proposal to place ketamine in an international schedule. comment from janssen

Janssen Research & Development, LLC Global Regulatory Affairs

1125 Trenton-Harbourton Road, P.O. Box 200 Titusville NJ 08560

February 26, 2015

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, Maryland MD 20852

RE: Docket FDA 2015 -N-0045, International Drug Scheduling: Convention on

Psychotropic Substances; World Health Organization Scheduling

Recommendations for Ketamine and CND Proposal to Place Ketamine in

Schedule I of the 1971 Psychotropic Convention

Dear Sir/ Madam:

The Janssen pharmaceutical companies of the Johnson & Johnson family of

companies welcome the opportunity to provide to the Food and Drug

Administration (FDA) our comments in response to the FDA Federal Register

Notice, 80 Fed. Reg. 4283 (January 27, 2015) in the above-captioned matter.

Executive Summary

Ketamine has important approved anesthetic uses in humans and animals in the

United States, and is already appropriately regulated under Schedule III of the

Controlled Substances Act (CSA) (21 CFR. 1308.13(c)(7)). Given the approved

medical uses of ketamine products in the United States, as well as its relative low

potential for abuse, classification is contrary to the CSA and Drug Enforcement

Administration regulations. Drug regulation and scheduling, whether pursuant to

United States law or international treaty, should maintain a proper balance

between regulating to prevent or deter abuse and maintaining availability of

substances for medical purposes. The United States placement of ketamine on

Schedule III provides a good example of that appropriate balance of ketamines

medical importance against its abuse potential and actual low levels of abuse.

Given the heterogeneous distribution of ketamine abuse and appropriate national

governmental approaches to ketamine regulation, regional or national level

regulation appears to be more appropriate to address this issue. Potential new

medical uses of ketamine and its isomer esketamine for treatment resistant

depression (TRD) should be considered in any scheduling decision. New

medications to treat TRD would address an important unmet medical need as

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Docket FDA 2015 -N-0045

February 26, 2015 2

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demonstrated by the FDA breakthrough therapy designation of esketamine in

TRD, and if approved, patients should not be subjected to additional barriers to

treatment. We respectfully request that the United States strongly oppose and vote

against any proposal or recommendation to classify ketamine under Schedule I of

the 1971 Convention.

I. Introduction

The FDA has requested comments on United Nations (UN) Economic and Social

Council published recommendations for action to be taken by the UN Commission

on Narcotic Drugs (CND) at the March 2015 meeting, including a request from the

Chinese Government that the CND vote to place ketamine in Schedule I of the

Convention on Psychotropic Substances of 1971 (1971 Convention). The Council

recommended that the CND should decide whether it wishes to place ketamine in

Schedule I of the 1971 Convention or, if not, what other action, if any, might be

required. The World Health Organizations (WHO) recommendation to the CND

was that ketamine should not be scheduled under international treaties. We

understand that pursuant to 21 U.S.C. 811(d)(2)(B), the Department of Health

and Human Services (HHS) is required to request public comments and provide a

recommendation that is binding on representatives of the United States in

discussions and negotiations at the CND meeting in Vienna, Austria in March

2015.

Ketamine is used as an anesthetic in human and veterinary medicine, and is

considered a core medicine (defined as a minimum medical need for a basic health

care system) by the WHO (WHO Model List Essential Medicines 2011).

Ketamine is one of the most commonly used anesthetic agents in developing

countries because it is inexpensive, readily available and easy to use, and is the

only available anesthetic in most rural areas of developing countries (Ketcham

1990). 1 Scheduling ketamine may leave entire countries with no alternative

anesthesia for essential surgery (WHO Expert Peer Review 2, 2014). 2 Ketamine

1 The ease of parenteral administration gives ketamine a major advantage when anesthetic gases are

impossible to use due to limited equipment and lack of appropriately trained specialists (WHO Expert Peer

Review 3, 2014). In countries with limited resources and infrastructure, ketamine is an ideal anesthetic

because it is inexpensive, has a wide margin of safety when compared with other anesthetic agents (WHO

2014), and does not suppress the cardiorespiratory system (WHO 2012). According to the WHO Critical

Review of Ketamine, general medical practices in Africa rely on ketamine for anesthesia (WHO 2012).

