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Propofol

Scheduling Review Document: Eight Factor Analysis

Drug and Chemical Evaluation Section, 

Office of Diversion Control, Drug Enforcement Administration

September 2010

Introduction

Propofol is a short-acting intravenous (i.v.) sedative-hypnotic used for the induction and 

maintenance of general anesthesia or sedation for medical procedures. On March 18, 2008, the 

Drug Enforcement Administration (DEA) received a petition requesting that 21 CFR §1308.13 

be amended so that propofol be controlled as a schedule III substance under the Controlled 

Substances Act (CSA). 

The basis of the petition was the reports of increased incidences of propofol abuse during 

the past decade. The petitioner stated as the main argument in support of the request was that 

“Propofol is the most common intravenous anesthetic in the United States today but over the 

course of the decade, documented cases of abuse have been steadily increasing over the past 10 

years... Unfortunately, there is also a very high mortality rate (greater than 33%) associated 

with this abuse.” The petitioner cited a published article which indicated that a seven-fold 

decrease in the abuse of propofol occurred when access to propofol was controlled in a secured 

facility by the hospital pharmacy. The petitioner stated that controlling propofol as a scheduled 

drug would require health care professionals to strictly monitor the access and use of propofol 

and possibly save lives.

Pursuant to 21 U.S.C. 811(a) and (b), DEA gathered and evaluated the available data on 

propofol and on July 2, 2009, DEA requested that the Department of Health and Human Services 

(DHHS) provide a scientific and medical evaluation of the available information and a 

scheduling recommendation for propofol, in accordance with 21 U.S.C. 811(b).

On May 14, 2010, pursuant to 21 U.S.C. 811(c), the Department of Health and Human 

Services (DHHS) provided to the DEA a scientific and medical evaluation entitled “Basis for the 

Recommendation for the Control of Propofol and Its Salts in Schedule IV of the Controlled 

Substances Act” and a scheduling recommendation (DHHS review, 2010). Following 

consideration of the eight factors and findings related to the substance’s abuse potential, 

legitimate medical use, and dependence liability, DHHS recommended that propofol and its salts 

be controlled in schedule IV of the CSA under 21 U.S.C. 812 (b). 
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The CSA requires DEA to determine whether the DHHS’ scientific and medical 

evaluation and scheduling recommendation and all other relevant data constitute substantial 

evidence that the substance should be scheduled (21 U.S.C. 811(b)). This document contains an 

explanation of the relevant data that DEA considered. Pursuant to 21 U.S.C. 811(c), the 

Attorney General reviews the facts and all relevant data. This document is a review of the 

relevant data, law enforcement information and a determination to place propofol and its salts 

into schedule IV of the CSA.

Factor 1. Actual or Relative Potential for Abuse

Propofol was approved in 1989 under the commercial name Diprivan®as an ultra-short 

i.v. anesthetic. Diprivan®is an injectable emulsion (10 mg/mL). There are three approved 

generic versions. Two veterinary versions, Rapinovet and PropoFlo/PropoVet, were approved 

for marketing in 1999 and 2000, respectively. Though propofol is not controlled under the CSA, 

the labels for its products include a section entitled Drug Abuse and Dependence due to the 

occurrences of diversion and abuse of propofol among health care professionals.

The motivation for abuse of propofol is generally for its sedative and relaxing properties 

and induction of euphoric effects. There have also been reports that propofol’s ability to induce 

sexual illusions and disinhibition contributes to its appeal as a drug of abuse (Brandner et al., 

1997; Fritz and Niemczyk, 2002; Kranioti et al., 2007; Roussin et al., 2007). Anecdotal reports 

of propofol abusers describe their experiences as “pleasant,” “euphoric,” and “relaxing” (Wilson 

et al., 2010).

It has been shown that the risk of misusing or abusing drugs is higher among healthcare 

professionals compared to the general population. The major factor contributing to the increased 

risk of drug misuse or abuse among healthcare professionals is that they can easily access drugs 

which have significant abuse potential in medical facilities (Bell et al., 1999). 

According to the DHHS review (2010), health care professionals who have access to 

propofol and are trained to administer i.v. drugs are at risk of abusing propofol. It has been 

shown that for many cases involving propofol abuse, the abuse was only detected upon the death 

of the abusers. Therefore, it can be assumed that there are more instances of propofol abuse than 

are being reported 

DHHS provided data from FDA’s Adverse Events Reporting System (AERS), and it was 

searched to identify domestic cases of abuse, dependence, and overdose associated with 

propofol, from date of the drug approval to August 27, 2009. There were 26 cases of propofol 

diversion and abuse reported; ten of these cases resulted in death. In 25 of the cases (96%), the 

abusers were health care providers or in training to become a health care professional. 
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In a survey of 126 academic anesthesiology programs, 18 percent reported diversion or 

abuse of propofol. Of the 25 individuals reported to have abused propofol, seven (28%) had died 

due to propofol abuse. The individuals who died were affiliated with health care facilities in 

which there were no pharmacy or security mechanisms to control access to propofol 

(Wischmeyer et al., 2007).

