Ahmet Akin

Gülhane Military Medical Academy

Department of Aerospace Medicine

Eskisehir 26020, Turkey

Arvind K. Chaturvedi

Civil Aerospace Medical Institute

Federal Aviation Administration

Oklahoma City, OK 73125

May 2003

Final Report

This document is available to the public

through the National Technical Information

Service, Springfi eld, Virginia 22161.

 

Offi ce of Aerospace Medicine

Washington, DC 20591

Prevalence of Selective 

Serotonin Reuptake Inhibitors 

in Pilot Fatalities of Civil 

Aviation Accidents, 1990-2001

DOT/FAA/AM-03/7
NOTICE

This document is disseminated under the sponsorship of

the U.S. Department of Transportation in the interest of

information exchange. The United States Government

assumes no liability for the contents thereof.
i

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ACKNOWLEDGMENTS

The Government of Turkey is acknowledged for allowing the participation of Dr. Ahmet Akin in 

the FAA International Exchange Visitor Program at the FAA’s Civil Aerospace Medical Institute (CAMI), 

Oklahoma City, OK. 

The authors wish to thank Dr. Dennis V. Canfi eld of CAMI for his timely advice, valuable comments, and assistance in the data gathering process and the manuscript development. Without his support, this study would not have been possible. The authors are grateful to Patrick S. Cardona of CAMI for 

providing assistance in drawing the chemical structures of SSRIs and to Dr. John W. Soper and Dr. James 

E. Whinnery of CAMI for critically and enthusiastically reviewing the manuscript. Their comments and 

suggestions improved the quality of this report. 

iii

1

PREVALENCE OF SELECTIVE SEROTONIN REUPTAKE INHIBITORS IN PILOT

FATALITIES OF CIVIL AVIATION ACCIDENTS, 1990-2001

INTRODUCTION

Selective serotonin reuptake inhibitors (SSRIs), a new 

generation of antidepressants, are effective medications 

for the treatment of depression (4,8). There are currently 

5 drugs—fl uoxetine, sertraline, paroxetine, fl uvoxamine, 

and citalopram—classifi ed as SSRIs (Figure 1). However, 

in the United States, fl uvoxamine (Luvox®) is approved 

only for treating obsessive compulsive disorder (31). Fluoxetine was the fi rst SSRI marketed in the United States in 

1988, followed by other SSRIs. Since their availability 

(Table I), fl uoxetine (Prozac®), sertraline (Zoloft®), paroxetine (Paxil®), and citalopram (Celexa®) have preferentially 

been prescribed because of low incidences of untoward 

adverse effects associated with their use, allowing these 

4 SSRIs to remain in the top 200 drugs of the most dispensed prescriptions in the United States pharmaceutical 

industry (9,10,27,28,37-41,47-49). By being a part of the 

general population, aviators are subject to similar social 

pressures as other individuals of the society. Therefore, 

aviators have the potential for the need-based use of SSRIs, 

but these psychotropic medications are not approved by 

United States aeromedical regulatory authorities for use 

by aviators in order to avoid a possible compromise with 

aviation safety (15,20,22). 

SSRIs are considered safe in comparison with other 

groups of antidepressants (6,30,44), though SSRIs have 

been linked to adverse effects primarily associated with 

the serotonin syndrome and drug metabolism inhibition 

(4,19,45). The former can be effectively treated, but the 

latter can lead to severe adverse effects in multi-drug users. 

All 5 SSRIs are extensively metabolized by the cytochrome 

P450 (CYP) enzyme system (4,17). Except for paroxetine 

and fl uvoxamine, other SSRIs have active metabolites, 

as well (4,5,17). Fluoxetine, sertraline, their active 

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Figure 1: Chemical structures of selective serotonin reuptake inhibitors (SSRIs) and their 

active metabolites.
2

metabolites, paroxetine, and fl uvoxamine inhibit certain 

CYP isoenzymes involved in the biotransformation of 

other drugs. Excluding citalopram, SSRIs inhibit their own 

metabolism by saturating their metabolizing CYP enzymes 

at higher SSRI (substrate) concentrations (17,19,33,34). 

Since patients with depression are frequently treated with 

multiple drugs, inhibition of the metabolism of these drugs 

by SSRIs can lead to drug-drug interactions, toxicity, 

and even death. Apparent association between the use 

of SSRIs and an increased risk of suicide has also been 

suggested in a few deaths (18,23,29,51). However, it 

should be remembered that the increased risk of suicide 

is an intrinsic risk of the disease itself (7,18). A study on 

the postmortem forensic toxicology of SSRIs has been 

published describing the cause and manner of death of 

168 death-investigation cases (19). Fewer than 12 out of 

the 168 deaths were due to an intentional acute overdose 

of an SSRI on its own; however, the contributory role of 

an SSRI in the deaths resulting from overdoses of other 

drugs could not be ruled out primarily because of the drug 

metabolizing enzyme inhibitory properties of SSRIs. 

Little is known about the postmortem aviation forensic 

toxicology of SSRIs. Since this fi eld is basically a humanperformance related postmortem forensic toxicology endeavor (42), fi ndings on the prevalence of SSRIs in aviation 

accident pilot fatalities with the concentrations of SSRIs 

in the associated postmortem biosamples will be useful in 

the investigations of SSRI-associated aviation accidents. 

