First-Generation H1

Antihistamines Found in Pilot 

Fatalities of Civil Aviation 

Accidents, 1990–2005

Ahmet Sen

Ahmet Akin

Gülhane Military Medical Academy

Department of Aerospace Medicine

Eskisehir 26020, Turkey

Kristi J. Craft

Dennis V. Canfield 

Arvind K. Chaturvedi

Civil Aerospace Medical Institute

Federal Aviation Administration

Oklahoma City, OK 73125

May 2007

Final Report

DOT/FAA/AM-07/12

Office of Aerospace Medicine

Washington, DC 20591
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.

___________

This publication and all Office of Aerospace Medicine 

technical reports are available in full-text from the Civil 

Aerospace Medical Institute’s publications Web site: 

www.faa.gov/library/reports/medical/oamtechreports/index.cfm
i

Technical Report Documentation Page 

1. Report No. 2. Government Accession No. 3. Recipient's Catalog No. 

DOT/FAA/AM-07/12 

4. Title and Subtitle 5. Report Date

First-Generation H1 Antihistamines Found in Pilot Fatalities of May 2007 

Civil Aviation Accidents, 1990–2005 6. Performing Organization Code 

7. Author(s) 8. Performing Organization Report No. 

Sen A,1 Akin A,1 Craft KJ,2 Canfield DV,2 Chaturvedi AK2

9. Performing Organization Name and Address 10. Work Unit No. (TRAIS) 1

Department of Aerospace Medicine 2FAA Civil Aerospace Medical Institute 

Gülhane Military Medical Academy P.O. Box 25082 11. Contract or Grant No. 

Eskisehir 26020, Turkey Oklahoma City, OK 73125 

12. Sponsoring Agency name and Address 13. Type of Report and Period Covered 

Office of Aerospace Medicine 

Federal Aviation Administration 

800 Independence Ave., S.W. 

Washington, DC 20591 14. Sponsoring Agency Code 

15. Supplemental Notes 

This work was accomplished under the approved task AM-B-07-TOX-202. 

16. Abstract 

First-generation H1-receptor antagonists are popularly used for alleviating allergy and cold symptoms, but these 

antihistaminics cause drowsiness and sedation. Such side effects could impair performance and, thus, could be the cause or a 

factor in accidents. Therefore, the prevalence of these antagonists was evaluated in aviation accident pilot fatalities. During

civil aircraft accident investigations, postmortem samples from pilots involved in fatal aviation accidents are submitted to the

Civil Aerospace Medical Institute (CAMI) for toxicological analyses. These analytical findings are stored in a database. This 

CAMI Toxicology Database was examined for the presence of the first-generation antihistamines in pilot fatalities of civil 

aircraft accidents that occurred during a 16-year (1990–2005) period. Of 5383 fatal aviation accidents from which CAMI 

received specimens, there were 338 accidents wherein pilot fatalities (cases) were found to contain the antihistaminics 

brompheniramine, chlorpheniramine, diphenhydramine, doxylamine, pheniramine, phenyltoloxamine, promethazine, and 

triprolidine. Of the 338 accidents, 304 were general aviation accidents; 175 of the 338 pilots held private pilot airman 

certificates. Antihistamines were detected alone in 103 fatalities (1 antihistamine in 94 fatalities and 2 antihistamines in 9),

while other drug(s) and/or ethanol were also present in an additional 235 fatalities. Thirty-five of the 338 fatalities had more

than 1 antihistamine. The antihistamines were found in approximately 4 and 11% of the fatalities/accidents in 1990 and in 

2004, respectively. Although blood was not available for the analyses in all 338 cases, the blood concentrations (ng·mL•1) were 

5–200 (n = 8) for brompheniramine; 4–6114 (n = 67) for chlorpheniramine; 9–3800 (n = 125) for diphenhydramine; 10–

1309 (n = 33) for doxylamine; and 4 (n = 1) for phenyltoloxamine. The use of antihistamine(s), with/without other drug(s) 

and/or ethanol, was determined by the National Transportation Safety Board to be the cause in 13 and a factor in 50 of the 

338 accidents. The majority of the accidents were of the general aviation category. There was an overall increasing trend in the

use of antihistamines by aviators during the 16-year span. Blood levels of the antihistaminics were in the sub-therapeutic to 

toxic range. Findings from this study will be useful in investigating future accidents involving antihistamines. 

17. Key Words 18. Distribution Statement 

Forensic Sciences, Toxicology, Pilot Fatalities, FirstGeneration Antihistamines, Antihistaminics, Aviation 

Accident Investigation 

Document is available to the public through the 

Defense Technical Information Center, Ft. Belvior, 

VA 22060; and the National Technical Information 

Service, Springfield, VA 22161 

19. Security Classif. (of this report) 20. Security Classif. (of this page) 21. No. of Pages 22. Price 

Unclassified Unclassified 17 

Form DOT F 1700.7 (8-72) Reproduction of completed page authorized 

iii

ACKNOWLEDGMENTS

The Government of Turkey is acknowledged for allowing the participation of 

Dr. Ahmet Akin and Dr. Ahmet Sen in the Federal Aviation Administration (FAA) 

International Exchange Visitor Program at the FAA Civil Aerospace Medical Institute, Oklahoma City, Oklahoma.

The authors are grateful to Dr. Selim Kilic, Department of Epidemiology, Gülhane 

Military Medical Academy, Ankara, Turkey, for performing statistical analyses.

