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Sex Transm Dis. Author manuscript; available in PMC 2024 November 01.
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Published in final edited form as:

Sex Transm Dis. 2023 November 01; 50(11): 701–712. doi:10.1097/OLQ.0000000000001865.

Safety of longer-term doxycycline use: A systematic review

and meta-analysis with implications for bacterial STI
chemoprophylaxis
Philip A. Chan, MD, MS1,2, Danielle L. Le Brazidec, MPH1, Jeffrey S. Becasen, MPH3,
Harrison Martin, BA1, Jhanavi Kapadia, BS1, Hilary Reno, MD2,4, Laura Bachmann, MD,
MPH2, Lindley A. Barbee, MD, MPH2
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1Department of Medicine, Brown University, Providence, Rhode Island, USA

2Divisionof STD Prevention, National Center for HIV, Viral Hepatitis, STD and TB Prevention,
Centers for Disease Control and Prevention, Atlanta, Georgia, USA
3Divisionof HIV Prevention, National Center for HIV, Viral Hepatitis, STD and TB Prevention,
Centers for Disease Control and Prevention, Atlanta, Georgia, USA
4Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA

Abstract
Background: Sexually transmitted infections (STIs) such as syphilis, gonorrhea, and chlamydia
have significantly increased over the past decade in the United States. Doxycycline as
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chemoprophylaxis (i.e., post-exposure prophylaxis [PEP]) offers promise for addressing bacterial
STIs. The goal of the current study was to evaluate the safety of longer-term doxycycline use
(defined as eight or more weeks) in the context of potential use as STI chemoprophylaxis through
a systematic literature review and meta-analysis.

Methods: This review used the Preferred Reporting Items for Systematic Reviews and Meta-
Analyses (PRISMA) guidelines to search MEDLINE/PubMed for clinical studies published from
August 2003 through January 2023 that reported on adverse events with doxycycline use with a
focus on side-effects and metabolic effects of long-term use.

Results: A total of 67 studies were included in the systematic review. Overall, studies on
longer-term doxycycline use reported 0% to over 50% adverse events ranging from mild to
severe. Most common adverse events included gastrointestinal symptoms (i.e., nausea, vomiting,
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and abdominal pain), dermatologic (i.e., rash), and neurological (i.e., headache and dizziness)
symptoms. Discontinuation of doxycycline due to adverse events was relatively uncommon in
most studies. A meta-analysis of placebo controlled clinical trials (N=18) revealed gastrointestinal
and dermatological adverse events were more likely to occur in the doxycycline group.

Correspondence: Philip A. Chan, MD, Department of Medicine, Brown University, Providence, RI 02912. Phone: (401) 793-4859;
[email protected].
Disclaimer: The findings and conclusions in this manuscript are those of the authors and do not necessarily represent the official
position of the Centers for Disease Control and Prevention.
 Chan et al. Page 2

Conclusion: Longer-term (8+ weeks) doxycycline use is generally safe and may be associated
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with minor side-effects. Further research is needed on the potential metabolic impact of longer-
term doxycycline use.
Short Summary:
A systematic review of longer-term doxycycline (8+ weeks) found the medication was generally
well-tolerated and safe. Findings have implications for doxycycline as chemoprophylaxis for the
prevention of sexually transmitted infections.

INTRODUCTION
Bacterial sexually transmitted infections (STIs) such as syphilis, gonorrhea, and chlamydia
have significantly increased over the past decade in the United States (US) with
approximately 2.5 million reported cases in 2021 (1). Importantly, cases of STIs
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disproportionately impact certain populations including gay, bisexual, and other men who
have sex with men (MSM) and transgender women (TGW), as well as African American/
Black and Hispanic/Latino communities. One potential approach to addressing the
increasing burden of STIs includes chemoprophylaxis with antimicrobials and specifically
doxycycline. Recent studies have evaluated doxycycline as post-exposure prophylaxis
(PEP), taking the medication after a potential STI exposure, and found that this approach
effectively reduces bacterial STIs in MSM and TGW (2–5). This novel approach offers a
potentially powerful tool to address the increasing burden of bacterial STIs in the US.