Such information will also be important to aeromedical regulatory authorities for making a possible future 

decision on the use of SSRIs by aviators. Therefore, the 

Civil Aerospace Medical Institute’s (CAMI’s) Toxicology 

Database (Oklahoma City, O.K.), the Federal Aviation 

Administration’s (FAA’s) National Aviation Safety Data 

Analysis Center (NASDAC) Database (Washington, 

D.C.), and the National Transportation Safety Board’s 

(NTSB’s) Aviation Accident Database (Washington, 

D.C.) were searched to obtain the applicable information. Findings from those database searches are presented 

in this study.

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3

MATERIALS AND METHODS

Postmortem Pilot Forensic Toxicology Samples

During the investigation of aircraft accidents occurring 

within the jurisdiction of the United States, autopsied 

biological samples collected from pilot fatalities of civil 

aircraft accidents are submitted to CAMI for toxicological 

evaluation (3). Such sample submission is coordinated 

through the FAA’s Offi ce of Accident Investigation by the 

NTSB, which is responsible for investigating all United 

States civilian aircraft accidents. The collected samples 

are shipped to CAMI in the FAA’s TOX-BOX evidence 

containers (14). 

Toxicological Evaluation

The submitted pilot fatality biological samples are 

routinely analyzed for the presence of combustion 

gases (carbon monoxide and hydrogen cyanide), alcohol/

volatiles, and drugs (11-14,43). All of these foreign substances (analytes) in the samples are analyzed according 

to established standard laboratory procedures, including 

screening and confi rmatory/quantitative analyses (14). 

Analytes found in a pilot fatality case might not have 

necessarily been detected, or even analyzed, in each of 

the sample types submitted for toxicological evaluation 

from that particular accident pilot fatality. Analyses are 

dependent upon the nature of analytes, the sensitivity and 

specifi city of analytical methods used, and the availability 

of sample types and amounts. 

Drugs include a wide range of prescription, nonprescription, and illicit drugs. As with the majority 

of the drugs, SSRIs in the biosamples are screened by 

high performance liquid chromatography and by gas 

chromatography/mass spectrometry (GC/MS) and are 

confi rmed/quantitated by GC/MS. Types and names of 

drugs found by CAMI during postmortem forensic toxicology of pilot fatalities associated with 1989-1993 and 

1994-1998 civil aviation accidents have been published 

elsewhere (11,12).

Databases

Since 1990, toxicological fi ndings of civil aircraft 

accident fatalities are electronically stored in a database 

maintained at CAMI. In the present study, this CAMI 

Toxicology Database was descriptively examined for the 

presence of SSRIs, with or without any other drug(s) 

and/or ethanol, in pilot fatalities of civil aviation accidents that occurred during a 12-year (1990-2001) period. 

Additionally, the database was searched to ascertain the 

number of 1990-2001 aviation accidents and associated 

pilot fatalities (cases) from which CAMI received postmortem biological samples. For this report, such aviation 

accidents are referred to as “CAMI accidents” and related 

pilot fatalities as “CAMI cases.” Fatalities (cases) included 

in the present study consisted of only pilots—copilots 

are not included. Information on the types of airman 

certifi cates of those SSRI-associated pilots was retrieved 

from the CAMI Toxicology Database and from the NTSB 

Aviation Accident Database. The number of fatal aviation accidents reported by the NTSB for the 1990-2001 

period was obtained from the FAA’s NASDAC Database. 

The NTSB Aviation Accident Database was also used for 

obtaining information about the SSRI-related accidents, 

including the probable cause and/or factor(s) of those 

accidents, as determined and reported by the NTSB. 

RESULTS 

Fatal Civil Aviation Accidents

As reported in the FAA’s NASDAC Database, the 

number of all the United States fatal civil aviation accidents for the 1990-2001 period was 5,449. Of these 

accidents, 4,570 were under the general aviation fl ight 

category (Title 14 CFR Part 91), 305 were under the air 

taxi and commuter fl ight category (Title 14 CFR Part 

135), 168 were under the agricultural fl ight category 

(Title 14 CFR Part 137), 8 were under the ultralight fl ight 

category (Title 14 CFR Part 103), and the remaining 

398 were under other fl ight categories (Table II). The 

Title 14 CFR Part 135 category included accidents of 

scheduled, as well as nonscheduled, fl ights. The NASDAC 

Database includes information primarily associated with 

the accidents of registered aircraft—information on the 

accidents of unregistered aircraft may not necessarily be 

included in this database.

CAMI Aviation Accidents and Pilot Fatalities

CAMI received postmortem biological samples for 

toxicological evaluation from 4,128 pilots (CAMI cases) 

associated with 4,184 fatal accidents (CAMI accidents) 

that occurred during the 12-year period (Table II). Out 

of these 4,184 accidents, 3,643 accidents with 3,611 

pilot fatalities were related to general aviation fl ights, 

220 accidents with 218 pilot fatalities were related to 

air taxi and commuter fl ights, 127 accidents with 127 

pilot fatalities were related to agricultural fl ights, 44 accidents with 44 pilot fatalities were related to ultralight 

fl ights, and 150 accidents with 128 pilot fatalities were 

related to other categories of fl ights. The CAMI Toxicology Database includes both registered and unregistered 

aircraft accidents.
4

SSRI-Involved Aviation Accidents and Pilot Fatalities 

Flight categories: Of the 4,184 CAMI accidents, SSRIs 

were found in 61 pilot fatalities (CAMI cases) associated 

with 61 aviation accidents (Table II). Of these 61 accidents, 56 involved general aviation fl ights, 2 air taxi and 

commuter fl ights, 2 agricultural fl ights, and 1 ultralight 

fl ight. Out of the 61 pilot fatalities, 22 had only SSRIs, 

and 39 also had other drug(s) and/or ethanol.