1

First-Generation H1 Antihistamines Found in Pilot Fatalities

of Civil Aviation Accidents, 1990–2005

INTRODUCTION

Although many drugs are pharmacologically classified under the category of first-generation H1

-receptor 

antagonists (FGH1AIs), all of them are not used for alleviating allergy and common cold symptoms (24). The 

most commonly used FGH1AIs for treating these medical 

conditions are azatadine, bromazine, brompheniramine, 

carbinoxamine, chlorpheniramine, clemastine, diphenhydramine, doxylamine, pheniramine, phenyltoloxamine, 

promethazine, pyrilamine, and triprolidine (27). These 

13 antihistaminics are primarily marketed as nonprescription medications; however, depending upon their 

pharmaceutical formulations and preparations, they are 

also marketed as prescription drugs. These FGH1AIs are 

available in various tablet, capsule, caplet, elixir, ointment, and/or injection forms with or without analgesics, 

decongestants, antitussives, expectorants, and/or other 

H1 antagonists (19,20).

FGH1AIs depress the Central Nervous System (CNS), 

causing diminished alertness, slowed reaction times, dizziness, and sedation (24). Therefore, patients are cautioned 

against operating a vehicle or machinery while using the 

medications (20,27). FGH1AI-induced sedation does 

not only comprise subjective symptoms, like sleepiness, 

lethargy, or subtle confusion, but also reflects the objective impairment of superior cognitive functions (15). 

The first-generation antihistamines have been reported 

to be associated with significant sleepiness and impaired 

performance on flight tasks, resulting in slowed reaction times, memory difficulties, and impaired vigilance 

(6,12,16–18,22,28,29). Consequently, this group of 

medications is known to impair superior cognitive functions and, thus, these drugs have the potential for impairing in-flight performance. Because of the adverse effects, 

the first-generation antihistamines are not approved for 

use by civilian aviators (10,13,23). 

The presence of pheniramine in aviation accident 

fatalities has been documented as early as the 1960s (5). 

Brompheniramine, diphenhydramine, and pheniramine 

have been reported to be present in the ground transportation fatalities in 1978–1979 (9) and chlorpheniramine in 

civil aviation accident pilot fatalities in 1991–1996 (25). 

However, detailed information about the prevalence and 

causal effects of FGH1AIs in fatal civil aviation accidents 

is not well documented. Since the field of aviation forensic toxicology is basically a human performance-related 

postmortem forensic toxicology undertaking, findings on 

the prevalence of FGH1AIs in civil aviation accident pilot 

fatalities, along with their concentrations in the associated postmortem blood samples, would be useful in the 

investigations of FGH1AI-involved aviation accidents. 

Therefore, relevant databases were searched to retrieve 

the applicable necessary information. The findings from 

the database searches are presented herein.

METHODS

Postmortem Samples

During the investigation of civil aviation accidents 

occurring within U.S. jurisdiction, autopsied biological samples—blood, urine, vitreous fluid, spinal fluid, 

brain, lung, heart, liver, kidney, and/or other sample 

types—collected from pilot fatalities are submitted to 

the Civil Aerospace Medical Institute (CAMI) for toxicological evaluation (3). The submission of specimens is 

coordinated through the Federal Aviation Administration’s 

(FAA’s) Office of Accident Investigation by the National 

Transportation Safety Board (NTSB), which is responsible 

for investigating all U.S. civilian aircraft accidents. The 

collected samples are shipped in the FAA’s TOX-BOX 

evidence containers (8). The aviation accidents include 

accidents associated with registered, as well as unregistered, aircraft.

Toxicology

The submitted biological samples are routinely analyzed for the presence of carbon monoxide and hydrogen 

cyanide, ethanol and other volatiles, and drugs (7,8). The 

drugs include a wide range of prescription, nonprescription, and illicit drugs. The analyses of all of these foreign 

substances (analytes) are conducted according to established standard laboratory procedures, including initial 

and confirmatory/quantitative analyses (8). Such analyses 

are dependent upon the nature of analytes, the sensitivity 

and specificity of analytical methods used, and the availability of specimen types and their amounts. FGH1

AIs 

in the biological samples were screened (initial analysis) 

by high-performance liquid chromatography and by gas 

chromatography/mass spectrometry (GC/MS) and were 

confirmed/quantitated by GC/MS. The quantitative 

analyses of the antihistamines were generally conducted 

in blood specimens and the confirmatory analyses in other 

sample types. In those cases wherein blood samples were 
2

not available for the analysis, the FGH1AIs were analyzed 

in other available specimen types.

Databases

The CAMI’s Toxicology Database (Oklahoma City, 

OK), maintained since 1990, was descriptively examined 

for the presence of the 13 first-generation antihistamines 

azatadine, bromazine, brompheniramine, carbinoxamine, 

chlorpheniramine, clemastine, diphenhydramine, doxylamine, pheniramine, phenyltoloxamine, promethazine, 

pyrilamine, and triprolidine (with or without any other 

drug(s) and/or ethanol) in pilot fatalities of civil aviation 

accidents that occurred during a 16-year (1990–2005) 

period. The Toxicology Database was also searched to 

ascertain the number of 1990–2005 aviation accidents 

and associated pilot fatalities from which CAMI received 

postmortem biological samples. The percentage of the 

FGH1AI-involved fatal accidents in the total pilot fatality-involved accidents for each year was determined for 

the period of 1990 to 2005. Such percentages reflected 

the equivalent values of the antihistamine-associated pilot 

fatalities in the total pilot fatalities from which samples 

were received for those years.

Since each fatality is given a specific CAMI case number, 

the fatality is also referred to as a case. Therefore, “fatality” and “case” are used interchangeably in the present 

study. Fatalities included herein consisted of only pilots; 

copilots were not included. 