Doxycycline was initially evaluated as pre-exposure prophylaxis (PrEP) to prevent bacterial

STIs in a pilot study in 2015 which suggested potential benefits in a small cohort (N=30)
of MSM with HIV when taken daily before an exposure occurred (5). Subsequent studies
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have evaluated doxycycline as PEP taken as a single 200mg dose ideally within 24 hours
and up to 72 hours after condomless sex. The IPERGAY study conducted from July 2015
to January 2016 among MSM and TGW receiving HIV PrEP demonstrated efficacy of
doxycycline as PEP in preventing syphilis and chlamydia but not gonorrhea (3). In 2022,
the DoxyPEP study conducted in Seattle and San Francisco demonstrated that doxycycline
as PEP prevented syphilis, gonorrhea and chlamydia in both MSM and TGW with HIV
and those taking HIV PrEP (2). Other recent studies have confirmed that doxycycline is
effective as PEP in preventing bacterial STIs in MSM and TGW (4). A single study found
that doxycycline as PEP was not significant in cis-gender heterosexual women (6), which
has been attributed to low adherence (7). Further studies of cis-gender women and other
populations which also include doxycycline as PrEP for STI prevention are ongoing.

One important consideration for doxycycline as STI chemoprophylaxis is the safety of

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longer-term, intermittent use of the medication. Doxycycline was initially approved by the
US Food and Drug Administration (FDA) in 1967. Doxycycline is generally well absorbed
and tolerated, with a half-life of approximately 12 hours (8,9). The medication has been
extensively used longer-term to treat acne and rosacea (10) and for prophylaxis to prevent
scrub typhus (11), Lyme disease (12), tick-borne relapsing fever (13,14), leptospirosis (15–
18), and malaria (19). Adverse effects most commonly associated with doxycycline hyclate
have included photosensitivity (20) and esophageal erosion and ulceration (21). Adverse

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effects generally resolve with discontinuation of the medication. However, despite the broad
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use of doxycycline, limited data is available on the longer-term safety of the medication.

A prior systematic review on the safety of doxycycline was published by Smith and Leyden,
and reviewed data from 1966 to 2003 (22). The overall findings of this review included
24 clinical trials of doxycycline with a “very low” incidence of adverse events in general.
Gastrointestinal adverse events were the most common side-effects reported. This review did
not specifically focus on longer-term use and included a total of three studies with 20 days
or longer use.

The goal of the current study was to evaluate the safety of longer-term doxycycline use
(defined as eight or more weeks) in the context of potential use as STI chemoprophylaxis
through a systematic literature review and meta-analysis.
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METHODS
We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses
(PRISMA) guidelines (23) to search MEDLINE/PubMed for clinical studies that reported
on adverse events with doxycycline use with a focus on side-effects and metabolic effects
of long-term use. The following search terms were used: “doxycycline” AND (“adverse
reaction” OR “adverse event” OR “side effect”). The review was conducted for studies that
were published from August 2003 through January 2023. We also included studies from a
prior systematic review conducted for studies published from 1966 to August 2003 (22).
Inclusion criteria for our initial screening included any retrospective or prospective clinical
study with an average duration of two months (eight weeks) or more on doxycycline. Eight
weeks or more was chosen given that people on doxycycline chemoprophylaxis would likely
be taking the medication for months. There were no restrictions in regards to country;
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publication language; date; or patient age, race, gender, or sexuality. Exclusion criteria
included: non-human subjects or in-vitro studies, unrelated papers, duplicates, unavailable
full texts, abstract-only publications, and case reports. Papers that reported on doxycycline
use in combination with other oral medications were generally excluded since it was difficult
to identify the side effects from doxycycline alone. However, studies with multiple oral
medications including doxycycline that evaluated metabolic effects were included given the
overall paucity of data on this topic. After our initial screening, we also reviewed other
review articles from the initial search to identify additional studies to include.

Each included article was manually reviewed for information about the study period, study
type, and study population. We also collected information about the formulation, dose, and
duration of doxycycline in each study. Articles were also reviewed for information about
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doxycycline adverse events, including severity of events (mild, moderate, severe) and type of
clinical event (neurological, gastrointestinal, dermatological/skin, other). Severity of events
was classified according to the definitions used by the study which reported the event.
There was some variation, but in general, mild or moderate adverse events referred to those
causing minimal or some interference with daily activities. Severe adverse events were those
causing an inability to perform daily activities or those that were potentially life-threatening
or resulted in hospitalization. For the clinical event type, we broadly included any specific

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symptom of the clinic event type in the overarching group. For example, one study may have
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reported only nausea or diarrhea, and another included abdominal pain. All these various
symptoms would be included under the gastrointestinal event type.