Airman certifi cate categories: Out of these 61 SSRI-involved pilots, 37 held private pilot certifi cates (36 United 

States private pilot certifi cate holders and 1 Canadian 

private pilot certifi cate holder), 13 held commercial pilot 

certifi cates, 4 held airline transport pilot certifi cates, 3 held 

student pilot certifi cates, and 1 held a recreational pilot 

certifi cate. The 3 remaining pilots were non-certifi ed. Of 

the 37 private pilot certifi cate holders, 36 were involved 

in general aviation accidents, while 1 was involved in an 

ultralight accident. In the group of the 13 commercial 

pilot certifi cate holders, 9 were involved ingeneral aviation 

accidents, 2 in air taxi and commuter accidents, and 2 in 

agricultural accidents. The remaining pilot fatalities—4 

airline transport pilot certifi cate holders, 3 student pilot 

certifi cate holders, 1 recreational pilot certifi cate holder, 

and 3 non-certifi cated pilots—were involved in general 

aviation accidents. 

Accidents and pilot fatalities: As is exhibited in Figure 

2, there were no SSRI-associated pilot fatalities (cases) 

in the 1990 accidents, but the number of SSRI-involved 

fatalities increased from 1 in the 1991 accidents to 18 in 

the 2001 accidents. In the 12-year accidents, the highest 

number of pilot fatalities was associated with fl uoxetine, 

which was fi rst SSRI marketed in the U.S. in 1988. No 

fl uvoxamine-associated pilot fatality was seen during the 

12-year period. The trend of SSRI-involved pilot fatalities 

and associated accidents was consistent with the pattern of 

the SSRIs dispensed in the U.S. pharmaceutical industry 

during the 1990-2001 period (Figure 2; Table I). 

Fluoxetine: This SSRI was found in 33 pilot fatalities 

(cases). In 13 cases, only fl uoxetine and/or its primary 

active metabolite (norfl uoxetine) were detected (Table 

Table II. Operation Type-Based Comparative Categorization of 1990-2001 Fatal Civil Aviation 

Accidents Reported in the FAA' s National Aviation Safety Data Analysis Center (NASDAC) 

Database and in the CAMI's Toxicology Database 

CAMI Toxicology Database‡

Operation Type*

FAA's 

NASDAC

Database 

Accidents†

CAMI 

Accidents CAMI Cases 

CAMI SSRI-Related 

Accidents (Pilot Fatalities) 

General aviation 

(Title 14 CFR Part 91) 

4,570 3,643 3,611 56 

Air taxi and commuter 

(Title 14 CFR Part 135) 

305 220 218 2 

Agricultural 

(Title 14 CFR Part 137) 

168 127 127 2 

Ultralight 

(Title 14 CFR Part 103) 

8 44 44 1 

Other operation types 398 150 128 – 

Total 5,449 4,184 4,128 61

*

Code of Federal Regulations (CFR), Title 14—Aeronautics and space, Chapter I, Subchapters F and G (16). 

†

May not include fatal accidents of unregistered aircraft. 

‡

Includes fatal accidents of registered, as well as unregistered, aircraft from which postmortem biological 

samples were submitted for toxicological evaluation. Such aviation accidents are referred to as "CAMI 

accidents" and related pilot fatalities as "CAMI cases." Details are also given in the text of the Materials and 

Methods section. 
5

III)—blood, the toxicologically preferred sample type, 

was not available in 2 of these cases. Blood concentration 

ranges of fl uoxetine and norfl uoxetine were 61−1,121 

ng·mL−1 and 52−1,388 ng·mL−1, respectively. In the remaining 20 cases, other drugs—for example, analgesics, 

antihistaminics, benzodiazepines, narcotic analgesics, amphetamines and other sympathomimetics, cocaine and 

its metabolites, and/or tetrahydrocannabinol carboxylic 

acid—and/or ethanol were also detected (Table IV). Blood 

was not available in 6 of the 20 cases. Blood fl uoxetine 

and norfl uoxetine concentrations in those cases wherein 

other drugs and/or ethanol were present ranged from 11 

to 778 ng·mL−1 and from 87 to 764 ng·mL−1, respectively. 

Ethanol was found in only 3 cases—blood was not available in 1 of these cases. Blood ethanol concentrations 

in the 2 cases were 39 and 246 mg·dL−1. Out of the 33 

fl uoxetine-involved cases, the use of the SSRI, with or 

without other drug(s), was determined by the NTSB to 

be a contributing factor in 7 accidents, of which 1 pilot 

fatality had only fl uoxetine and norfl uoxetine, while the 

remaining 6 pilot fatalities also had other drug(s). All of 

these 7 accidents were of the general aviation category. 

The cause/factor of 1 accident was undetermined, and 

the fi nal reports of 3 accidents were not yet available in 

the NTSB database. The drug use was not reported to be 

a cause/factor in 22 of the 33 accidents by the NTSB.

Sertraline: Fourteen pilot fatalities (cases) had sertraline. In 4 cases, only sertraline and/or its active 

metabolite (desmethylsertraline) were detected (Table 

V). Blood concentration of this SSRI in 1 of the 4 cases 

was considerably high—sertraline: 13,102 ng·mL−1 and 

desmethylsertraline: 889 ng·mL−1. In the remaining 10 

cases, other drug(s) and/or ethanol were also detected 

(Table VI). Blood was not available in 1 of these 10 cases. 