Information on the types of airman medical and flying 

certificates held by those FGH1AI-involved pilots was 

retrieved from the CAMI Toxicology Database and from 

the NTSB’s Aviation Accident Database (Washington, 

DC). However, it should be noted that not all of the pilots 

involved in the accidents had the appropriate airman flying and/or medical certificates required to legally pilot an 

aircraft. The number of fatal aviation accidents reported 

by the NTSB for the 1990–2005 period was obtained 

from the FAA’s National Aviation Safety Data Analysis 

Center (NASDAC) Database (Washington, DC). The 

information for the FGH1AI-related accidents, including the probable cause and contributing factors of those 

accidents, as determined and reported by the NTSB, was 

retrieved from the NTSB Aviation Accident Database. 

The cause and factors-related information included in 

the study is based on the findings reported in the NTSB 

Database through September 2006. Since 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. However, the CAMI Toxicology Database might also include information for the 

unregistered aircraft accidents.

Statistics

The proportion (percentage) of the FGH1

AI-involved 

fatal accidents/pilot fatalities in the total pilot fatalityinvolved accidents/pilot fatalities per year was calculated 

for each year. The difference of percentages in years was 

analyzed by Chi-square test using SPSS® for Windows® 

10.0 (SPSS Inc., Chicago, IL). The proportional values 

were plotted against the corresponding years, and a trend 

line was drawn by using Microsoft® Office Excel 2003 

(Redmond, WA).

RESULTS

Accidents and Pilot Fatalities

As reported in the NASDAC Database, the number of 

all the U.S. fatal civil aviation accidents for the 1990–2005 

period was 7194 (Table I). Out of these accidents, 5891 

were of general aviation, 376 air taxi and commuter, 

51 air carrier, 199 agricultural, and 6 ultralight vehicle 

categories. The remaining 671 accidents were of other 

flight categories. The accidents under the air taxi and 

commuter category included both scheduled and nonscheduled flights. 

During 1990–2005, CAMI received and toxicologically evaluated postmortem samples from 5281 pilot fatalities associated with 5383 accidents (Table I). Of the 5383 

accidents, 4734 (4655 pilots) were of general aviation, 

271 (265 pilots) air taxi and commuter, 27 (20 pilots) 

air carrier, and 157 (157 pilots) agricultural categories; 

194 accidents (184 pilots) were associated with other 

categories, including ultralight vehicle and public use 

categories. Therefore, the 5281 pilot fatalities correspond 

to the equivalent number of aviation accidents wherein 

pilot fatalities occurred and their postmortem samples 

were toxicologically evaluated.

Antihistamine-Involved Accidents and Pilot Fatalities

Flight categories: Of the 5383 accidents from which 

postmortem samples were submitted to CAMI, FGH1AIs 

were found in 338 pilot fatalities, translating into the 

equivalent number of aviation accidents (Table I). Of 

the 338 accidents, 304 were general aviation, 15 air taxi 

and commuter, 1 air carrier, 8 agricultural, 2 rotorcraft, 

and 4 ultralight vehicle flights. The remaining 4 accidents 

occurred during public use and other flights.

Airman flying and medical certificate categories: Out 

of the 338 FGH1AI-involved pilots, 175 held private, 88 

commercial, 48 airline transport, 20 student, 1 foreign, 

and 1 recreational airman flying certificates (Fig. 1). The 

remaining 5 pilots were non-certificated. Of the 175 private pilot certificate holders, 172 were involved in general 

aviation accidents, while 3 in ultralight vehicle accidents. 
3

Table I. Operation Type-Based Categorization of Fatal Civil Aviation Accidents (1990–2005) 

Reported in the FAA NASDAC Database and in the CAMI Toxicology Database 

CAMI Toxicology Database‡

Operation Categories* Accidents in FAA 

NASDAC 

Database†

Aviation

Accidents

Pilot

Fatalities§

FGH1AI-Related Pilot 

Fatalities§

General aviation 5891 4734 4655 304 

(14 CFR Part 91) 

Air taxi and commuter

(14 CFR Part 135) 

376 271 265 15 

Air carrier

(14 CFR Part 121) 

51 27 20 1 

Agricultural

(14 CFR Part 137) 

199 157 157 8 

Rotorcraft

(14 CFR Part 133) 

43 30 29 2 

Ultralight vehicle 

(14 CFR Part 103) 

6 47 47 4 

Public use 63 69 66 2 

Other categories 565 48 42 2 

Total 7194 5383 5281 338 

*

Code of Federal Regulations (CFR), Title 14 Parts (11). 

†

May not include fatal accidents of unregistered aircraft, such as ultralight vehicles. 

‡

Includes fatal accidents of registered and unregistered aircraft from which postmortem biological samples were submitted for 

toxicological evaluation. 

§

Translates into the equivalent number of aviation accidents.
4

Part 91

Part 135

Part 121

Part 137

Part 133

Part 103

Public Use

Other

Other

Non-Certificated

Student

Airline Transport

Commercial

Private

172

3

72

5 7

1 2 1

35

10

1 1 1

18

1 1

5

2

0

20

40

60

80

100

120

140

160

180

Antihistamine-Involved Pilot Fatalities

Flight Categories (Title 14 CFR Parts)

Figure 1. Antihistamine-associated pilot fatalities with respect to airman flying certificates and 

flight categories (Title 14 CFR Parts) of the aircraft involved in the fatal accidents (1990–2005). 

The description of flight categories under Title 14 CFR Parts are given in Table I. 

In the 88 commercial pilot certificate holders, 72 were 

involved in general aviation, 5 in air taxi and commuter, 

7 in agricultural, 1 in rotorcraft, 2 in public use, and 1 

in other flight accidents. Under the category of the 48 

airline transport pilot certificate holders, 35 were involved 

in general aviation, 10 in air taxi and commuter, 1 in air 

carrier, 1 in agricultural, and 1 in rotorcraft accidents. 

There were 20 student pilot certificate holders. Of these 

student pilots, 18 were involved in general aviation, 1 

in an ultralight vehicle, and 1 in other flight accidents. 