2 Parties to the Convention are obliged to prohibit any medical use of a Schedule I substance except by

"persons directly under control of the government, and even use for and by those persons is very restricted

(Art. 7). Restricting availability of ketamine under Schedule I could compromise health outcomes in

situations where ketamine would ordinarily be used. Providers in non-government institutions and

clinicians in remote areas, especially in resource poor settings, will be unable to use ketamine if it is placed

in Schedule I. Since many countries have no appropriate or affordable alternatives, scheduling ketamine

would force patients in those regions to forego lifesaving essential surgery (Ketcham 1990). In addition, as




February 26, 2015 3

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is also the primary anesthetic used in veterinary practice in the United States and

worldwide, and is used for the provision of analgesia in certain circumstances.

Limiting its availability would be a major loss to animal welfare, as well as have a

negative impact on the agricultural economy.3 Similarly, access for new medical

uses of ketamine and its enantiomer esketamine currently under investigation may

also be negatively impacted if the new uses are approved. Therefore, we strongly

request that HHS recommend that the United States oppose any action to schedule

ketamine as a Schedule I drug under the 1971 Convention. As described more

fully herein, we strongly support the WHOs recommendation that ketamine not

be scheduled under international treaties. In view of the well-accepted medical

uses for ketamine, placement in Schedule I, reserved for agents which have limited

medical uses, is not appropriate and would be disruptive and raise unnecessary

obstacles for human and veterinary medical practice.

II. Ketamine Scheduling and Approved Uses in the United States

United States regulations implementing the CSA provide for scheduling of

ketamine, its salts, isomers, and salts of isomers as a psychotropic at Schedule III

(21 CFR 1308.13). Drugs scheduled as Schedule III have the following

findings:

(A) The drug or other substance has a potential for abuse less than the drugs

or other substances in schedules I and II.

(B) The drug or other substance has a currently accepted medical use in

treatment in the United States.

(C) Abuse of the drug or other substance may lead to moderate or low

physical dependence or high psychological dependence.

In the United States, ketamine is indicated for human use as the sole anesthetic

agent for diagnostic and surgical procedures that do not require skeletal muscle

relaxation, for the induction of anesthesia prior to the administration of other

general anesthetic agents, and to supplement low-potency agents, such as nitrous

oxide (Ketamine HCl USPI JHP). Ketamine is also indicated for use in animals: in

cats, for restraint or as the sole anesthetic agent for diagnostic or minor, brief,

noted in the 2014 WHO Expert Report, scheduling will likely lead to the decrease in availability and

accessibility of ketamine to the same level of other controlled medications, which would result in a public

health crisis (WHO Expert Peer Review 2, 2014).

3 In the critical review report for the 35th Expert Committee on Drug Dependence (ECDD), several

Member States indicated that ketamine is indispensable for its indications in veterinary medicine (WHO

Expert Peer Review 2, 2014).




February 26, 2015 4

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surgical procedures that do not require skeletal muscle relaxation, and in

subhuman primates for restraint (Ketamine HCl USPI Mylan).

Given the approved medical uses of ketamine products in the United States, a

Schedule I designation is not authorized by the CSA (21 CFR 812(b)(1)):

Except where control is required by United States obligations under an international treaty, convention, or protocol, in effect on October

27, 1970, and except in the case of an immediate precursor, a drug or

other substance may not be placed in any schedule unless the

findings required for such schedule are made with respect to such

drug or other substance. The findings required for each of the

schedules are as follows:

(1) Schedule I.

(A) The drug or other substance has a high potential for abuse.

(B) The drug or other substance has no currently accepted

medical use in treatment in the United States.

(C) There is a lack of accepted safety for use of the drug or other

substance under medical supervision.

All drugs listed in Schedule I have no currently accepted medical use in treatment

in the United States and therefore may not be prescribed, administered, or

dispensed for medical use. In contrast, drugs listed in Schedules II through V all

have some accepted medical use and therefore may be prescribed, administered, or

dispensed for medical use.