In the 9 cases, the blood concentration range of sertraline was 47−1,860 ng·mL−1 and of desmethylsertraline 

it was 42−4,685 ng·mL−1. Other drugs found in these 

10 pilot fatalities were analgesics, sympathomimetics, 

diphenhydramine, and/or tramadol. Ethanol was found 

in 3 cases wherein no other drugs were detected—only 

sertraline was present. The NTSB determined the use of 

the SSRI, with other drug and/or ethanol, to be a contributing factor in 2 of the 14 sertraline-related accidents; 

both accidents were of the general aviation category. The 

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Figure 2: Numbers of selective serotonin reuptake inhibitor (SSRI)-associated pilot fatalities (CAMI 

cases) in civil aviation accidents that occurred during 1990-2001. Postmortem biological samples from 

the pilots of fatal aircraft accidents were submitted to CAMI for toxicological evaluation. Details are given 

in the text.
6

Table III. Fluoxetine and Norfluoxetine Found in Pilot Fatality (Case) Biological Samples Without 

Other Drugs and/or Ethanol 

Fluoxetine/Norfluoxetine (ng·mL−1 or ng·g −1)

Case Blood Urine Liver 

SSRI Use a 

Contributing Factor in 

the Accident per NTSB 

Report*

1 1,121/1,388 592/809 –† Undetermined 

2 200/300 – 6,200/15,000 Not mentioned 

3 583/254 344/195 – Not mentioned 

4 ND‡

/52 ND/D§ ND/155 Not mentioned 

5 923/1,320 – 1,724/988 Not mentioned 

6 61/D – 20/ND Not mentioned 

7 ND/55 – ND/1,182 Not mentioned 

8 ND/ND – 13/16 Not mentioned 

9 211/861 – 10,161/36,277 Not mentioned 

10 405/299 – 12,840/17,750 Yes (contraindicated 

drug-caused impaired 

judgment) 

11 203/715 – D/D Not mentioned 

12¶

 Blood not 

available 

– 700/1,500 Not mentioned 

13** Blood not 

available 

– 31,000/74,000 Not mentioned 

*

As reported in the NTSB Aviation Accident Database at the time of the writing of this report. 

†

No data, because the sample type was either not available or not analyzed. 

‡

Not detected. 

§

Detected; no quantitative value. 

¶

Fluoxetine (200 ng·g –1) and norfluoxetine (200 ng·g –1) were also detected in kidney. 

**Kidney contained 3,200 ng·g –1 fluoxetine and 18,000 ng·g –1 norfluoxetine, and lung contained 4,900 ng·g –1

fluoxetine and 56,000 ng·g –1 norfluoxetine.
7

Table IV. Fluoxetine and Norfluoxetine Found in Pilot Fatality (Case) Biological Samples with Other Drug(s) and/or Ethanol 

Case Samples 

Fluoxetine/ 

Norfluoxetine 

(ng·mL−1 or 

ng·g−1)

Other Drugs/Their Metabolites (ng·mL−1 or ng·g−1) and/or 

Ethanol (mg·dL−1 or mg·hg−1)

SSRI Use [With Other 

Drug(s)/Ethanol] a 

Contributing Factor in 

the Accident per 

NTSB Report*

1 Blood 

Urine 

83/138 

D†/D

Temazepam (44) Temazepam (D) 

Yes (prescription drug) 

2 Blood 

Urine 

197/87 

D/D

Amphetamine (D), methamphetamine (16) Amphetamine (229), methamphetamine (1,578) 

Yes (drug-caused impairment) 

3 Blood 

Liver Kidney 

11/148 

D/D

D/43 

Nordiazepam (93), etomidate (D), lidocaine (D), atropine (D) Nordiazepam (D), etomidate (D), lidocaine (100), atropine (D)

–

‡

Not mentioned 

4 Blood 

Liver Lung 

488/698 

D/DD/D

Phenylpropanolamine (D), ephedrine (D), pseudoephedrine (D), chlorpheniramine (148), chlordiazepoxide (D), nordiazepam (152), diltiazem (D), salicylate (8,000), acetaminophen (21,900) Phenylpropanolamine (D), ephedrine (D), pseudoephedrine (D), chlorpheniramine (121), chlordiazepoxide (D), nordiazepam (D), diltiazem (D) Phenylpropanolamine (D), ephedrine (D) 

Yes (drug-caused impairment of judgment and performance) 

5 Blood 

Urine Liver 

89/101 89/101 98/100 

Amphetamine (603) Amphetamine (7,816), carbamazepine (2,300) Carbamazepine (4,400) 

Yes (medication-caused impairment) 

6 Blood 

Urine 

778/764 

D/D

Diphenhydramine (75), diltiazem (D) Diphenhydramine (D), diltiazem (D), acetaminophen (9,300) 

Not mentioned 

7 Blood 

Urine Liver 

293/333 

–

1,170/1,790 

Nordiazepam (D) Temazepam (D), nordiazepam (31), oxazepam (D) Nordiazepam (46), salicylate (69,800) 

Not mentioned 

8 Blood 

Urine Liver 

642/676 

D/D

1,639/1,601 

Phenylpropanolamine (D), ephedrine (D), tetrahydrocannabinol carboxylic acid (D) Phenylpropanolamine (D), ephedrine (D), tetrahydrocannabinol carboxylic acid (20), salicylate (215,500) Phenylpropanolamine (D), ephedrine (D) 

Not mentioned 

9 Blood 

Urine 

367/185 

73/33 

Ephedrine (D) Phenylpropanolamine (D), ephedrine (D), salicylate (31,000) 