For the meta-analysis, we limited the included studies to only those reporting generally
healthy individuals and reported adverse events for participants in both the doxycycline
treatment arm and placebo groups. All statistical analyses and calculations of effect sizes
were conducted in R using the Metafor statistical package (24). We calculated relative risk
estimates and corresponding 95% confidence intervals (CIs) using a random-effects model
to assess the rate of adverse events between the treatment group receiving doxycycline and
a comparison group receiving placebo. We repeated all analyses using only studies that
provided 100–200 mg dosages of doxycycline per day to reflect the dosage of doxycycline
used as PEP to prevent STIs. Relative risk estimates were only calculated when three or
more studies reported data for the outcome. Heterogeneity was assessed with the Q-test
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statistic and I2 values, which describe the percentage of variation across studies that is
attributable to heterogeneity rather than chance (25).

RESULTS
Systematic Review Results
We identified a total of N=828 total articles (Figure 1). After review, N=678 were excluded
due to being unrelated and/or not clinical studies. The remaining 150 articles were manually
assessed for eligibility. We excluded a total of 103 of these articles for the following reasons:
doxycycline used for less than 8 weeks (n=61), non-clinical trial (n=17), doxycycline used
in combination with other drugs (n=12), case report/case series (n=7), protocol description
(n=3), non-oral doxycycline formulation used (n=1), commentary (n=1), and full text not
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available (n=1). The remaining 47 studies were included after this initial screening. We also
manually reviewed an additional 28 review articles to determine if there were any relevant
studies missed in our initial screening. This review led to 20 studies being identified and
added to the initial screening, for a total of 67 studies included in our systematic review
(Table 1). The 67 articles included in the review were published from 1987 to 2022. The
most common studies include those focused on rosacea treatment (N=14), acne treatment
(N=13), and malaria prophylaxis (N=11). One study specifically looked at doxycycline
for STI PEP. Populations included those 9 years of age and older. Most studies were
performed in the United States (N=21). Doxycycline doses ranged from 20mg to 200mg a
day depending on the study. Time on doxycycline ranged from eight weeks (minimum study
inclusion) to over three years. The total number of people in these studies who reported
being on doxycycline was N=10,106 (Range: 7–1,196). Twenty-two studies report at least
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mild or moderate side-effects or adverse events related to doxycycline use ranging from
0% to 88%. Severe side-effects or adverse events in people on doxycycline ranged from
0% to 14% per study. These results should be interpreted in the setting of the specific
study and patient population. For example, the study reporting 14% severe side-effects
or adverse events was in the setting of doxycycline use in people with osteoarthritis and
therefore potentially significant comorbidities (26). Although 14% of people reported severe
side-effects or adverse events in the doxycycline group, the authors did mention that these

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events were unlikely caused by doxycycline. Many studies that reported severe adverse
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events in individuals on doxycycline did not attribute the events to the medication (3,26–
31). In the studies that did report severe adverse events for individuals on doxycycline,
these included allergic reactions (27,30,32), dermatologic and skin reactions (33–35),
gastrointestinal (32,34,35), and neurological (34–37).