The remaining pilots—5 non-certificated and 2 other 

pilots—were involved in general aviation accidents.

Thirty-five of the 338 pilots held First-Class, 107 

Second-Class, and 182 Third-Class airman medical certificates (Fig. 2). The remaining 14 pilots did not hold 

valid medical certificates. Of the 35 First-Class medical 

certificate holders, 27 were involved in general aviation 

accidents, followed by 7 in air taxi and commuter, and 1 

in air carrier accidents. Out of the 107 pilots with SecondClass medical certificates, 85 were involved in general 

aviation, 8 in air taxi and commuter, 8 in agricultural, 2 

in rotorcraft, 1 in ultralight vehicle, 2 in public use, and 

1 in other category accidents. Three of the 182 ThirdClass medical certificate-holding pilots were involved in 

ultralight vehicle accidents, while the remaining in general 

aviation accidents. Thirteen of the 14 non-certificated 

pilots were involved in general aviation accidents and 1 

in other category accident.

Antihistamine-Related Toxicological Findings

The search of the Toxicology Database revealed the 

presence of 8 FGH1AIs—brompheniramine, chlorpheniramine, diphenhydramine, doxylamine, pheniramine, 

phenyltoloxamine, promethazine, and triprolidine—in 

the pilot fatalities during the 16-year period (Fig. 3). 

Fatalities with chlorpheniramine, diphenhydramine, and 

doxylamine were noted every year during 1990–2005. 

The highest number of 191 fatalities was associated with 
5

Part 91

Part 135

Part 121

Part 137

Part 133

Part 103

Public Use

Other

Without Certificate

First-Class

Second-Class

Third-Class

179

3

85

8

8

2 1 2 1

27

7

1

13

1

0

20

40

60

80

100

120

140

160

180

Antihistamine-Associated Pilot Fatalities

Flight Categories (Title 14 CFR Parts)

Figure 2. Antihistamine-involved pilot fatalities with respect to airman medical certificates and 

flight categories (Title 14 CFR Parts) of the aircraft associated with the fatal accidents, 1990–

2005. Flight categories under Title 14 CFR Parts are described in Table I. 

diphenhydramine, followed by 112 with chlorpheniramine, and 50 with doxylamine (Table II). 

As given in Table II, 94 of the 338 pilots had only 1 antihistamine, while 244 had other drug(s) and/or ethanol as 

well. Two antihistaminics—one being diphenhydramine 

and the other being brompheniramine, chlorpheniramine, 

doxylamine, or promethazine—were detected in 9 pilots 

without any other drug or ethanol. However, any 2 of 

the antihistaminics—brompheniramine, chlorpheniramine, diphenhydramine, doxylamine, pheniramine, 

phenyltoloxamine, and promethazine—were found in 

25 pilots with other drug(s) and/or ethanol. In 1 fatality 

(case), 3 antihistaminics—chlorpheniramine, diphenhydramine, and doxylamine—were detected along with 

other drugs. There were 209 fatalities in which only 1 

antihistamine, along with other drugs and/or ethanol, 

was present. Excluding the 8 FGH1AIs (Table II), other 

drugs found in the fatalities entailed amphetamines 

and other sympathomimetics, analgesics (narcotic and 

non-narcotic), antidepressants, atropine, barbiturates, 

benzodiazepines, cardiovascular agents, cocaine, lidocaine, 

and tetrahydrocannabinol carboxylic acid. Carboxyhemoglobin (>10%) and/or blood cyanide (> 0.25 μg·mL−1) 

were determined to be elevated in 14 pilot fatalities. Fire 

was reported in 12 of these 14 accidents.

The percentages of the antihistamine-involved pilot 

fatalities with respect to the total number of pilot fatalities 

(cases), during the 16-year period, from which samples 

were received at CAMI, clearly suggested a steady increase 

in the number of fatalities with these medications (Fig. 4). 

For example, the antihistamine-associated fatalities/aviation accidents were approximately 4 and 11% in 1990 and 

2004, respectively. The difference in the proportions of 

the FGH1AI-involved fatal accidents/pilot fatalities in the 

total fatal accidents/pilot fatalities per year was statistically 

significant (Chi-square = 57.22; df = 15; p < 0.001). 
6

2 3

6 9

5 6

5

15

6

10

5

7

5 6 5

9

6 7

6

7

5 4

7

10

12

15

10

10

12

14

27

21

19

12

5

2

4

3

5

3

3

3

9

5

3

1 1 1 1 1 1 1 1

1

1

1

1

1

1

1

1

1

1

1

1

1

0

5

10

15

20

25

30

35

40

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Years

Antihistamine-Involved Pilot Fatalities

Brompheniramine Chlorpheniramine Diphenhydramine Doxylamine 

Pheniramine Phenyltoloxamine Promethazine Triprolidine

Figure 3. First-generation antihistamine-associated pilot fatalities (cases) of civil aviation 

accidents, 1990–2005.
7

Table II. First-Generation Antihistamines Found in the 338 Pilot Fatalities (Civil Aviation 

Accidents, 1990–2005) 

Pilot Fatalities 

Antihistamines 

With Only 1 Antihistamine Also With Other 

Substance(s)*

Brompheniramine 2 11 

Chlorpheniramine 26 86 

Diphenhydramine 60 131 

Doxylamine 6 44 

Pheniramine 0 1 

Phenyltoloxamine 0 2 

Promethazine 0 2 

Triprolidine 0 3 

Total 94 280†

*

Includes other antihistamines, drugs, and/or ethanol. 

†

34 fatalities (cases) had 2 antihistaminics; 1 had 3 antihistaminics.