Not mentioned 
8

Table IV. Fluoxetine and Norfluoxetine Found in Pilot Fatality (Case) Biological Samples with Other Drug(s) and/or Ethanol (continued) 

Case Samples 

Fluoxetine/ 

Norfluoxetine 

(ng·mL−1 or 

ng·g−1)

Other Drugs/Their Metabolites (ng·mL−1 or ng·g−1) and/or 

Ethanol (mg·dL−1 or mg·hg−1)

SSRI Use [With Other 

Drug(s)/Ethanol] a 

Contributing Factor in 

the Accident per 

NTSB Report*

10 Blood§

Urine Vitreous fluid 

D/209 

ND¶/109 

–

Ethanol (246), pseudoephedrine (D), doxylamine (270), dextromethorphan (D), dextrorphan (D) Ethanol (220), phenylpropanolamine (D), ephedrine (D), pseudoephedrine (D), doxylamine (D), dextromethorphan (D), dextrorphan (D) Ethanol (289) 

Not mentioned 

11 Blood 

Liver Lung 

43/242 

2,252/D 

–

Lidocaine (11,760), atropine (D) 

–Lidocaine (D), atropine (D) 

Not mentioned 

12 Blood 

Liver Brain Muscle 

ND/400 

D/D

––

Ethanol (39) 

–Ethanol (36) Ethanol (55) 

Final NTSB report not yet available 

13 Blood 

Liver Kidney 

–

D/DD/D

Propoxyphene (172), norpropoxyphene (1,037) 

–Propoxyphene (2,240), norpropoxyphene (31,714) 

Final NTSB report not yet available 

14 Blood 

Liver Kidney 

ND/296 

–

ND/D

Cocaine (10), benzoylecgonine (212), cocaethylene (D) Benzoylecgonine (352) 

–

Not mentioned 

15** Liver 

Kidney 

7/109 

D/24 

Hydrocodone (496) Hydrocodone (D) 

Yes (contraindicated drug) 

16** Liver 

Kidney 

2,215/861 

353/108 

Cimetidine (D), diltiazem (D) Cimetidine (D), diltiazem (D) 

Yes (unapproved medication) 

17** Liver 

Kidney 

1,442/1,902 

448/582 

Desipramine (295), nordiazepam (251), phentermine (6,413), Bupropion (D), bupropion metabolite (D) Desipramine (97), nordiazepam (159), phentermine (3,486), Bupropion (D), bupropion metabolite (D) 

Not mentioned 
9

Table IV. Fluoxetine and Norfluoxetine Found in Pilot Fatality (Case) Biological Samples with Other Drug(s) and/or Ethanol (continued) 

Case Samples 

Fluoxetine/ 

Norfluoxetine 

(ng·mL−1 or 

ng·g−1)

Other Drugs/Their Metabolites (ng·mL−1 or ng·g−1) and/or 

Ethanol (mg·dL−1 or mg·hg−1)

SSRI Use [With Other 

Drug(s)/Ethanol] a 

Contributing Factor in 

the Accident per 

NTSB Report*

18** Liver 

Kidney Muscle 

7/145 

8/26 

–

–Ethanol (164) Ethanol (15) 

Not mentioned 

19** Liver 

Kidney 

ND/201 

ND/19 

Nordiazepam (269) Nordiazepam (191) 

Not mentioned 

20** Liver 

Kidney Muscle 

D/D

–

ND/D

Nordiazepam (D), verapamil (D), norverapamil (D) Nordiazepam (D), oxazepam (D) Verapamil (D), norverapamil (D) 

Final NTSB report not yet available 

*As reported in the NTSB Aviation Accident Database at the time of the writing of this report. †Detected; no quantitative value. ‡No data, because the sample type was either not available or not analyzed. §Contained 12% carboxyhemoglobin. ¶Not detected. **Blood not available. 
10

pilot fatalities associated with these 2 accidents not only 

had sertraline and/or desmethylsertraline but also had 

diphenhydramine or ethanol. The drug use was not 

mentioned to be a cause/factor in 9 accidents by the 

NTSB, and the fi nal reports of 3 accidents were not yet 

available in the NTSB database.

Paroxetine: As is given in Table VII, paroxetine 

was found in 11 pilot fatalities (cases). In 3 cases, only 

paroxetine was present. In the remaining 8 cases, other 

drugs—antihistaminics, sympathomimetics, alprazolam, 

butalbital, codeine, morphine, quinine, and/or verapamil—were also present. Ethanol was not detected in 

any of the 11 fatalities. Blood was not available in 3 of the 

11 cases. The blood concentration range of paroxetine, 

with or without any other drug(s), was 68−1,441 ng·mL−1. 

The drug use was not established to be a cause/factor in 8 

of the 11 accidents by the NTSB. The fi nal reports of 3 

accidents were not yet available in the NTSB database.

Citalopram: This SSRI was found in only 3 pilot fatalities (Table VIII). In 2 of these cases, only citalopram 

and its active metabolites—N-desmethylcitalopram and -desmethylcitalopram and 

di-N-desmethylcitalopram—were detected, whereas acetaminophen and diphenhydramine were also detected 

in 1 case. Blood was not available in 1 case. Ethanol was 

not detected in any of the citalopram-related pilot fatalities. In accidents associated with 2 of these 3 cases, the 

drug use was not established to be a cause/factor by the 

NTSB; the fi nal report of 1 accident was not yet available 

in the NTSB database.