In a study conducted by Bell et al., (1999), 2,500 actively practicing Certified Registered 

Nurse Anesthetists (CRNAs) were surveyed to determine the prevalence of misuse of controlled 

drugs and other licit drugs with drug abuse potential. Out of the 2,500 participants, 167 (11 

percent) of the respondents indicated that they had a history of or were currently misusing of 

controlled and non-controlled substances. Propofol was reported to be the fourth most preferred 

drug to misuse among this population. The respondents indicated that they highly preferred 

propofol due to its easy accessibility and its non-control status under the CSA 

There have been published case reports of individuals who became depended on 

propofol. The reports indicated that the individuals expressed a “craving” for propofol, causing 

them to compulsively self-inject daily. They were abusing propofol for its relaxing and euphoric 

effects (Schneider et al., 2001; Soyka and Schutz, 1997; Bonnet et al., 2008; Follette and Farley, 

1992; Fritz and Niemczyk, 2002). 

Zacny et al. (1992) examined the effect of subanesthetic doses of propofol on mood, 

subjective effects, and psychomotor and physiological performance in healthy volunteers with a 

history of recreational drug use. This was a prospective, randomized, placebo controlled, and

double blind study. Healthy volunteers (n=10) were administered either a placebo (Intralipid ®) 

or a loading dose of propofol and then infused with propofol at a given dose (0.5 – 2.0 mg/kg/hr) 

or placebo over a 20 min period. Each subject received placebo, low dose propofol (0.08 mg/kg 

loading dose and 0.5mg/kg/h infusion), moderate dose propofol (0.16 mg/kg loading dose and 1 

mg/kg/h infusion), and high dose propofol (0.32 mg/kg loading dose and 2 mg/kg/h infusion) in 

four sessions spaced one week apart. Before, during, and after the 20 min infusion, volunteers 

completed mood inventories (Drug effects/Liking questionnaire), including the Addiction 

Research Center Inventory; memory (i.e., immediate and delayed recall of words); and 

psychomotor tests (Digit Symbol Substitution test, DSST). Propofol did produce mood altering 

effects dose-dependently, but the effect was transient and the mood returned to baseline one hour 

after administration. The report of subjective effects also increased dose-dependently. Fifty 

percent of the volunteers reported “liking” the effects of propofol on a Visual Analogue Scale 

(VAS scale); thus, the authors stated that propofol may have a potential for abuse.

Zacny et al. (1993a) conducted a double-blind and randomized study with human healthy 

volunteers (n=10) with a history of recreational drug use. The purpose of the study was to assess 

the rewarding effects of propofol using a discrete-trials choice procedure. To assess subjective 

effects, the VAS and the Drug Effects/Liking questionnaires were used. Memory or short and 

delayed recall was also tested using lists of words and psychomotor performance was tested 
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using the DSST. Bolus i.v. subanesthetic doses of propofol 0.6 mg/kg and the placebo control

(Intralipid ®) were administered in a blind fashion twice to each subject. For the following three 

sessions, the subjects choice which drug, identified by a color code, they wanted to receive. 

Propofol was chosen by six of the subjects. During the sessions, propofol choosers reported 

acute pleasant effects with no unpleasant residual effects. The authors concluded that propofol 

may be rewarding to non-drug abusers, thus having abuse potential.

Zacny et al. (1993b) assessed the abuse potential of propofol in healthy human subjects 

(n=10). Using a randomized, double-blind, crossover method, the subjects were injected i.v. 

with subanesthetic doses of propofol (0.2-0.6 mg/kg) or placebo. The following was assessed 

before the injection and up to 1 h post-injection: mood (including drug liking), memory, and 

psychomotor performance. Propofol induced memory impairment negatively impacted 

psychomotor performance, these effects were acute. It also altered mood, 10 of 20 VAS mood 

ratings. Five of the subjects (50 percent) said that if they participated in another study that they 

would choose 0.6 mg/kg propofol over the placebo. The authors concluded that propofol has the 

potential for abuse and/or diversion, particularly with hospital personnel.

Generally, the studies demonstrated that propofol dose-dependently increased the 

reporting by the subject feeling “high,” relative to the placebo. In one study, when subjects were 

given a choice of either receiving i.v. propofol or placebo, about half of the subjects chose 

propofol over placebo. These studies demonstrate that propofol produces a reward effect in 

humans and the pattern is characteristic of the abuse potential of drugs in schedule IV. Subjects, 

who were previous drug users, reported an increase in sedation and “liking” scores. Several 

clinical case reports regarding propofol’s actual physical dependency and addiction are also 

reported in the published scientific literatures (Au et al., 1990; Follette and Farley, 1992; Tobias, 

2000; Cawley et al., 2003). 