0

2

4

6

8

10

12

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Years

Antihistamine-Involved Fatal Accidents/Pilot Fatalities (%) 

Figure 4. The percentage of the antihistamine-involved fatal accidents/pilot fatalities in the total pilot fatality-involved accidents/pilot 

fatalities per year from which samples were received at CAMI for toxicological evaluation. There is a statistically significant difference in 

percentages with respect to years (Chi-square = 57.22; df = 15; p < 0.001). 

Figure 4. The percentage of the antihistamine-involved fatal accidents/pilot fatalities in the total pilot fatalityinvolved accidents/pilot fatalities per year from which samples were received at CAMI for toxicological 

evaluation. There is a statistically significant difference in percentages with respect to years (Chi-square = 

57.22; df = 15; p < 0.001).
8

Diphenhydramine: Of the 191 diphenhydramine-associated pilots (cases), only diphenhydramine was detected 

in 60 cases (Table II). Blood was not available in 22 of 

the 60 cases. The blood concentration range of diphenhydramine was 14−3800 ng·mL−1 (n = 38; Table III). 

In the remaining 131 cases, other drugs and/or ethanol 

were also detected. Blood was not available in 44 of the 

131 cases. The blood diphenhydramine concentration 

in those cases wherein other drugs and/or ethanol were 

present ranged from 9 to 806 ng·mL−1 (n = 87). Ethanol 

was found in 23 cases. 

Chlorpheniramine: Out of the 112 pilots (cases) 

wherein chlorpheniramine was detected, only chlorpheniramine was found in 26 cases (Table II). Blood was 

not available in 12 of these cases. The chlorpheniramine 

concentration in blood was 7−151 ng·mL−1 (n = 14; 

Table III). In the remaining 86 cases, other drugs and/or 

ethanol were also found. Blood was not available in 33 

of the 86 cases. The blood chlorpheniramine concentration in those cases wherein other drugs and/or ethanol 

were present ranged from 4 to 6114 ng·mL−1 (n = 53). 

Ethanol was found in 18 cases.

Doxylamine: This drug was found in 50 pilot fatalities 

(cases). In 6 of these cases, only doxylamine was detected 

(Table II). Blood was not available in 3 of the 6 cases. The 

blood concentration range of doxylamine was 64−300 

ng·mL−1 (n = 3; Table III). In the remaining 44 cases, 

other drugs and/or ethanol were also present. Blood 

was not available in 14 of the 44 cases. The doxylamine 

concentration in blood of those cases wherein other drugs 

and/or ethanol were present ranged from 10 to 1309 

ng·mL−1 (n = 30). Ethanol was found in 6 cases. 

Brompheniramine: This antihistamine was found in 

13 pilots (cases). In 2 of the cases, only brompheniramine 

was detected (Table II). Blood was available in only 1 

case, and the blood concentration of brompheniramine 

was determined to be 200 ng·mL−1 (Table III). In the 

remaining 11 cases, other drugs and/or ethanol were 

also found. Blood was not available in 4 of the 11 cases. 

The blood brompheniramine concentration in those 

cases wherein other drugs and/or ethanol were present 

ranged from 5 to 100 ng·mL−1 (n = 7). Ethanol was 

found in 1 case. 

Triprolidine: Only 3 pilot fatalities (cases) were associated with this drug (Table II). Other drugs—butalbital, 

diazepam, ephedrine, paroxetine, phenylpropanolamine, 

pseudoephedrine, quinine, and/or tetrahydrocannabinol 

carboxylic acid—were also present in the fatalities. Blood 

was not available for the analysis in these cases.

Phenyltoloxamine: There were only 2 pilot fatalities 

(cases) associated with this antihistamine (Table II). 

Chlorpheniramine, ephedrine, phenylpropanolamine, 

and pseudoephedrine were also detected in one case and 

pheniramine and phenylpropanolamine in the other. 

Blood was available in 1 case; the concentration of the 

drug was 4 ng·mL−1 (Table III).

Table III. Blood Antihistamine Concentrations Found in Civil Aviation Accident Pilot 

Fatalities

Blood Concentration (ng·mLí1

)

Antihistamines Without Other Substance With Other Substance(s)*

Brompheniramine 200 (n = 1) 5 – 100 (n = 7) 

Chlorpheniramine 7 – 151 (n = 14) 4 – 6114 (n = 53) 

Diphenhydramine 14 – 3800 (n = 38) 9 – 806 (n = 87) 

Doxylamine 64 – 300 (n = 3) 10 – 1309 (n = 30) 

Pheniramine – – 

Phenyltoloxamine – 4 (n = 1) 

Promethazine – – 

Triprolidine – – 

*

Includes other antihistamines, drugs, and/or ethanol. 
9

Promethazine: As given in Table II, this drug was 

found in 2 pilot fatalities (cases). Ethanol was detected 

in both cases and pseudoephedrine in 1. Blood was not 

available in either case.

Pheniramine: This antihistamine was found in just 

1 fatality (Table II). Phenylpropanolamine and phenyltoloxamine were also detected. Blood was not available 

for analysis.

Antihistamine Use as Aviation Accident Cause/Factor

Based on the information available in the NTSB 

Database through September 2006, the use of the 

antihistamine(s) by pilots was determined to be the 

probable cause or a contributing factor in 63 of the 338 

accidents (Fig. 5). The reports of 330 accidents have been 

finalized, but 8 have not yet been completed. There were 

13 accidents in which the use of antihistamine(s) was 

determined to be the cause of the accidents. In 1 pilot 

fatality, only 1 antihistamine was found. However, other 

drugs and/or ethanol were also present in 12 fatalities. Of 

these, 5 had 2 antihistamines and 1 had 3 antihistamines. 

In 50 accidents, the use of antihistamine(s) was determined to be a contributing factor. This group of accidents 

entailed 7 fatalities in which only 1 antihistamine was 

found. Other drugs and/or ethanol (other substances) 

were also present in the remaining 43 fatalities. Five of 

the 43 cases had 2 antihistaminics.