In terms of specific side-effects and adverse events, studies varied on how they reported the
data (i.e., number of individuals with an adverse event versus the total number of adverse
events). Studies reporting neurological effects (i.e., headache and dizziness) ranged from 0%
to 30+% of individuals. The study with the highest reported neurological side effects per
individual (i.e., 33%) evaluated individuals taking doxycycline as malaria prophylaxis and
included side-effects of headaches, dizziness, dreams, somnolence, insomnia, palpitations,
and sexual dysfunction (38). In this study, the severity of adverse events was not
reported, but no individuals stopped the medication due to an adverse event. Reports of
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gastrointestinal side effects and adverse events (i.e., nausea, vomiting, and abdominal pain)
ranged from 0% to 50+%. The majority of gastrointestinal side-effects were noted to be
minor. No studies specifically looked at Clostridium difficile infection. In the study with
the highest reported gastrointestinal side effects per individual (i.e., 53%), individuals were
taking doxycycline to minimize endometrial bleeding and reported high rates of nausea,
vomiting and diarrhea (39). However, this was a smaller study (N=32 individuals) and no
severe adverse events were reported. Dermatologic and skin reactions (i.e., rashes) ranged
from 0% to 38% per individual and varied in terms of severity and symptoms. The study
with the highest reported dermatologic side effects (i.e., 38%) was small (N=32 individuals)
and reported acne as the major symptom with no reports of severe adverse events (39). A
number of studies also reported other side effects such as vaginal candidiasis which was
reported in a small number of individuals (28,30,39–43).
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A total of eight studies mentioned evaluating at least one metabolic effect of doxycycline
(i.e., weight, diabetes, cholesterol, and/or blood pressure) (26,28,31,44–48). No studies
comprehensively evaluated doxycycline on metabolism. Findings ranged from no changes in
weight and blood pressure (31,45,46) to significant weight gain (23%) (44) and/or elevated
blood pressure (26,28,48) and hypercholesterolemia (47). These studies were descriptive in
nature with limited sample sizes and lack of control groups.

In addition, few (N=6) studies focused on the effect of doxycycline on the microbiome
(i.e., oral, respiratory, gut) ranging from no changes to significant impacts. These included
three studies of the effect of doxycycline on the resistance profile of oral microflora bacteria
(two with no resistance found, and one study with resistance) (36,49,50), two descriptive
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studies evaluating variations of bacterial flora in the gastrointestinal tract (44,51), and one
study which found significant increases in bacterial resistance in the respiratory tract after
doxycycline use (52). However, these studies were largely descriptive in nature and limited
by sample size and lack of control groups.

Meta-analysis Results
From the 67 studies included in the review, we limited the meta-analysis to only placebo-
controlled studies with complete data reported for both arms (N = 18). For each type of

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adverse event, the number of studies included in the analysis varied. For example, eleven
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studies reported neurological adverse events while only nine studies reported dermatological
adverse events (Table 2). There was a significant difference in experiencing gastrointestinal
and dermatological adverse events between the treatment and placebo groups (Table 2).

Participants in the doxycycline treatment group had an increased risk of experiencing

gastrointestinal [RR: 1.68 (95% CI: 1.19, 2.38); p-value < 0.01] and dermatological [RR:
3.55 (95% CI: 1.39, 9.01); p-value = 0.01] adverse events compared to participants in
the placebo control group. Similarly, for studies that reported dosages of 100–200 mg of
doxycycline, participants in the doxycycline group had and increased risk of experiencing
gastrointestinal [RR: 1.78 (95% CI: 1.16, 2.74); p-value = 0.01] and dermatological [RR:
5.52 (95% CI: 1.75, 17.42); p-value < 0.01] adverse events compared to the placebo group
(Figure 2). No significant differences were observed for any, severe, or neurological adverse
events for all included studies and for studies that reported administering doses of 100–200
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mg of doxycycline.

Finally, we observed differences in participants withdrawing from the trial between the
groups. Participants were more likely to withdraw due to adverse events in the doxycycline
group compared to the placebo group for all included studies and among studies that
reported dosages of 100 – 200 mg; RR: 1.62 (95% CI: 1.12, 2.34); p-value = 0.01 and RR:
1.82 (95% CI: 1.06, 3.11); p-value = 0.03, respectively. Observed heterogeneity as measured
by I2 across all analyses was 1–82% with a median of 33%. In analysis of outcomes
where heterogeneity was high (45–82%), one to two studies (outliers) could explain the
between-study variance not from chance alone.

DISCUSSION
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This is the most comprehensive systematic review to date of longer-term doxycycline

use and risk of adverse events. Studies included in the review were diverse in terms of
population and reason for doxycycline use. Evaluation of adverse events was also limited
by lack of standardized reporting methods leading to different definitions and approaches
to analyzing adverse events. Overall, studies on longer-term doxycycline use reported 0%
to over 50% adverse events ranging from mild to severe. Most common adverse events
included gastrointestinal (i.e., nausea, vomiting, and abdominal pain), dermatologic (i.e.,
rash), and neurological (i.e., headache and dizziness) symptoms. However, discontinuation
of doxycycline due to adverse events was relatively uncommon in most studies, though
more likely among those on doxycycline than those taking a placebo. The meta-analysis of
placebo controlled clinical trials revealed an increased risk of individuals on doxycycline
experiencing gastrointestinal or dermatological adverse events compared to placebo. In
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summary, adverse events related to longer-term doxycycline use are commonly reported, but
serious side-effects are rare.