There was a report of propofol withdrawal upon discontinuation of administration in a 

10-month-old girl. The girl had been administered propofol for 2 weeks to provide sedation 

while she was mechanically ventilated. Upon cessation of administration of propofol, the patient 

exhibited “generalized twitching and jitteriness.” The symptoms disappeared over a 3-day 

period (Tobias, 2000). 

Au et al. (1990) reported a case of a 41-year-old man who required propofol for sedation 

after emergency surgery. He was administered propofol and papaveretum for five days, and 

administration was discontinued once he was extubated. Over the next few hours, he became 

confused, exhibited tremors, and had hallucinations. Ten hours later, he experienced several

short grand mal seizures, which subsided with the administration of diazepam. Propofol and 

papaveretum infusions were administered to the patient, and over the next 48 h, he was gradually 

weaned off of the drugs without any signs of a withdrawal syndrome. 
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Cawley et al. (2003) published a case report of a burn patient who required propofol 

administration for sedation. He was administered an infusion of propofol (10 mg/ml) at 5 

g/kg/min beginning on his 35th day of treatment, in conjunction with valproic acid and 

fluoxetine to treat the patient’s bipolar disease. After 79 days of continuous infusion of 

propofol, the infusion rate ranged from 5-35 g/kg/min, the infusion dose was weaned over a 

four day period from 25 g/kg/min for 64 h to 10 g/kg/min for the next 16 h, to finally 5 

g/kg/min for another 16 h. The patient demonstrated signs of abrupt agitation, tremors,

tachycardia, tachypnea, and hyperpyrexia 6 h after the administration of propofol had been

stopped. In order to improve the patient’s comfort, the propofol infusion (5 g/kg/min) was 

administered again, which resulted in an abrupt reduction of the tachycardia, tachypnea, and 

hyperpyrexia. Since the symptoms were resolved with administration of propofol, it was 

suspected that the patient experienced an acute propofol withdrawal reaction. A second attempt 

to wean him off of the propofol was done the following day; the dose was reduced to 2.5 

g/kg/min. He experienced withdrawal symptoms 39 h after the drop in dose. The dose was 

increased back to 5 micrograms/kg/min. Four days later, the propofol dose was decreased by 

increments of 0.25 g/kg/min. The incremental reduction was well-tolerated by the patient, the 

final infusion dose was 4.5 g/kg/min. No withdrawal symptoms were observed over a seven 

day period. The weaning off of propofol had to be stopped because the patient’s health was 

deteriorating due complications from the burn injury. The patient died after being in the hospital 

for 124 days. 

Animal self-administration studies demonstrated the reinforcing effects of propofol in rat, 

mouse, and primate models. (Weerts et al., 1999; LeSage et al., 2000) It has been demonstrated 

that drugs that are self-administered by animals also have drug abuse potential in humans

(Weerts et al., 1999; Ator and Griffith, 2003). Propofol has been demonstrated to have 

reinforcing effects comparable to methohexital, a schedule IV sedative-hypnotic. In rats trained 

to self-administer methohexital, propofol maintained a significant self-administration, indicating 

that propofol has rewarding properties comparable to methohexital (LeSage et al., 2000).

Weerts et al. (1999) evaluated the reinforcing effects of subanesthetic doses of propofol 

and methohexital in baboons using a standard cocaine (CII) substitution procedure. Both test

drugs were administered i.v. In two of the three baboons, the rates of self-injection were 

comparable to methohexital, but less that than the level of the cocaine-maintained animals. The 

animals maintained low to high mean rates of self-injection of subanesthetic doses of propofol, 

when substituting for propofol 

In rats, propofol induced a conditioned place preference paradigm at subanesthetic doses 

(30, 60 mg/kg, intraperitoneal or i.p.) and at recovery from propofol anesthesia (100 mg/kg). 

Subanesthetic doses of methohexital (10, 20, 30 mg/kg, i.p.) were used as a comparison; none of 

these doses induced a place preference paradigm, which is commonly observed with barbiturates. 
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The authors also emphasize that the level of place preference induced by 60 mg/kg propofol was 

comparable to that induced by other tested drugs, which caused a pleasant affective state, such as 

amphetamine (1.5 mg/kg) (Pain et al., 1996). 

In summary, both the preclinical and clinical data have demonstrated that propofol has a 

moderate abuse potential similar to that of other schedule IV sedative-hypnotics, such as 

midazolam and methohexital, and by extension, lower than that of other sedatives in schedule III. 

The reinforcing effects in animals following self-administration of propofol are predictive of 

human abuse. Abuse of propofol by humans has been observed, to a larger extent, in medical 

professionals. This is predominately due to propofol being available principally in medical 

facilities where it is easily accessible due to it not being stored as a controlled substance.. 