Diphenhydramine: Of the 191 diphenhydramineinvolved accidents, the use of this medication was determined by the NTSB to be the cause in 8 accidents, of 

which 1 pilot had only diphenhydramine, while 7 also 

had other drug(s). Additionally, the use of this antihistamine was determined to be a contributing factor in 26 

accidents, of which 3 pilots had only diphenhydramine, 

while 23 also had other drug(s) and/or ethanol (Fig. 5). 

Of the 34 (8 + 26) accidents, 31 were in general aviation, 

1 agricultural, 1 ultralight vehicle, and 1 public use categories. The cause/factor of 1 accident was undetermined, 

and the final reports of 3 accidents were unavailable in 

the NTSB database. The use of this antihistamine was 

not reported by the NTSB to be the cause or a factor in 

153 of the 191 accidents.

Figure 5. Fatal aviation accidents wherein the use of antihistamine(s) was determined by the NTSB to be the 

probable cause or a contributing factor. These accidents included the presence of first-generation 

antihistaminic(s), with or without other drugs and/or ethanol (other substances), in the associated pilot fatalities. 

Under the "Cause" group, 5 fatalities had 2 antihistamines and 1 fatality had 3; 5 fatalities had 2 antihistamines 

under the "Factor" group. 

4 4

15

3

23

5

1

9

7

3

1

0

5

10

15

20

25

30

Only With Other

Substances

Only With Other

Substances

Only With Other

Substances

Only With Other

Substances

Only With Other

Substances

Brompheniramine Chlorpheniramine Diphenhydramine Doxylamine Triprolidine

Antihistamine-Associated Aviation Accidents

Factor Cause
10

Chlorpheniramine: Of the 112 chlorpheniramineassociated accidents, the use of chlorpheniramine was 

established by the NTSB to be the cause of 9 accidents. 

Other drugs and/or ethanol were also found in the 9 

accident pilot fatalities. The use of chlorpheniramine 

was reported to be a contributing factor in 19 accidents, 

of which 4 pilots had only chlorpheniramine, while the 

remaining also had other drug(s) and/or ethanol (Fig. 5). 

Of the 28 (9 + 19) accidents, 26 were in general aviation, 

1 air taxi and commuter, and 1 agricultural categories. 

The cause/factor of 1 accident was not determined, and 

the final reports of 5 accidents were not available in the 

NTSB database. Chlorpheniramine use was not reported 

by the NTSB to be the cause or a factor in 78 of the 112 

accidents.

Doxylamine: Of the 50 doxylamine-involved cases, the 

use of this antihistamine was found by the NTSB to be the 

cause in 3 accidents and a contributing factor in 5. With 

all of the 8 (5 + 3) fatalities, other drug(s) and/or ethanol 

were also found (Fig. 5). Of these accidents, 7 were of 

general aviation and 1 air taxi and commuter categories. 

The cause/factor of 1 accident was undetermined. The 

use of doxylamine was not reported by the NTSB to be 

the cause or a factor in 41 of the 50 accidents.

Brompheniramine: The use of this drug was established 

by the NTSB to be a contributing factor in 4 of the 13 

brompheniramine-involved accidents. Other drugs were 

also found in the 4 aviation accident fatalities (Fig. 5). 

These 4 accidents were of general aviation category. The 

brompheniramine use was not reported by the NTSB to 

be the cause or a factor in 9 of the 13 accidents.

Triprolidine: The NTSB determined the use of 

medications to be a contributing factor in 1 of the total 

3 accidents related to this antihistamine. The use of this 

drug was not found to be the cause or a factor in the 

remaining 2 accidents.

Phenyltoloxamine: The drug use was not established 

to be the cause or a factor by the NTSB for the total 2 

accidents associated with this antihistamine.

Promethazine: In the total 2 accident pilot fatalities 

wherein this antihistamine was found, the use of the 

drug was not established to be the cause or a factor by 

the NTSB.

Pheniramine: There was only 1 accident involving 

pheniramine. The use of this FGH1AI was not determined by the NTSB to be the cause or a factor in the 

accident.

DISCUSSION

The physical and mental wellbeing of airmen plays 

a crucial role in the safe and successful operation of an 

aircraft, and this activity requires the integration of higher 

cognitive skills. Pilots are not only cautioned for the 

medical conditions that might interfere with flight safety, 

but also against the potential impact of some drugs, even 

when pilots feel better by taking them (13,23). Among 

these drugs, the most important are the ones that alter 

CNS functions. Although FGH1AIs are not CNS-specific 

drugs, as such, they have major side effects on the CNS 

(24,27). Because of this very reason, the package labeling 

of these medications contains precautionary statements, 

warning users against activities involving motor skills, 

such as operating a vehicle or machinery. However, patients—including aviators—do not appear to take these 

warnings seriously. The annual societal cost of FGH1AIassociated sedation, leading to impairment and accidents, 

has been estimated as $US11.3 billion versus the total 

societal benefit of treatment being $US7.7 billion (26), 

though these estimates are based on assumptions and, 

therefore, are subject to uncertainty. 

FGH1AIs are frequently used to treat seasonal allergic 

rhinitis and the common cold, and these conditions can 

be extremely debilitating and may significantly impair 

the quality of life. Besides the side effects of FGH1AIs, 

the allergic rhinitis itself is associated with sedation 

(15). These pathophysiological conditions can present a 

serious safety concern, making it necessary for pilots to 

receive medical treatment. Although some FGH1AIs—for 

example, diphenhydramine and promethazine—are also 

useful in the treatment of motion sickness (24), their use 

should be limited to passengers.