Not dissimilar to the United States scheduling criteria, the WHO has developed

specific criteria to include a substance in a particular schedule. WHO has been

entrusted with the responsibility to make medical and scientific findings related to

a drugs abuse potential and its medical usefulness (UN Convention on

Psychotropic Substances 1971, Article 2(5)). For Schedule I under the 1971

Convention this applies to substances whose liability to abuse constitutes an

especially serious risk to public health and which have very limited, if any,

therapeutic usefulness (WHO Guidance on the WHO Review of Psychoactive

Substances for International Control, 2010). This is consistent with the 1971

Convention itself which prohibits all use except for scientific and very limited

medical purposes (UN Convention on Psychotropic Substances 1971, Article

7(a)).




February 26, 2015 5

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Accordingly, placement of ketamine under Schedule I would be inconsistent with

United States law, the 1971 Convention and the WHO scheduling criteria.

III. The CND Should Consider the United States Experience in Striking an Appropriate Balance of Regulation and Medical Availability

Drug regulation and scheduling, whether pursuant to United States law or

international treaty, should maintain a proper balance between regulating to

prevent or deter abuse and maintaining availability of substances for medical

purposes. The federal CSA recognizes that scheduled drugs have a useful and

legitimate medical purpose and are necessary to maintain the health and welfare of

the American people (21 CFR 801(I)). The preamble to the 1971 Convention

states that use of psychotropic substances for medical and scientific purposes is

indispensable, and availability should not be unduly restricted. As an indication

of the importance of ketamine for health and welfare globally, ketamine is on the

WHO Model List of Essential Medicines and the Essential Medicines for

Children.4

Given the existing medical and veterinary use of ketamine, its classification under

Schedule III in the United States provides the necessary balance between medical

use and its abuse potential and actual low levels of abuse. Importantly, ketamine

abuse has not shown a tendency to increase between 2006 and 2013 in the United

States (SAMHSA 2013).

If ketamine were to be controlled under Schedule I of the 1971 Convention, then

additional controls may be necessary to fulfill United States obligations. Such

additional controls would impact the appropriate access to ketamine for patients in

the United States, in the form of stricter prescribing and dispensing limits and

manufacturing quotas. This may have detrimental effects on health outcomes.

a. Ketamine Abuse Potential

Ketamine has pharmacologic properties consistent with a drug with

abuse potential. As an N-methyl-D-aspartate (NMDA) receptor

4 The WHO defines essential medicines as those that satisfy the priority health care needs of the population.

They are selected with due regard to disease prevalence, evidence on efficacy and safety, and comparative

cost-effectiveness, and are intended to be available within the context of functioning health systems at all

times in adequate amounts, in the appropriate dosage forms, with assured quality, and at a price the

individual and the community can afford (WHO Essential Medicines and Health Products). The WHO

Model List of Essential Medicines was first published in 1977 and included 208 individual medicines

which together could provide safe, effective treatment for the majority of communicable and non-

communicable diseases. The list is updated every two years. Since 2007, a separate list for children up to

12 years (WHO Model List of Essential Medicines) has been released. The 18th edition for adults and the

4th edition for children were released in April 2013. Ketamine is included in both lists as an injectable

anesthetic.




February 26, 2015 6

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antagonist, it has reinforcing properties in animals and humans,

although these are probably weaker compared to higher-affinity

NMDA antagonists. Importantly, ketamine is not an opioid and is not

associated with serious opioid-related adverse events (eg, hypotension

and respiratory depression). Ketamine has a combination of stimulant,

depressant, hallucinogenic, and analgesic properties (US Dept. Justice

2004; WHO Ketamine Review 2006).

The WHO ECDD expert report (WHO Expert Peer Review 1, 2014)

notes that, while there are multiple reports of physical problems caused

by prolonged use of ketamine (or use in high doses), such as urinary

tract and biliary tract problems, there is no firm evidence regarding

dependence in recreational users. Reported deaths in users of ketamine

in the United States and the United Kingdom were in most cases due to

acute multidrug intoxications (WHO Expert Peer Review 2, 2014).

Ketamine is produced commercially in a number of countries.