Factor 2. Scientific Evidence of its Pharmacological Effects

The binding site of propofol is on the -aminobutyric acid subtype A (GABAA) receptor

and propofol both activates the GABAA receptor and acts as a modulator by potentiating the 

activity of GABA at the receptor in the central nervous system (CNS) (Pain et al., 1996; Weerts 

et al.; 1999; LeSage et al., 2000; Hall et al., 2010). Other psychoactive drugs, e.g., barbiturates

(schedule II and III), benzodiazepines (schedule IV), and volatile anesthetics, also potentiate 

GABA at the GABAA receptors (Zacny et al., 1993b; Weerts et al., 1999). As a major group of 

post-synaptic inhibitory membrane receptors, the GABAA receptor is a ligand-gated chloride 

channel that consists of five subunits and a central chloride channel. 

Propofol has been shown to have an effect on the GABA uptake and release presynpatically. Propofol inhibits the presynaptic uptake of GABA in a dose-dependent manner in 

the CNS (Weerts et al., 1999). Some studies have shown that propofol either enhances on the 

potassium-stimulated release or the spontaneous release of GABA. Other studies have shown 

that propofol does not enhance the potassium-stimulated release of GABA (DHHS review, 

2010).

At supratherapeutic concentrations, propofol also inhibits the activity of post-synaptic 

glutamate excitatory membrane receptors, such as N-methyl-D-asparate (NMDA) receptors. 

Ketamine (CIII), an anesthetic with significant abuse potential, also inhibits the NMDA receptors 

(Roussin et al., 2007). Thus, propofol shares a similar pharmacological property with ketamine, a 

schedule III controlled substance, by inhibiting the action of NMDA at the post-synaptic 

glutamate receptor (Roussin et al., 2007). 

Schwieler et al. (2003) demonstrated that propofol dose-dependently decreased the firing 

rate and burst firing activity of nigral dopamine neurons. Small doses of propofol (1-16 mg/kg) 

was administered, i.v., to rats. The effect was antagonized by pre-treatment with CGP35348, a 

GABAB receptor antagonist. Pain et al. (2002) demonstrated that propofol induces both 
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decreases and increases of the extracellular dopamine concentrations in the nucleus accumbens, 

depending on the dose of propofol administered. Rats were injected, i.p., with three doses of 

propofol, 9, 60, or 100 mg/kg, small, subanesthetic and anesthetic doses, respectively. The 9 

mg/kg dose decreased the extracellular dopamine concentration in the nucleus accumbens, and 

the 60 and 100 mg/kg doses increased the extracellular dopamine concentrations. Each dose of 

propofol induced significant changes in dopamine levels, compared to basal levels. The 100 

mg/kg dose also significantly increased homovanillic acid (HVA) levels, a dopamine metabolite. 

As is the case with other drugs of abuse, propofol increases the extracellular dopamine 

concentrations in the nucleus accumbens at sub- and anesthetic doses (Pain et al., 2002).

The reinforcing effects of propofol have been demonstrated via self-administration 

studies in various animal models, in the rat, mouse, and primates. (Weerts et al., 1999; LeSage et 

al., 2000) It has been demonstrated that drugs that are self-administered by animals also have 

drug abuse potential in humans (Weerts et al., 1999; Ator and Griffith, 2003). Zacny et al. 

(1992, 1993a, 1993b) have demonstrated through clinical trials that propofol had reinforcing and 

rewarding effects in humans. The subjective effects were most comparable to schedule IV 

sedatives, e.g., methohexital.

Propofol’s mechanism of action of inducting anesthesia is not known. 

In summary, the predominant binding site of propofol is on the GABAA receptor. 

Propofol, similar to other psychoactive drugs (e.g., barbiturates, and benzodiazepines) that are 

controlled under the CSA, acts as a modulator on the GABAA receptor; it potentiates the GABA

activity at the receptor. 

Factor 3. The State of Current Scientific Knowledge Concerning the Substance.

Chemistry

Propofol, or 2,6-diisopropylphenol, has a molecular weight of 178.271 g/mol. The 

molecular formula of propofol is C12H18O. The chemical structure of propofol is below.

Propofol is slightly soluble in water and is formulated in an oil-in-water emulsion that is 

milky-white in appearance. The formulation has a neutral pH with a pKa in water of 11. The 

octanol/water partition coefficient for propofol is 6761:1 at a pH of 6-8.5. Fospropofol, the 
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water-soluble O-methyl-phosphate disodium salt, a prodrug of propofol, has been recently 

controlled as a schedule IV substance under the CSA. 

Pharmacokinetics

In humans, the pharmacokinetic profile of propofol is described by a three compartment 

linear model, similar to that in animals, with compartments in plasma, rapid equilibrating tissues, 

and slow equilibrating tissues, mainly the adipose tissue (Iwersen-Bergmann et al., 2001). 

Following a bolus dose of infused, i.v., propofol, there is a rapid equilibration between plasma 

and central nervous system which leads to a rapid onset of anesthesia. Plasma concentrations 

decline rapidly due to the distribution and metabolic clearance in almost equivalent effects. 

Propofol is highly protein bound and is metabolized by conjugation in the liver (Levitzsky and 

Vargo, 2008).