Although common side-effects of doxycycline have been well described, longer-term

doxycycline use could have other effects including on the microbiome and/or metabolism.
No comprehensive evaluation of longer-term doxycycline use has rigorously evaluated
changes in the microbiome or metabolism. Longer-term use (i.e., 24 months) of lower dose

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doxycycline (i.e., doses ranging from 10mg a day to 20mg twice a day) does not seem
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to lead to an effect on the composition of doxycycline resistant species of the intestinal

or vaginal flora (53,54), or increase the risk of C. difficile infection (55). In the current
review, metabolic outcomes were not routinely evaluated. Studies that did include aspects
of metabolism did not rigorously or comprehensively evaluate outcomes. Further research is
needed to identify longer-term impact of doxycycline use on metabolism.

In the context of chemoprophylaxis for bacterial STIs, the current study has several
important implications. First, severe adverse events due to longer-term doxycycline use
are uncommon which is reassuring. Second, further study is needed on other possible
longer-term side-effects including adverse impacts on metabolism. Third, all the reviewed
studies focused on daily doxycycline use. Current bacterial STI chemoprophylaxis studies
have evaluated doxycycline use as PEP which would generally represent intermittent, not
daily use. We would hypothesize that intermittent doxycycline use would lead to fewer
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side-effects in general, although how much less is unclear. Previous studies have and other
studies are currently evaluating daily doxycycline use as PrEP. Doxycycline as PEP for
bacterial STI prophylaxis may be ideal in in terms of balancing risk for adverse events
as well as antimicrobial resistance concerns compared to daily use as PrEP though further
investigation is warranted.

Available studies varied in terms of study population, dosing, comparator drugs, co-
morbidities, and outcomes evaluated. Importantly, the measures used to evaluate adverse
events were not standardized requiring us to reduce the number of studies included in
the meta-analysis. The meta-analysis demonstrated an increased risk of individuals on
doxycycline experiencing gastrointestinal or dermatological adverse events compared to
placebo which is consistent with the systematic review and clinical experience. Lack of
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systematic approaches in evaluating adverse events led to further challenges. In addition,

the current study did not evaluate adverse pregnancy outcomes related to doxycycline use.
Despite these challenges, the current study provides important insights into the safety of
longer-term doxycycline in the context of STI chemoprophylaxis.

In conclusion, a significant number of studies have evaluated longer-term (8+ weeks)

doxycycline use. Mild to moderate side-effects are common including gastrointestinal,
dermatologic and potentially neurological. More serious side-effects are less common but
do occur. There is likely a dose dependent relationship on side-effects. Of note, almost all
studies evaluated daily doxycycline use. It is unknown whether episodic use would lead to
fewer side-effects or adverse events.
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FIGURE 1:
PRISMA Diagram
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FIGURE 2:
Forest plots of (A) gastrointestinal, (B) dermatologic and (C) neurological adverse events
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among those taking 100–200mg of doxycycline daily compared to placebo.

*AE=Adverse Events, CI=Confidence Intervals, RE=Random Effects

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TABLE 1:

Characteristics of studies identified by the systematic literature review that assess longer-term1 doxycycline use and adverse events

First Author Publication Study Population Study Site Drug Duration Doxycycline Mild* (n) Moderate* Severe* Stopped
Chan et al.