DISCUSSION

Because SSRIs are popularly prescribed in the general 

population for effectively treating depression, and pilots 

are also a part of the population, there have been genuine concerns whether pilots should offi cially be granted 

permission to use SSRIs. Such a decision would require 

the assurance that SSRIs can be prescribed without 

compromising aviation safety. The SSRI-use-related 

safety issue was discussed in great detail at the 2002 

Aerospace Medical Association (AsMA) scientifi c meeting (21,24,26,36,46,50). The reluctance of aeromedical 

regulatory authorities to allow the use of SSRIs by aviators primarily stems from the very basic pharmacological 

nature of SSRIs as being psychotropic drugs. These drugs 

have the potential to affect the central nervous system 

(CNS), thus might impair performance and ultimately 

compromise aviation safety. Because of these reasons, 

the FAA has been reluctant to approve the use of SSRIs 

by aviators.

Although pilots have the potential to use SSRIs, 

the presence of SSRIs in pilot fatalities is apparently 

less than expected, considering their heavy use in the 

general population (9,10,27,28,37-41,47-49), as only 

61 SSRI-associated pilot fatalities were found out of the 

4,128 pilot fatalities from the 4,184 CAMI accidents. 

The number of SSRI-associated pilot fatalities was higher 

in the general aviation fl ight category than in any other 

fl ight categories, which is consistent with the higher number of general aviation fatal accidents than the aviation 

Table V. Sertraline and Desmethylsertraline Found in Pilot Fatality (Case) Biological Samples 

without Other Drugs and/or Ethanol 

Sertraline/Desmethylsertraline (ng·mL−1 or ng·g−1)

Case Blood Urine Liver Brain 

SSRI Use a 

Contributing 

Factor in the 

Accident per 

NTSB Report*

1 13,102/889 –† 587/330 985/1,311 Not mentioned 

2 211/498 D‡/D – – Not mentioned 

3 D/83 D/D D/D – Not mentioned 

4 ND§

/D – D/283 – Final NTSB report 

not yet available 

*

As reported in the NTSB Aviation Accident Database at the time of the writing of this report. 

†

No data, because the sample type was either not available or not analyzed. 

‡

Detected; no quantitative value. 

§

Not detected. 
11

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Table VI. Sertraline and Desmethylsertraline Found in Pilot Fatality (Case) Biological Samples with Other Drug(s) and/or Ethanol (continued) 

Case Samples 

Sertraline/ 

Desmethylsertraline 

(ng·mL−1 or ng·g−1)

Other Drugs/Their Metabolites (ng·mL−1 or ng·g−1)

and/or Ethanol (mg·dL−1 or mg·hg−1)

SSRI Use [With Other 

Drug(s)/Ethanol] a 

Contributing Factor in the 

Accident per NTSB Report*

8 Blood 

Urine Liver Brain Vitreous fluid Muscle 

1,672/2,983 

D/D D/D 

–––

Ethanol (55) Ethanol (78) 

–Ethanol (57) Ethanol (71) Ethanol (41) 

Final NTSB report not yet available 

9 Blood 

Liver 

47/230

D/D 

Diphenhydramine (251) Diphenhydramine (D) 

Yes (drug-caused impairment)

10** Liver 

Kidney 

23,239/49,573 

3,727/10,133 

Phenylpropanolamine (D), pseudoephedrine (D), ephedrine (D), diphenhydramine (1,157) Pseudoephedrine (D), diphenhydramine (213) 

Not mentioned 

*As reported in the NTSB Aviation Accident Database at the time of the writing of this report. †Not detected. ‡Detected; no quantitative value.

§No data, because the sample type was either not available or not analyzed. 

¶General aviation accident. **Blood not available. 
13

Table VII. Paroxetine Found in Pilot Fatality (Case) Biological Samples with or without Other Drug(s) 

and/or Ethanol*

Case Samples 

Paroxetine 

(ng·mL−1

or ng·g −1)

Other Drugs/Their Metabolites 

(ng·mL−1 or ng·g −1)

SSRI Use 

[With or Without Other 

Drug(s)] a Contributing 

Factor in the Accident 

per NTSB Report†

1 Blood 

Urine 

68

19

None detected 

None detected 

Not mentioned 

2 Blood 

Urine 

96

D‡

None detected 

None detected 

Not mentioned 

3 Blood 

Urine 

Liver 

–§

D

228

–

Diphenhydramine (D), morphine (73), codeine 

(D), hydrocodone (72), dihydrocodeine (46) 

Diphenhydramine (149) 

Not mentioned 

4 Blood¶

Urine 

283

D

Pseudoephedrine (D) 

Phenylpropanolamine (D), ephedrine (D), 

pseudoephedrine (D) 

Not mentioned 

5 Blood 

Urine 

374

1,040

–

Alprazolam (D), -hydroxyalprazolam (D) 

Not mentioned 

6 Blood 

Urine 

1,441

D

Verapamil (D), norverapamil (D) 

Verapamil (D), norverapamil (D) 

Final NTSB report not 

yet available

7 Blood 

Urine 

619

D

Phenylpropanolamine (D), ephedrine (D), 

pseudoephedrine (D) 

Phenylpropanolamine (D), ephedrine (D), 

pseudoephedrine (D) 

Final NTSB report not 

yet available

8 Blood 

Urine 

Liver 

355

D

D

–

Codeine (49), morphine (1,658) 

–

Use of prohibited 

drugs, as a finding **

9†† Liver 

Kidney 

1,608

710

None detected 

None detected 

Not mentioned 

10†† Liver 

Muscle 

24,400

208

Diphenhydramine (6,240) 

–

Not mentioned 

11†† Liver 

Muscle 

Heart 

D

–

D

Butalbital (681), quinine (D), 

Triprolidine (D) 

Butalbital (241) 

Quinine (D), triprolidine (D) 

Final NTSB report not 

yet available 

*

No ethanol was detected in this group of pilot fatalities. 