Clinical studies show that there are no gender differences in the distribution of propofol, 

but there are age differences; elderly subjects achieve higher peak plasma concentrations of 

propofol. In the geriatric population, the dose of propofol required to achieve a similar 

anesthetic end point as that in the non-elderly adults is lower. The higher peak plasma 

concentrations of propofol in the elderly can pre-dispose them to adverse cardio-respiratory 

effects including hypotension, apnea, airway obstruction, and/or arterial oxygen de-saturation

(Heuss et al., 2003). 

The metabolism of propofol occurs very rapidly after intravenous administration. 

Metabolized propofol is excreted extensively by the kidneys with a rate reaching to almost onethird of the total body clearance (DHHS review, 2010). Its clearance rate exceeds hepatic blood 

flow and may suggest an extra-hepatic site of elimination. Binding highly with plasma proteins, 

propofol is extensively metabolized to glucuronide conjugates (Iwersen-Bergmann et al., 2001; 

Kranioti et al., 2007). According to the DHHS review (2010), the conjugation of glucuronide to 

propofol is predominantly catalyzed by the uridine diphosphate glucuronosyltransferase-1 family 

enzymes.

According to the DHHS review (2010), once the medical administration of propofol is 

ceased, either for maintenance of anesthesia or sedation, the plasma concentration of propofol 

decreases and subsequently, the patient awakens rapidly. Clinically, anesthetics are generally 

administered with opioids for various medical procedures, so the knowledge of the drug-to-drug 

interactions of propofol with opioids is very important for patients’ safety. It has been 

demonstrated that 50-60 M of propofol inhibited the metabolism of alfentanil and sufentanil by 

50 percent. Since it is very common to use these opioids concomitantly with propofol clinically,

it is imperative that anesthesiologists be aware of propofol’s effect of inhibiting the metabolism 

of certain opioids and increasing the half-life of opioids (DHHS review 2010).
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In summary, the pharmacokinetic profile of propofol is identified by a three compartment 

linear model (similar to that in animals) with compartments in plasma, rapid equilibrating 

tissues, and slow equilibrating tissues. Following a bolus dose, there is a rapid equilibration of 

propofol between plasma and central nervous system, which leads to a rapid onset of anesthesia. 

The plasma concentration will decline rapidly due to the distribution and metabolic clearance in 

almost equivalent effects. Propofol is highly protein bound in vivo and is metabolized by 

conjugation in the liver. It is slowly eliminated from adipose tissues. Its rate of clearance 

exceeds the average level of the hepatic blood flow, suggesting an extra-hepatic site of 

elimination. There is an age difference in the propofol metabolism, but no evidence was found 

to support gender differences. Under the same administrated dose of propofol, the elderly 

subjects may achieve a higher peak plasma concentration than the non-elderly adults.

Factor 4. Its History and Current Pattern of Abuse

Propofol is currently marketed as a non-controlled anesthetic in the U.S. and in other 

countries. The current abuse profiles of propofol indicate that propofol is principally abused by 

anesthesiologists and other health care professionals, e.g., nurse anesthetists and resident 

physicians. These professionals have access to propofol easily due to its availability in medical 

facilities. It has been observed that the lack of secured controls to the access of propofol in 

hospitals and clinics has resulted in the abuse of propofol by medical professionals (Schneider et

al., 2001; Weetman et al. 2004; DHHS review, 2010). 

In a survey of 126 academic anesthesiology programs in the U.S., 18 percent of the 

programs reported diversion or abuse of propofol. Of the 25 individuals reported to have abused 

propofol, seven (28 percent) had died from propofol abuse. The individuals who died were 

affiliated with health care facilities in which there were no pharmacy or security mechanisms to 

control the access to propofol (Wischmeyer et al., 2007). 

In a study conducted by Bell et al. (1999), 2,500 actively practicing Certified Registered 

Nurse Anesthetists (CRNAs) were surveyed to determine the prevalence of misuse of controlled 

drugs and other licit drugs with drug abuse potential. One hundred sixty-seven (11 percent) of 

the respondents indicated that they had a history of or were currently misusing of controlled and 

non-controlled substances. Propofol was reported to be the fourth most preferred drug to misuse 

among this surveyed population. The respondents indicated that they highly preferred propofol 

due to its easy accessibility and its remarkable non-control status under the CSA. 

Though propofol is not controlled under the CSA, the labels for its products include a 

section entitled Drug Abuse and Dependence due to the occurrences of diversion and abuse of 

propofol among health care professionals. Several databases, such as National Survey on Drug 

Use and Health (NSDUH), Monitoring the Future (MTF), and Treatment Episode Data Set 

(TEDS), were accessed to obtain information on trends and/or patterns of propofol abuse. None 

of the above public databases contained data on propofol-related abuse. According to the DHHS 
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review (2010), this may be due to the availability of propofol being limited to medical 

professionals instead of the general public.

