Assisted Psychotherapy (KAP): Patient 
Demographics, Clinical​ ​Data and Outcomes in Three Large Practices Administering Ketamine 
with Psychotherapy. ​J Psychoactive Drugs​.​ 2019 Mar 27:1​-​10​.​ doi: 
10.1080/02791​0​72.2019.1587556​.​ [Epub ahead of print] 
PMID: 30917760 
. 
Fine PG. Low-dose ketamine in the management of opioid nonresponsive terminal 
cancer pain. J Pain Symptom Manage. 1999; 17(4):296–300​.​ [PubMed: 10203883] 


 
Fitzgibbon EJ, Hall P, Schroder C, Seely J, Viola R. Low dose ketamine as an analgesic 
adjuvant in difficult pain syndromes: a strategy for conversion from parenteral to oral 
ketamine. J Pain Symptom Manage. 2002; 23(2):165–70​.​ [PubMed: 11844639] 
Fontana A (1974) Terapia atidepresiva con ketamine. Acta Psiquiatr Psicol Am Lat 
20:32 ​Herd DW​,​ Anderson BJ​,​ Holford NH ​(2007) Modeling the norketamine metabolite in 
children 
and the implications for analgesia. ​Paediatr Anaesth. ​Sep;17(9):831-40. 
 
Hijazi Y​,​ Boulieu R (2002) Contribution of CYP3A4​,​ CYP2B6​,​ and CYP2C9 isoforms to 
N-demethylation of ketamine in human liver microsomes​.​ Drug Metab Dispos 
30(7):853–858 
 
Iglewicz A, et al. Ketamine for the Treatment of Depression in Patients Receiving 
Hospice Care: A Retrospective Chart Review of Thirty-One Cases​.​ Psychosomatics. 
2015; 56(4): 329–337 
 
Irwin SA, Iglewicz A. Oral ketamine for the rapid treatment of depression and anxiety in 
patients receiving hospice care. J Palliat Med​.​ 2010; 13(7):903–8​.​ [PubMed: 20636166] 
 
Irwin SA, Iglewicz A, Nelesen RA, Lo JY, Carr CH, Romero SD, et al. Daily oral ketamine 
for the treatment of depression and anxiety in patients receiving hospice care: a 28-day 
open-label proof of-concept trial​.​ J Palliat Med​.​ 2013; 16(8):958–65​.​ [PubMed: 23805864] 
 
Jansen, K. ​Ketamine: Dreams and Realities ​2004 MAPS 
 
Kannan TR, Saxena A, Bhatnagar S, Barry A. Oral ketamine as an adjuvant to oral 
morphine for neuropathic pain in cancer patients​.​ J Pain Symptom Manage​.​ 2002; 
23(1):60–5. [PubMed:11779670] 
 
Krystal JH. Ketamine and the potential role for rapid-acting antidepressant 
medications. Swiss Med Wkly​.​ 2007; 137(15–16):215–6​.​ [PubMed: 17525875] 
Lapidus KA, Levitch CF, Perez AM, Brallier JW, Parides MK, Soleimani L, Feder A, 
Iosifescu DV, Charney DS, Murrough JW (2014) A randomized controlled trial of intranasal 
ketamine in major depressive disorder​.​ Biol Psychiatry 76(12):970–976 
 
Lara DR, Bisol LW, Munari LR (2013) Antidepressant, mood stabilizing and procognitive 
effects of very low dose sublingual ketamine in refractory unipolar and bipolar depression. Int J 
Neuropsychopharmacol 16(9):2111–2117 
 


Little B, Chang T, Chucot L, Dill W, Enrile L, Glazko A, Jassani M, Kretchmer H, Sweet A 
(1972) Study of ketamine as an obstetric anesthetic agent​.​ Am J Obstet Gynecol 
113(2):247–260 
 
Lossignol DA, Obiols-Portis M​,​ Body JJ​.​ Successful use of ketamine for intractable 
cancer pain. Support Care Cancer​.​ 2005; 13(3):188–93. [PubMed: 15480820] 
 
Matthew S, Zarate C. Ketamine for Treatment Resistant Depression. 2016 Adis 
 
Paslakis G, Gilles M, Meyer-Lindenberg A, Deuschle M (2010) Oral administration of the 
NMDA receptor antagonist S-ketamine as add-on therapy of depression: a case series. 
Pharmacopsychiatry 43(1):33 
 
Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as adjuvant analgesic to 
opioids: a quantitative and qualitative systematic review​.​ Anesth Analg​.​ 2004; 99(2):482–95 
 
Wan L, Levitch C, Perez A, Brallier J, Iosifescu D, Chang L, Foulkes A, Mathew S,
 
 
 
 
 
 
  
 
 
  
 
 
 
 
Charney D, Murrough J (2015) Ketamine safety and tolerability in clinical trials for
 
 
  
 
 
 
 
 
 
 
 
 
treatment-resistant depression​.​ J Clin Psychiatry 76(3):247–252 
 
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concentrations after nasal and iv administration in anesthetized children. Paediatr Anaesth 
14(12):983–988 
 
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in man. Anaesthesist 24(6):260–263 Zarate CA, Singh JB, Carlson PJ, 
 
Wolfson P​,​ Hartelius​,​ G​,​ The Ketamine Papers MAPS 2016 
 
 
 
Appendix A 
1.Treatment Options 
 
 
•
2. Anesthesia 
 
•
3. Ketamine 
 
•
4. Breastfeeding Warnings 
Print Share 
 


Ketamine use 
while 
Breastfeeding 
 
Drugs containing Ketamine: Ketalar, LidoProfen, MKO Melt Dose 
Pack, MKO Troche 
 
Medically reviewed ​by Drugs.com. Last updated on Dec 12, 2018. 
 