Several studies have compared the effects of FGH1AIs 

with second-generation H1 antagonists and found that 

some of the second-generation antihistaminics are free 

of sedation or cognitive impairment (6,16–18,28). Some 

of these drugs—fexofenadine, loratadine, and desloratadine—are approved by aeromedical authorities (13,23), 

but it is obvious from the present study that some pilots 

continue to take sedating first-generation antihistaminics 

while performing aviation duties. This practice may be 

partly because these pilots do not feel any sedation and, 

thus, consider that the drug is safe. However, one should 

be cautioned that there are 2 aspects of sedation—(i) 

sleepiness and lethargy and (ii) impairment of superior 

cognitive functions (15). Therefore, pilots may not even 

be aware of the serious effects of these drugs on their 

performance.
11

Postmortem aviation toxicological findings in the 

present study demonstrated that, during the 16-year 

period, approximately 6.4% of all pilots (5281) have had 

FGH1AIs in their system. The number of FGH1AI-associated pilot fatalities was higher in the general aviation 

category than in any other operation categories, which 

is consistent with the observations reported earlier 

(1,7,25). Of the 338 antihistamine-associated pilot 

fatalities, 69.5% of pilots also had other drug(s) and/or 

ethanol in their system. Some of the drugs—atropine, 

lidocaine, and analgesics—found in the pilots 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—for example, antidepressants, cardiovascular 

agents, sympathomimetics, and even abused drugs—and 

ethanol were very likely present in the system of the pilots 

prior to the accidents. The presence of CNS-affecting 

substances, along with FGH1AIs, suggests concurrent 

use of these substances, thereby additively impairing 

motor skills (24,27). 

Therapeutic blood and/or plasma (serum) concentration ranges of brompheniramine, chlorpheniramine, 

diphenhydramine, doxylamine, pheniramine, promethazine, and triprolidine are reported to be 5–17, 8–40, 

8–112, 69–138, 10–89, 2–99, and 4–85 ng·mL−1, 

respectively (4,14). The relationship between the plasma 

(serum) and the whole blood concentrations of all of the 

8 antihistaminics is not known, and the plasma (serum) 

to blood concentration ratio of an antihistamine may not 

necessarily be equivalent to 1. For example, the plasma 

to blood concentration ratios of chlorpheniramine, diphenhydramine, and promethazine are reported to be 

0.83, 1.3, and 1.5, respectively (14). Also, depending 

upon the postmortem interval, there is the potential for 

postmortem redistribution of the antihistamines (2,21), 

thereby altering their blood concentrations after the fatal 

accident. The presence of other drugs and/or ethanol 

in the fatalities may further affect the distribution of 

antihistamines; thus, their blood concentrations may be 

different in relation to situations when an individual is 

exposed to only 1 antihistamine. Therefore, the blood 

antihistamine concentrations found in the present study 

may not truly represent their antemortem plasma (serum) 

levels. Toxic and lethal concentrations of FGH1AIs in 

whole blood are not clearly established based on the 

postmortem forensic toxicology of death investigation 

cases, though the lowest blood concentrations determined to have resulted in death were 200 ng·mL−1 for 

brompheniramine; 500 ng·mL−1 for chlorpheniramine; 

5000 ng·mL−1 for diphenhydramine; 700 ng·mL−1 for 

doxylamine; 1900 ng·mL−1 for pheniramine; and 2400 

ng·mL−1 for promethazine (4,14)

Although the NTSB has determined the use of 

FGH1AIs as the probable cause or a contributing factor in at least 18.6% of the 338 antihistamine-related 

accidents, the final reports of 2.4% of the accidents 

are not yet available in the public domain database. As 

those reports are finalized, the number of accidents may 

increase wherein the use of an FGH1AI by pilots was the 

probable cause or a contributing factor. In 8 accidents 

wherein FGH1AIs were involved, the use of ethanol or 

other CNS depressants by pilots was mentioned by the 

NTSB as the cause or a factor. However, since antihistamines were also present in these fatalities, the potential 

interactive effects of these substances (CNS depressants 

and antihistamines) on impairing cognitive functions 

cannot be ruled out. Additionally, even if drugs were not 

determined as the cause or a factor in an accident, they 

still had subtle effects on cognitive functions. For example, 

in a fatality where tetrahydrocannabinol carboxylic acid 

and chlorpheniramine were found to be present, the 

NTSB determined the probable cause of this accident as 

“The pilot’s failure to maintain clearance from electrical 

power lines.”

Ideally, considering the prohibition for the use of the 

antihistaminics by civilian aviators, a sedating antihistamine should not have been found in any pilot fatality. 

The antihistamine-involved pilots were identified only 

because they were victims of fatal accidents and their 

postmortem samples were toxicologically evaluated. 

Even though contributing roles of other factors—for 

example, weather conditions, mechanical deficiencies, 

and/or piloting errors—cannot be completely ruled out 

in the 338 accidents, this number is of concern to aviation safety, particularly when there is an overall increasing trend in the prevalence of FGH1

AI-associated fatal 

aviation accidents.
12

CONCLUSION

Although sedating antihistamines are prohibited and 

there are alternative drugs available that are safe to use 

during aviation duties, there is an increasing trend in 

the use of FGH1AIs by civilian pilots. To prevent this 

problem from becoming more serious in the future, more 

emphasis should be given to controlling the use of the 

antihistaminics by civil aviators. It would be beneficial 

to educate and alert aviators during their flight training 

and medical examinations, with real-life examples of the 

adverse effects of antihistamines and associated unwanted 

serious outcomes.

REFERENCES

1. Akin A, Chaturvedi AK. Selective serotonin reuptake inhibitors in pilot fatalities of civil aviation 

accidents, 1990–2001. Aviat Space Environ Med 

2003; 74:1169–76.