According to the DHHS review (2010), generally, propofol is abused alone, but there 

have been some reports of abuse of propofol in combination with other psychoactive drugs and 

substances, e.g., lidocaine, midazolam, and alcohol. When propofol is abused, it has been 

reported to be “ultra-short acting” causing the abuser to frequently inject the propofol in order to 

maintain a high level of euphoria. Though propofol, when abused, is reported to be short-acting, 

it has been reported that propofol can adversely affect the abuser’s work performance 

In summary, abuse of propofol has been observed to predominantly exist among medical 

professionals. This is due to propofol being available primarily in medical facilities. None of 

the above public drug abuse databases contained data on propofol-related abuse. This might be 

due to the current non-controlled status of propofol under the CSA. The incidences of propofolrelated abuse may be monitored and tracked continuously through the above-mentioned 

databases. 

Factor 5. The Scope, Duration, and Significance of Abuse

DEA has searched the scientific literature and the State and Federal forensic laboratory 

databases to assess the scope of propofol abuse in the United States. The forensic laboratory 

databases such as National Forensic Laboratory Information System (NFLIS) and System to 

Retrieve Information from Drug Evidence (STRIDE) compiled data from Federal, State and 

local laboratories regarding seizures of propofol from 1999-2009 (Table 1). 

The American Society of Anesthesiologists (ASA) and the American Association of 

Nurse Anesthetists (AANA) have recently endorsed the control of propofol under the CSA in 

order to prevent the occurrence of diversion and abuse among their respective professions. In 

June 2009, the AANA issued a position statement insisting that medical facilities which use 

propofol to implement standard practices to reduce the likelihood of diversion and abuse of 

propofol, e.g. storing propofol in a secured location. In October 2009, the ASA reiterated their 

previous position statement that the propofol should only be administered by persons trained in 

the administration of general anesthesia.

Table 1. Seizures of Propofol from 1999-2009 in the United States

NFLIS (State and Local Levels)

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Exhibits 1 0 0 0 5 0 1 1 1 1 4

STRIDE (Federal Level)

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Exhibits 0 0 0 0 1 0 0 0 0 0 0
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On the Federal, State and local levels, the seizures of propofol are very low, due to 

propofol not being available to the general public. Propofol is not currently controlled by either 

the federal government or state governments, and may not be a target or priority of law 

enforcement. Therefore, information on reported seizures and cases from federal, state and local 

law enforcement agencies is very limited. As previously stated, medical professionals are the 

predominant population to abuse propofol. 

According to the DHHS review (2010), in many of the published case reports about 

propofol abuse, the abuse of propofol was only detected upon death of the abuser. So, it is 

probable that there are more instances of propofol abuse, than what has been reported. 

Factor 6. What, if Any, Risk There is to the Public Health 

Propofol abuse is directly associated with significant adverse health effects, including 

death. The known major adverse effects include pancreatitis, pulmonary edema, and 

cardiovascular and respiratory depression. The cause of death with propofol toxicity is due to 

respiratory depression ( Roussin et al., 2007; Iwersen- Bergmann et al., 2001; DHHS review, 

2010). In a survey conducted among health-care providers and health center workers, the 

mortality rate among anesthesiologists abusing propofol was 28 percent, and 38 percent among 

hospital residents also abusing propofol (Wischmeyer et al., 2007). 

There have been reports of incidences of apnea associated with the induction of 

anesthesia using propofol. The Food and Drug Administration (FDA)-approved label for 

Diprivan®states that seven percent of adult patients receiving 2-2.5 mg/kg experienced apnea for 

less than 30 seconds, 20 percent experienced apnea for 30-60 seconds, and 12 percent of patients 

experienced apnea for less than 60 seconds. In pediatric patients (from birth to 16 years of age) 

that received 1-3.6 mg/kg, 12 percent experienced apnea for less than 30 seconds, 10 percent 

experienced apnea for 30-60 seconds, and five percent experienced apnea for more than 60 

seconds.

Though propofol, when abused, is reported to be short-acting, it has been indicated that 

propofol can still adversely affect the abuser’s work performance (Soyka and Schütz, 1997). 

Thus, since the populations who are abusers of propofol are predominantly medical 

professionals, this fact could potentially pose a significant risk to the health and safety of the 

patients under their care.

According to the DHHS review (2010), there have been reports of the use of propofol in 

the carrying out of criminal activities. In one reported case, a medical professional used propofol 

in the sexual assault of a patient. In another case, a nurse used propofol to murder one of his 

acquaintances. There have been published cases of driving while under the influence of propofol

abuse. Within a 12 month period, three drivers were apprehended who were driving while 
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simultaneously self-injecting propofol. All three individuals were males who were associated 

with a hospital (Odell, 1999). 

In summary, propofol abuse has various adverse effects and can potentially result in 

death of the abuser. The abuse of propofol also has been shown to negatively affect the work 

performance of abusers. Propofol poses a considerable threat to the public health because it can 

be used in the commission of criminal activity, e.g. sexual assault and murder, and it also impair

an individual’s ability to safely operate a motor vehicle. This fact also demonstrates a pattern of

diversion of the propofol from the legitimate applications. Overall, the risks associated with the 

abuse of propofol are similar to those associated with the abuse of other sedative hypnotics and 

CNS depressants, such as midazolam and methohexital, which are controlled in schedule IV of 

the CSA.