Ketamine synthesis is a complex and time-consuming process, making

clandestine production impractical (US Dept. Justice 2004; WHO

Expert Peer Review 1, 2014). Levels of use in the general population

are therefore low, with higher levels in groups that have access (eg,

medical and veterinarian professionals) (WHO Expert Peer Review 2,

2014).

b. Ketamine Abuse Data

The actual rates of ketamine abuse in the United States and worldwide

are low. Of the 64 countries who responded to the 2008 WHO

questionnaire for the preparation of the 35th WHO ECDD, 16 countries

reported on the use of ketamine in a harmful way, with reported

lifetime use of less than 2% (WHO Critical Review Ketamine 2012).

The 2013 National Survey on Drug Use and Health (NSDUH),

administered by the Office of Applied Studies of the Substance Abuse

and Mental Health Services Administration (SAMHSA), found that

nonmedical use of ketamine was low relative to other drugs of abuse.

Lifetime nonmedical use was reported by 0.9% to 1% of the

population, compared to the rates of 39% to 42% for marijuana, 13% to

15% for cocaine, and 5% to 6% for methamphetamine over the same

time period. There was no tendency for increased lifetime use in the

younger age groups between 2006 and 2013 (in persons 12 to 17 years

of age, the use remained unchanged, from 0.3% in 2006 to 0.2% in




February 26, 2015 7

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2013, and in persons 18 to 25 years of age, it steadily decreased from

2.8% in 2006 to 1.5% in 2013) (SAMHSA 2013).

The Drug Abuse Warning Network (DAWN 2011) survey reported that

ketamine accounted for a very minor proportion of drug-related

emergency department visits. Such visits for ketamine in 2009-2011

were consistently at the levels below 0.01% of the total emergency

department visits associated with illicit drug use (WHO Critical Review

Ketamine 2012).

Abuse of ketamine appears to be heterogeneously distributed, with

higher levels reported in specific regions/countries (WHO Critical

Review Ketamine 2006). Thus, regional or national level regulation

appears to be more appropriate to address this issue, as evidenced in the

governments comments solicited by the WHO in 2014 (UN Economic

and Social Council 2014). In fact, local measures are taken to curb its

misuse. In 2009, a total of 55 governments reported that ketamine had

been placed on the list of substances controlled under national

legislation intended to regulate its availability (WHO Expert Peer

Review 2, 2014).

However, such local action does not warrant placement of ketamine in

Schedule I of the 1971 Convention and, in fact, demonstrates that such

action would be detrimental to the public health.

c. Many Countries support Regional or National Level Regulation Rather than International Scheduling to Achieve the Right

Balance

The UN Secretary-General solicited comments on economic, social,

legal, administrative or other factors relevant to the possible scheduling

of ketamine and received input from 26 governments as of December

2014. Only two countries supported Schedule I (Italy and the Republic

of Moldova). Several governments (e.g., Czech Republic, Hungary,

Latvia, Poland, Russian Federation, and Ukraine) objected specifically

to Schedule I classification, raising concerns about significant possible

consequences to veterinary practice, and the use of ketamine as an

anesthetic, and indicating that international control under Schedule II,

III or IV would be acceptable. A number of governments (including

Austria, Belgium, Ecuador, Germany, Latvia, Mexico, Netherlands,

and Switzerland), objected to scheduling altogether, citing existing

local regulations and suggesting that regional control measures could

be taken wherever relevant problems with the substance were observed.




February 26, 2015 8

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The comments cited the need to find the appropriate balance between

the level of controls required to mitigate misuse and the protection of

legitimate use (UN Economic and Social Council 2014).

IV. Potential New Medical Uses for Ketamine and its Enantiomer Esketamine Should Be Considered in Any Scheduling Decision

In addition to its established use as an anesthetic and analgesic, ketamine has

demonstrated promising results in early clinical trials for uses in psychiatry. There

is currently heightened interest in the scientific community regarding the use of

ketamine in the treatment of major depressive disorder (MDD) (DeWilde 2015).