†

As reported in the NTSB Aviation Accident Database at the time of the writing of this report. 

‡

Detected; no quantitative value. 

§

No data, because the sample type was either not available or not analyzed. 

¶

Contained 17% carboxyhemoglobin and 0.31 μg·mL−1 cyanide. **Air taxi and commuter accident. 

††Blood not available. 
14

Table VIII. Citalopram and its Metabolites Found in Pilot Fatality (Case) Biological Samples with or without Other Drugs and/or Ethanol

*

Concentration (ng·mL−1 or ng·g−1)

Case Samples Citalopram 

N-Desmethylcitalopram Di-N-desmethyl- citalopram Other Drugs/Their Metabolites 

SSRI Use [With or Without 

Other Drug(s)] a Contributing 

Factor in the Accident per 

NTSB Report†

1 Blood 

Liver 

314

D‡

157

D

11

650

None detected None detected 

Not mentioned 

2 Blood 

Urine 

462

D

114

D

24

D

Diphenhydramine (194) Diphenhydramine (D), acetaminophen (17,406) 

Final NTSB report not yet available 

3§ Liver 

Kidney 

DD

DD

DD

None detected None detected 

Not mentioned 

*No ethanol was detected in this group of pilot fatalities. †As reported in the NTSB Aviation Accident Database at the time of the writing of this report. ‡Detected; no quantitative value. §Blood not available. 
15

 accidents of other operation categories. This conclusion 

is supported by the observations that (i) 56 (92%) of 

the 61 SSRI-involved accidents and 3,643 (87%) of the 

4,184 CAMI accidents were associated with the general 

aviation fl ights, (ii) all of the 9 accidents in which the 

use of an SSRI was determined to be a contributing factor were of the general aviation category, and (iii) the 

majority of the 61 pilots held airman certifi cates at the 

levels that authorized them for fl ying under the general 

aviation category. 

The number of fatalities associated with an individual 

SSRI was consistent with its marketing year—for example, fl uoxetine, marketed in 1988, was present in 33 

pilot fatalities; whereas citalopram, marketed in 1998, 

was found in only 3 pilot fatalities. Although fl uoxetine, 

sertraline, paroxetine, and citalopram were found in the 

61 pilot fatalities, fl uvoxamine was not detected in any 

of the total 4,128 CAMI aviation accident pilot fatalities. 

The absence of fl uvoxamine in the pilot fatalities could 

be because this medication has not yet been approved 

in the U.S. for the treatment of depression—this drug is 

approved in the U.S. only for the treatment of obsessive 

compulsive disorder (31). Additionally, fl uvoxamine is 

not a popularly prescribed medication—this drug has 

never been in the top-200 drug list of the most dispensed 

prescription drugs in the U.S. (9,10,27,28,47-49). The 

prevalence of fl uvoxamine, in relation to other SSRIs, 

was also considerably low in a general forensic toxicology 

death investigation study consisting of 168 cases (19). In 

this study, fl uvoxamine was present in only 5 death cases, 

whereas fl uoxetine was found in 60 death cases, sertraline 

in 75 death cases, and paroxetine in 28 death cases.

SSRIs, themselves, may not exhibit considerable 

adverse effects on human performance at the recommended therapeutic doses, but depression, itself, has 

a signifi cant potential for performance impairment. 

Nonetheless, because of the pharmacological potencies 

and drug metabolism inhibitory properties of SSRIs and 

their metabolites (4,5,17,19,45), SSRIs may adversely affect the CNS function and cause drug-drug interactions. 

Since SSRIs inhibit their own metabolism at high doses 

(17,19,33,34), the potential for the inhibition of the 

metabolism of other drugs is further increased in those 

cases wherein SSRIs are taken in high doses. Thus, SSRIs 

taken in conjunction with other drugs might interactively 

cause drug toxicity, even when other drugs are taken in 

therapeutic doses. Blood concentrations of those other 

drugs could be higher than their typical therapeutic blood 

levels because of the SSRI-caused inhibition of their metabolism, thereby their accumulation in blood. 

Out of those 61 SSRI-associated pilot fatalities, 39 

(64%) pilot fatalities also had other drug(s) and/or 

ethanol in their system. Some of the drugs—such as 

atropine, lidocaine, etomidate, and analgesics—found 

in the pilot fatalities could have been administered by 

emergency health care providers at accident scenes, or at 

hospitals, for resuscitation, pain reduction, and/or surgical 

procedures. Whereas, other drugs—such as antihistaminics, benzodiazepines, sympathomimetics, cardiovascular 

medications, and even abused drugs—and ethanol were 

very likely present in the system of the pilots prior to the 

accidents. Thus, pharmacodynamic and pharmacokineticlevel interactions of SSRIs and their active metabolites 

with other drug(s) and ethanol could realistically lead to 

performance impairment and unpredictable toxicopharmacological effects. Such performance impairment and 

adverse effects may well be increased at fl ying altitudes 

because of the reduced availability of oxygen to the brain 

and other organs.

Inhibition of their own metabolism is known to 

cause changes in the ratios of the parent SSRIs and their 

metabolites (17,19,33): These ratios are less at low SSRI 

doses in comparison with the ratios at high SSRI doses. 