2. Anderson WH, Prouty RW. Postmortem redistribution of drugs. In: Baselt RC, ed. Advances in 

analytical toxicology, Vol. II. Chicago, IL: Year 

Book Medical Publishers, Inc.; 1989:70–102.

3. Aviation Safety Research Act of 1988, Public Law 

100–591 [H.R. 4686]. 100th U.S. Cong., 2nd 

Sess. 102 Stat. 3011 (Nov 3, 1988). 

4. Baselt RC. Disposition of toxic drugs and chemicals in man. 6th ed. Foster City, CA: Biomedical 

Publications, 2002.

5. Blackmore DJ. Aircraft accident toxicology: 

U.K. experience 1967–1972. Aerosp Med 1974; 

45:987–94.

6. Bower EA, Moore JL, Moss M, et al. The effects 

of single-dose fexofenadine, diphenhydramine, and 

placebo on cognitive performance in flight personnel. Aviat Space Environ Med 2003; 74:145–52.

7. Chaturvedi AK, Craft KJ, Canfield DV, Whinnery 

JE. Toxicological findings from 1587 civil aviation 

accident pilot fatalities, 1999–2003. Aviat Space 

Environ Med 2005; 76:1145–50.

8. Chaturvedi AK, Smith DR, Soper JW, et al. Characteristics and toxicological processing of postmortem 

pilot specimens from fatal civil aviation accidents. 

Aviat Space Environ Med 2003; 74:252–9.

9. Cimbura G, Lucas DM, Bennett RC, et al. Incidence and toxicological aspects of drugs detected 

in 484 fatally injured drivers and pedestrians in 

Ontario. J Forensic Sci 1982; 27:855–67.

10. Code of Federal Regulations. Title 14—Aeronautics 

and space, Chapter I (1-1-06 Edition)—Federal 

Aviation Administration, Department of Transportation, Subchapter D—Airmen, Part 67—Medical 

standards and certification. Washington, DC: U.S. 

Government Printing Office, 2006.

11. Code of Federal Regulations. Title 14—Aeronautics 

and space, Chapter I (1-1-06 Edition)—Federal 

Aviation Administration, Department of Transportation, Subchapter F—Air traffic and general 

operating rules and Subchapter G—Air carriers and 

operators for compensation or hire: certification and 

operations. Washington, DC: U.S. Government 

Printing Office, 2006.

12. Gilliland K, Schlegel RE, Nesthus TE. Workshift 

and antihistamine effects on task performance. 

Washington, DC: Federal Aviation Administration, 

Office of Aviation Medicine; Dec. 1997 Report No: 

DOT/FAA/AM-97/25.

13. Guide for aviation medical examiners. Washington, 

DC: Federal Aviation Administration, Office of 

Aerospace Medicine. Retrieved July 5, 2006, from 

the World Wide Web: http://www.faa.gov/about/

office_org/headquarters_offices/avs/offices/aam/

ame/guide

14. Moffat AC, Osselton MD, Widdop B, eds. Clarke’s 

analysis of drugs and poisons. 3rd ed. Vol. 2. London: Pharmaceutical Press; 2004.

15. Mohler SR, Nicholson A, Harvey P, et al. The use 

of antihistamines in safety-critical jobs: a meeting 

report. Curr Med Res Opin 2002; 18:332–7.

16. Nicholson AN, Stone BM, Turner C, Mills SL. 

Antihistamines and aircrew: usefulness of fexofenadine. Aviat Space Environ Med 2000; 71:2–6.

17. Nicholson AN, Turner C. Central effects of the 

H1-antihistamine, cetirizine. Aviat Space Environ 

Med 1998; 69:166–71.

18. Nicholson AN. Central effects of H1

 and H2

antihistamines. Aviat Space Environ Med 1985; 

56:293–8.

19. PDR® for nonprescription drugs, dietary supplements, and herbs. The definitive guide to OTC 

medications. 27th ed. Montvale, NJ: Thomson 

PDR, 2006.

20. Physicians’ desk reference. 60th ed. Montvale, NJ: 

Thomson PDR, 2006.
13

21. Pounder DJ, Jones GR. Post-mortem drug redistribution — a toxicological nightmare. Forensic Sci 

Int 1990; 45:253–63.

22. Rice VJ, Snyder HL. The effects of Benadryl® 

and Hismanal® on psychomotor performance and 

perceived performance. Aviat Space Environ Med 

1993; 64:726–34.

23. Silberman WS. Medications in civil aviation: what 

is acceptable and what is not? Aviat Space Environ 

Med 2003; 74:85–6.

24. Skidgel RA, Erdös EG. Histamine, bradykinin, and 

their antagonists. In: Brunton LL, Lazo JS, Parker 

KL, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 11th ed. New York, NY: 

McGraw-Hill, 2006; 629–51.

25. Soper JW, Chaturvedi AK, Canfield DV. Prevalence 

of chlorpheniramine in aviation accident pilot 

fatalities, 1991–1996. Aviat Space Environ Med 

2000; 71:1206–9.

26. Sullivan PW, Follin SL, Nichol MB. Cost-benefit 

analysis of first-generation antihistamines in the 

treatment of allergic rhinitis. Pharmacoeconomics 

2004; 22:929–42.

27. Sweetman SC, ed. Martindale: the complete drug 

reference. 34th ed. London: Pharmaceutical Press, 

2005. 

28. Valk PJL, Van Roon DB, Simons RM, Rikken G. 

Desloratadine shows no effect on performance during 6 h at 8,000 ft simulated cabin altitude. Aviat 

Space Environ Med 2004; 75:433–8.

29. Weiler JM, Bloomfield JR, Woodworth GG, et 

al. Effects of fexofenadine, diphenhydramine, and 

alcohol on driving performance. A randomized, 

placebo-controlled trial in the Iowa driving simulator. Ann Intern Med 2000; 132:354−63.