Factor 7. Its Psychic or Psychological Dependence Liability

Animal and human studies have demonstrated that propofol has remarkable physiological 

dependence liability. There has been a published case demonstrating that propofol has 

physiological dependence potential, though none of the reports directly compare the 

psychological dependence potential of propofol with that of other drugs. There have been 

reports that propofol induces psychological dependence, characterized by craving, compulsion to 

constantly self-inject, and to continue to use propofol in spite of adverse consequences (Soyka 

and Schütz, 1997; Roussin et al., 2007). Another study reported about the abusers experiencing 

tolerance to the relaxing and euphoric effects during episodes of continuous self-administration

of propofol (Schneider et al., 2001). The observed reinforcing effects in animals following selfadministration of propofol are supportively predictive of human abuse potential and dependency 

liability.

Schneider et al. (2001) published a case report of a 25-year-old male patient who was 

diagnosed with a propofol dependence upon being admitted to the hospital. He was initially 

treated by an anesthesiologist with propofol to treat the symptoms associated with tension 

headaches. Though the propofol treatment was effective, by the following year, the 

anesthesiologist refused to continue to treat the patient with propofol. Upon not being able to 

obtain propofol through his physician, the patient began to administer 200 mg propofol. One 

week prior to him being admitted to the hospital for his propofol dependence, he was using 

propofol daily, injecting 200 mg of propofol up to 10-15 times per day. Though the patient 

reported that he had not experienced any withdrawal symptoms, he did experience an intense 

craving for propofol, which caused him to compulsively inject propofol multiple times daily

Soyka and Schutz (1997) reported on a case about a 31-year-old general practitioner, who 

was admitted to the hospital in order to detoxify from propofol. He had started injecting 

propofol ten months prior and was injecting almost daily. He had initially started injecting 50 
DEA/OD/ODE Page 13 of 18 11/3/2010

mg i.v,, his purpose of abusing propofol was he was to relieve boredom, to relax, and to treat 

symptoms associated with depression. After injecting propofol, the patient rapidly experienced a 

mild euphoria and relaxation, followed by a strong sedation and loss of consciousness. He 

constantly craved the feelings associated with propofol abuse so he compulsively injected 

propofol, up to 100 times a day; only stopping upon consuming the entire quantity he possessed 

on each occasion. He did not experience any withdrawal symptoms.

Bonnet et al. (2008) reported a case about a 30-year-old physician who had been admitted

to the hospital due to a vehicle accident and during treatment developed symptoms similar to a 

benzodiazepine withdrawal syndrome. The subject was abusing propofol and cigarettes without 

an addiction history of benzodiazepines. The subject met the International Classification of 

Diseases-10 (ICD-10) criteria for diagnosis of dependency on sedatives which includes positive 

psychological (craving propofol, loss of control) and physical (tolerance, withdrawal syndrome 

with hyperhidrosis, tachycardia, anxiety, and insomnia) components and negative social 

sequelae, such as burglary to acquire propofol. His positive physical symptoms reduced over the 

three weeks of treatment while psychological symptoms did not decrease, instead became more

intense leading to negative behaviors associated with addiction, e.g., burglary of propofol and

job loss (Bonnet et al., 2008).

Follette and Farley (1992) published a report about an anesthesiologist in his early 30’s 

who had developed an addiction to propofol. At the peak of the addiction, he was injecting a 

constant amount of propofol 10 to 15 times per day both at home and at work. The compulsion 

and craving to abuse propofol became the principal motivators for abuse after he initially began 

to abuse propofol for its relaxing effects. He later enrolled in an extended-care drug 

rehabilitation program after he was found unconscious in the emergency room following selfinjecting 100 mg of propofol.

Fritz and Niemczyk (2002) reported a case about a patient who had been treated with 

propofol by an anesthesiologist who was using propofol to treat the patient’s tension headaches. 

After several treatment sessions with the propofol, the patient began to self-inject propofol. With 

a previous history of abusing drugs including benzodiazepines, morphine and marijuana, he

obtained propofol prescriptions from veterinarians for a false purpose of anesthetizing fish. He 

self-injected propofol three to four times a week with each session lasting one to two hours. He 

was admitted into a treatment program, but checked himself out after seven days.

Chronic administration of propofol can produce significant physical dependence and 

withdrawal symptoms. There have been published reports of withdrawal symptoms upon abrupt 

cessation of propofol administration after several days of treatment (Au et al., 1990; Follette and 

Farley, 1992; Tobias, 2000; Cawley et al., 2003). The symptoms included agitation, tremors, 

tachycardia, tachypnea, hyperpyrexia, confusion, and hallucinations. The withdrawal symptoms 

improved once an administration of propofol was reinitiated, and the dosages were tapered over 
DEA/OD/ODE Page 14 of 18 11/3/2010

a two-day period. However, the withdrawal induced -delusional state may last up to seven days 

before full recovery of mental functions. Cawley et al. (2003) recommended that after a 

prolonged administration of propofol, the cessation of administration should be done cautiously 

and the patient should be monitored for any signs of a withdrawal syndrome.. 