 
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Ketamine Levels and Effects 
while Breastfeeding 
Summary of Use during Lactation 
 
Breastmilk levels of ketamine have not been measured after 
administration to humans. Minimal data indicated that ketamine use in nursing 
mothers may not affect the breastfed infant or lactation. Until more data are 
available, ketamine 
should only be used with careful monitoring during breastfeeding. 
Alternate agents are preferred. 
 
Drug Levels 
 
Maternal Levels. Relevant published information was not found as of the 
revision date. 
 
Infant Levels. Relevant published information was not found as of the 
revision date. 
 
Effects in Breastfed Infants 
 
Four mothers who received epidural analgesia with lidocaine and 
bupivacaine for cesarean section also received general anesthesia with ketamine 
and midazolam (dosages not specified). Their infants were either breastfed or 
received their mother's breastmilk by bottle. No adverse effects were reported in 
the infants.[1] 
 
Effects on Lactation and Breastmilk 
 
A pregnant woman sustained 28% body surface area burns near term. 
She underwent an emergency cesarean section on her due date under ketamine 
anesthesia. Although the infant required vigorous resuscitation, the infant began 


breastfeeding immediately. The infant had transient jaundice that resolved in a 
few days.[2] 
 
A study compared women undergoing cesarean section who received 
either placebo or S-ketamine (esketamine) 0.5 mg/kg intramuscularly, followed 
by a continuous infusion of 2 mcg/kg/minute for 12 hours. This low dose was 
used to enhance analgesia and reduce residual pain rather than to provide 
anesthesia. All women received intraspinal bupivacaine 8 to10 mg and sufentanil 
5 mcg for analgesia, as well as midazolam 0.02 mg/kg intravenously before the 
S-ketamine or placebo injection. Postoperatively, patients received 
patient-controlled intravenous morphine for 24 hours, followed by 
acetaminophen, oral ketorolac and a single dose of ondansetron 8 mg 
intravenously as needed. Of the 56 patients enrolled in the study (28 in each 
group), 13 in each group were contacted at 3 years postpartum. Patients who 
received placebo reported breastfeeding for an average of 10.5 months and 
those who received S-ketamine 
reported breastfeeding for an average of 8 months; however, the 
difference was not statistically significant.[3] 
 
A randomized, double-blind study compared the effects of intravenous 
propofol 
0.25 mg/kg, ketamine 0.25 mg/kg, ketamine 25 mg plus propofol 25 mg, 
and saline placebo for pain control in mothers post-cesarean section. A single 
dose was given immediately after clamping of the umbilical cord. The time to the 
first breastfeeding was 58 minutes in those who received placebo, 31.9 minutes 
with 
ketamine and 25.8 minutes with propofol plus ketamine. The 
time was significantly shorter than the other groups with the 
combination.[4] 
 
APPENDIX B—INTAKE FORM 
 
 
 
 
DATE: 
The Ketamine Research Foundation 
STUDY INTAKE FORM 
 
 


 
Confidential Client Information 
 
Welcome to our Study. 
Please fill out the following as completely as possible. 
This information is confidential. 
 
• 1.
Name:  
 
 
•
2. Address: 
Street/PO box 
 
 
• 3.
City:
State:
Zip/Postal Code:  
 
• 4.
Home Phone:
Cell Phone:
Work:  
 May I leave a message?  
 
Email:_ 
 
 
•
5.
SS#: 
 
 
• 6.
Age:
Birth date:
Gender:  
 Do you identify as 
transgender?  
 
 
•
7.
Education (grade/degree completed, any post secondary):  
 
 
•
8.
Current 
Occupation:  
 
 
•
9.
Person to alert in the event of a medical emergency:  
 
 
Address: _ 
 
 
Relationship to you:
Phone:  
 
 
•
10.
Family Doctor:
Phone:  
 
 


•
11.
Relationship status (circle one): Single  Married  Partnered 
Separated  Divorced  Widowed If not married, are you currently in a relationship? ​¨ ​Yes  ​¨ ​No
If yes, for how long? 
 
•
12.
Spouse’s/partner’s 
name:
Phone:  
 
 
•
13.
Children (gender, age):  
 
 
 
 
APPENDIX C 
FOLLOW-UP CALL AT 4 WEEKS 
Fundamentally, this is an open conversation with subjects to ascertain the 
aftermath effects of the two ketamine sessions. 
Questions  that are included will focus on: 
 ​Any adverse effects on subjects or infants​: Have you felt or noticed and problems 
with your physical state; or your emotional state since your ketamine sessions?  If so, do you 
attribute these to your ketamine experiences.  
Were there positive effects that you have noted? 
Have you noticed any changes in your infant since your ketamine experiences? Do 
you attribute these to ketamine? 
Difficulties in resuming breast feeding​: Did you have any difficulties with your infant 
as a result of the suspension of breast feeding?   How long did this last if there were 
problems?  Do you have a view of how long suspension of breast feeding is tolerable to you? 
To your infant? 
 
 
              Have you experienced any psychological difficulties or insights you have not 
discussed in the prior 4 weeks of follow-up?