Therapeutic serum level ranges of fl uoxetine, sertraline, 

paroxetine, and citalopram are established to be 100–500, 

25–50, 30–100, and 75–150 ng·mL−1, respectively (4). 

The relationship between the plasma (or serum) concentrations of SSRIs and their whole blood concentrations 

is not fully established, and the blood to plasma (or serum) concentration ratios of SSRIs may not necessarily 

be equivalent to 1. Therefore, the SSRI blood concentrations found in the present study may not truly represent 

their plasma or serum levels. Although therapeutic, toxic, 

and lethal levels of SSRIs in whole blood are not clearly 

determined based on the postmortem forensic toxicology of death investigation cases, the lowest blood levels 

determined to have resulted in death were 630 ng·mL−1 for 

fl uoxetine; 1,500 ng·mL−1 for sertraline; and 400 ng·mL−1

for paroxetine (19). Anastos et al. (1) have concluded 

therapeutic and lethal concentrations of citalopram in 

blood to be 400 ng·mL−1 and 800 ng·mL−1, respectively. 

The majority of pilot fatality blood SSRI levels, in the 

absence of other drug(s) and/or ethanol, observed in the 

present postmortem aviation forensic toxicology study 

fell below, or close to, the reported values in the death 

investigation cases (1,19). The blood sertraline concentration of 13,102 ng·mL−1 found in 1 of the pilot fatalities 

(Table V) is approximately 4-fold higher than the upper 

blood value of the sertraline concentration range reported 

in the 75 sertraline-related death investigation case study 

(19). Therefore, the 13,102 ng·mL−1 blood sertraline level 

could be considered as a supra-toxic or lethal concentration. Reaching such a high concentration in blood 

could be attributed to (i) the intentional ingestion of a 
16

considerable amount of the SSRI, (ii) the contamination 

of the postmortem blood sample by the gastrointestinal 

track (GI) contents, and/or (iii) the postmortem redistribution of the SSRI among various body compartments, 

particularly from a higher concentration gradient of the 

SSRI in the GI track to a lower concentration gradient 

of the SSRI in the blood compartment.

Including sertraline, SSRIs are chemically basic drugs, 

and extensive postmortem redistribution has been reported with basic drugs (2,32,35). Therefore, blood concentrations of SSRIs found after death may not necessarily 

represent their antemortem blood levels. In view of this, 

during the investigations of aviation accidents involving 

SSRIs, the postmortem blood levels of SSRIs should be 

carefully evaluated and interpreted, particularly when 

other drug(s) and/or ethanol are also present. As is true 

with any drug, in the 13 pilot fatalities wherein the toxicologically preferred sample—blood—was not available, 

levels of SSRIs in other biological sample types cannot 

be correctly correlated with the degree of performance 

impairment or adverse effects, since such levels merely 

indicate the exposure of those victims to SSRIs.

The NTSB has determined “the use of drug” as a 

contributing factor in at least 9 (15%) out of the 61 

SSRI-related accidents, which does not necessarily imply 

only SSRIs—this may also very well refer to other drug(s) 

and/or ethanol present in those accident-related pilots. 

Final NTSB reports of 10 out of those 61 accidents are not 

yet available in the public domain database. Once those 

reports are fi nalized, the number of accidents wherein 

the use of an SSRI, with or without other drug(s) and/or 

ethanol, was a contributing factor may increase. 

The low number of SSRI-associated pilot fatalities has 

a realistic practical relevance, especially when SSRIs have 

been a popularly prescribed group of medications in the 

U.S. (9,10,27,28,37-41,47-49). Ideally, considering the 

prohibition for use of SSRIs by aviators, an SSRI should 

not have been found in any pilot fatality. The SSRI-related 

61 pilots were identifi ed only because those pilots were 

victims of fatal accidents and their postmortem samples 

were toxicologically evaluated. Even though contributing roles of weather conditions, mechanical defi ciencies, 

and/or piloting errors cannot be completely ruled out in 

the 61 accidents, this number is of concern with reference 

to aviation safety. This concern is further deepened by 

the fact that the 61 SSRI-associated accidents are 12% of 

the total (505) prescribed-medication related 1990-2001 

CAMI accidents, particularly realizing that this percentage 

represents only 4 prescription drugs. On the other hand, 

the number of SSRI-associated pilots is a fraction of the 

pilot population and may not necessarily represent the 

true spectrum of the usage of SSRIs in aviators. Therefore, a well-designed population study on pilots could 

reveal a much higher usage of SSRIs in pilots, as refl ected 

during a presentation at the 2002 AsMA scientifi c meeting (21) and during an FAA aviation medical examiner 

seminar (25). 

CONCLUSIONS

Findings from the present study clearly suggest low 

numbers of accidents wherein drug use was determined 

to be a contributing factor and/or wherein pilot fatalities 

had SSRIs in the presence or absence of other drug(s) 

and/or ethanol. Nevertheless, the absolute number of 

SSRI-related accidents and associated fatalities cannot be 

condoned. In the upcoming years, the number of SSRIassociated fatal aviation accidents may potentially increase 

as the use of SSRIs in the general population, including 

pilots, increases as a function of time. Information on the 

prevalence of SSRIs in aviation accident pilot fatalities 

along with SSRI concentrations in biological samples will 

continue to be useful in the investigations of accidents 

wherein SSRIs and other substances are involved. Additionally, fi ndings from this study should guide future 

research and be utilized in making a possible future decision concerning the use of SSRIs by aviators. 

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17

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http://www.cami.jccbi.gov/aam-400A/index.html

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