In summary, the pharmacological action of propofol, the published abuse potential data 

and case reports, collectively suggest that propofol has potential to cause psychological and 

physical dependence. Propofol’s abuse liability combining with its psychological and physical 

dependence are comparable to other controlled drugs in schedule IV, such as midazolam and 

methohexital.

Factor 8. Whether the Substance is an Immediate Precursor of a Substance Already 

Controlled

Propofol is not an immediate precursor of any substance currently controlled under the 

CSA.
DEA/OD/ODE Page 15 of 18 11/3/2010

Findings

After consideration of the above eight factors determinative of control of a substance (21 

U.S.C. § 811(c)), and a review of the scientific and medical evaluation and scheduling 

recommendation provided by the DHHS, DEA finds that propofol, including its salts, isomer, 

salts of isomers whenever the existence of such isomers, esters, ethers, and salts is possible as 

summarized below meet the criteria for placement in schedule IV of the CSA, under 21 U.S.C. § 

812 (b)(4). 

1) Propofol has a low potential for abuse relative to the drugs or other substances in 

schedule III.

The binding site of propofol is on the -aminobutyric acid subtype A (GABAA) receptor, 

acting as a modulator by potentiating the GABA activity at the receptor (Pain et al., 1996; 

Weerts et al., 1999). Other psychoactive drugs, such as barbiturates, benzodiazepines, and 

volatile anesthetics, potentiate GABA at the GABAA receptors in the CNS (Zacny et al., 1993b; 

Weerts et al., 1999). GABA is the main inhibitory neurotransmitter in the CNS. 

Animal self-administration studies demonstrated the reinforcing effects induced by

propofol in rat, mouse, and primate models. Propofol has been demonstrated to have reinforcing 

effects comparable to methohexital, a schedule IV sedative-hypnotic. Baboons self-administered 

sub-anesthetic doses of propofol in a pattern comparable to methohexital (Weerts et al., 1999). 

In rats trained to self-administer methohexital, propofol maintained self-administration, 

indicating that propofol has rewarding properties comparable to other controlled substances, such 

as methohexital (LeSage et al., 2000).

There have been several published abuse liability studies of propofol in humans in which 

the reinforcement and reward effects have been demonstrated. Zacny et al. (1992, 1993a, 

1993b) showed that propofol produced subjective effects most comparable to schedule IV 

sedatives, e.g., methohexital. Generally, the studies demonstrated that propofol dosedependently increased the reporting by the subject feeling “high,” relative to the placebo. In one 

study, when subjects were given a choice of either receiving i.v. propofol or placebo, about half 

of the subjects chose propofol over placebo. These studies demonstrate that propofol produces a 

reward effect in humans and the pattern is characteristic of the abuse potential of drugs in 

schedule IV. Subjects, who were previous drug users, reported an increase in sedation and 

“liking” scores. 

It has been observed that the lack of secured controls to the access of propofol in 

hospitals and clinics had resulted in an increase of the abuse of propofol by health care 

professionals, e.g., anesthesiologists, nurse anesthetists and resident physicians (Schneider et al., 

2001; Weetman et al, 2004; DHHS review, 2010).
DEA/OD/ODE Page 16 of 18 11/3/2010

In a survey of 126 academic anesthesiology programs, 18 percent reported diversion or 

abuse of propofol. Of the 25 individuals reported to have abused propofol, seven (28 percent) 

had died as a result of propofol abuse. The individuals who died were affiliated with health 

centers in which there was no secured pharmacy accounting system for propofol dispersion 

(Wischmeyer et al., 2007).

2) Propofol has a currently accepted medical use in treatment in the United States. 

Propofol was approved, under the commercial name of Diprivan@, in 1989, as an ultrashort acting i.v. anesthetic. Propofol is indicated in adults for the initiation and maintenance of 

Monitored Anesthesia Care (MAC) sedation, combined sedation, and regional anesthesia, and for 

Intensive Care Unit (ICU) sedation of intubated and mechanically ventilated patients. For 

children, propofol is indicated for induction and maintenance of general anesthesia. Propofol is 

also approved for use as a veterinary anesthetic.

3) Abuse of propofol may lead to limited psychological or physical dependence relative to 

the drugs or other substances in schedule III.

There have been reports of withdrawal symptoms following a long-term use of propofol 

suggesting its physical dependence potential. The withdrawal symptoms are resolved by slowly

tapering the dose of the propofol administrated, thus indicating the limited dependence potential. 

Psychic dependence potential of propofol is identified by intravenous drug self-administration 

studies in animals and subjective effects in propofol abusers. 
DEA/OD/ODE Page 17 of 18 11/3/2010

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