Major depressive disorder is a serious, recurrent, and disabling psychiatric illness,

and is the leading cause of disability worldwide (WHO Depression Fact Sheet

2012; Vos 2010). About 30% of patients fail to achieve remission despite

treatment with multiple antidepressant medications, and are considered to have

TRD (Rush 2006; Fava 2003). In patients who respond to antidepressants, the

time to onset of effect is typically 4 to 7 weeks, during which time patients

continue to suffer from their symptoms and continue to be at risk of self-harm, as

well as being impacted by the associated harm to their personal and professional

lives (Rush 2006; Saveanu 2015). Therefore, there is a significant need to develop

novel treatments based upon relevant pathophysiologic pathways underlying MDD

for the rapid relief of symptoms of depression, especially in patients with TRD

(DeWilde 2015).

Ketamine is approved and widely used for the induction and maintenance of

anesthesia via intramuscular (IM) or intravenous (IV) administration (Ketamine

HCl USPI JHP). The desired analgesic-anesthetic effects of ketamine and

esketamine are attributed to the blockade of ionotropic NMDA glutamate

receptors.

Monoamines (serotonin, norepinephrine, and/or dopamine) are only modulatory

transmitters; therefore, conventional monoaminergic antidepressants would not be

expected to robustly affect synaptic transmission, activity-dependent release of

brain-derived neurotrophic factor (BDNF), or synaptogenesis (Duman 2012). In

contrast, the mechanism of action of ketamine is distinct from conventional

antidepressants and ketamine profoundly affects fast excitatory glutamate

transmission, increases BDNF release, and stimulates synaptogenesis (Duman

2012).

Most literature reports of the antidepressant effects of ketamine describe

studies using IV administration of the racemate, with a few exceptions (Cusin

2012). Janssen is developing esketamine for antidepressant therapy. Moreover,

intranasal administration is being investigated instead of IV administration, since




February 26, 2015 9

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intranasal administration can offer better convenience and ease of use for patients

(McGirr 2015; Opler 2015).

Janssen has completed several Phase 1 and 2 studies with esketamine and

ketamine. Data from a Phase 2 study conducted by Janssen have shown that IV

esketamine has a similar, rapid, and robust antidepressant effect as that seen with

IV ketamine.

In November 2013, the FDA granted Breakthrough Therapy designation to

esketamine for TRD. A breakthrough therapy is a drug (1) intended alone or in

combination with one or more other drugs to treat a serious or life threatening

disease or condition and (2) preliminary clinical evidence indicates that the drug

may demonstrate substantial improvement over existing therapies on one or more

clinically significant endpoints, such as substantial treatment effects observed

early in clinical development (FDA SIA Section 902).

In light of the evidence showing that esketamine can be an effective treatment for

patients with TRD, the promising results from early studies in this population, and

the FDAs recognition of the importance to patients of this potential new treatment

by granting Breakthrough Therapy designation, there is a heightened level of

interest among government bodies, academic institutions and the pharmaceutical

industry to confirm these early findings in future studies.

As previously mentioned, Janssen is currently investigating an intranasal

formulation of esketamine in TRD. The Janssen development program includes an

ongoing Phase 2 trial of intranasal esketamine in subjects with TRD, with plans to

initiate several global Phase 3 studies in 2015. Should the planned Phase 3 studies

confirm the earlier evidence that TRD patients can benefit from intranasal

esketamine and with an acceptable safety and tolerability profile, Janssen would

seek to make this medicine available to patients worldwide by submitting

marketing applications for approval in the United States and other regions.

Given the promising studies and potential for increased medical use of

ketamine and, if approved, esketamine, placement of ketamine under Schedule I of

the 1971 Convention may have a detrimental impact for ongoing and planned

research with ketamine and esketamine. For example, if Janssens investigational

formulation containing esketamine were approved for use in TRD, this would

represent a new treatment for patients who desperately need more effective

options to treat this illness, thus fulfilling an unmet medical need. Restricting or

eliminating the availability of this drug, if approved, would subject these patients

to additional barriers to obtaining treatment deemed necessary by their health care

professional.




February 26, 2015 10

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V. Conclusion and Requested Action

We respectfully request that the United States strongly oppose scheduling of

ketamine and vote against any recommendation or proposal to schedule ketamine

under Schedule I of the 1971 Convention.

Sincerely,

Husseini Manji

Signature:

Email:

Title:

Husseini Manji (Feb 26, 2015)Husseini [email protected]

Global Therapeutic Area Head


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