Year (Days) (N) (n) (n) (adverse

events)

Akhyani (56) 2008 Rosacea Treatment 27–72 Iran Doxycycline 100mg 91 30 NR NR NR 0

years old once daily

Alexis (57) 2012 Rosacea Treatment 18+ years United Doxycycline 40mg 84 1196 NR NR NR NR
old States once daily (30 mg
immediate release and
10 mg delayed release
beads) once daily

Andersen 1998 Malaria Prophylaxis 18–55 Kenya Doxycycline 100mg 70 55 NR NR NR 1

(58)** years old once daily

Angelakis 2014 Q Fever Endocarditis 18+ years France Doxycycline 100mg 540+ 48 NR NR NR NR
(44) Treatment old twice a day (and
hydroxychloroquine)

Arman (59) 2015 Rosacea Treatment Adults Turkey Doxycycline 100mg 90 19 NR NR NR NR

BID for one month
then once daily for
two months

Babaeinejad 2011 Acne Treatment 13+ years Iran Doxycycline 100mg 90 50 4 0 0 0

(60) old once daily

Baudon (61) 1999 Malaria Prophylaxis Adult Gabon and Doxycycline 100mg 120+ 171 NR NR NR 11
soldiers the Central once daily
African
Republic

Baxter (43) 2002 Abdominal Aortic 54–84 United Doxycycline 100mg 90+ 36 NR NR NR 3
Aneurysm Treatment years old States twice per day
(Multiple
States)

Sex Transm Dis. Author manuscript; available in PMC 2024 November 01.
Berende (27) 2016 Lyme Disease Treatment Adults Netherlands Doxycycline 100mg 84 86 39 (Mild 39 (Mild 3 3
twice a day or or
Moderate) Moderate)

Brandt 2005 Osteoarthritis Treatment 45–64 United Doxycycline 100mg 900 218 NR NR 31 25
(26)** years old States twice a day
(Indiana)

Brill (52) 2015 COPD Treatment 45+ years United Doxycycline 100mg 91 25 2 (Mild or 2 (Mild or 0 0
old Kingdom once daily Moderate) Moderate)

Caton (36)** 2000 Chronic Periodontitis 30–75 United Doxycycline 20mg 274 93 NR NR 1 1
years old States twice a day
(Multiple)
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Del Rosso 2007 Rosacea Treatment 18+ years United Doxycycline 112 269 133 (Mild 133 (Mild 16 19
(28)** old States and monohydrate 40mg or or
Puerto Rico once daily Moderate) Moderate)
(formulation: 30-mg
immediate-release
and 10-mg delayed-
Chan et al.

release beads)

Del Rosso 2022 Acne Treatment 12+ years United Doxycycline 120mg 84 133 3 (Mild or 3 (Mild or 0 0
(62)** old States once daily (with Moderate) Moderate)
(Multiple trifarotene cream)
Sites)

Del Rosso 2022 Rosacea Treatment 18–80 United Doxycycline 40mg 84+ 300 12 (Mild 12 (Mild 0 0
(63)** years old States modified-release or or
(Multiple capsules once daily Moderate) Moderate)
Sites)

Del Rosso 2012 Rosacea Treatment Adults United Doxycycline 84 1196 NR NR NR NR

(64) States modified-release
40mg once daily
(30mg immediate-
release and 10 mg
delayed-release)

Del Rosso 2018 Acne Treatment 12+ years United Doxycycline hyclate 84 175 26 (Mild 26 (Mild 1 4
(33) old States delayed-release or or
100mg twice daily moderate) moderate)

Del Rosso 2008 Rosacea Treatment 18+ years United Doxycycline 100mg 112 91 16 18 6 9
(65) old States daily or 40mg
delayed-release daily
(with topical
metronidazole 1%
gel)

Donta (29)** 2004 Gulf War Illness Treatment Adult United Doxycycline 200mg 365 245 NR NR 12 7
veterans States once daily
(Multiple
sites)

Frenzel (30) 2008 Treatment of Brain Vascular 15–78 United Doxycycline 100mg 730 13 NR NR 1 2
Malformations years old States twice a day

Sex Transm Dis. Author manuscript; available in PMC 2024 November 01.
(California)

Gollnick (48) 2010 Rosacea Treatment 19–91 Germany Doxycycline 100mg 84 143 NR NR NR NR
years old once daily for 14 days
then 50mg once daily

Golub (49) 2001 Chronic periodontitis 18–75 United Doxycycline 20mg 84 75 NR NR NR 3

treatment years old States once or twice daily

Kaneshiro 2012 Prevention of Menstrual 18–45 United Doxycycline 40mg 84 32 NR NR NR 0

(39)** Bleeding years old States once daily
females

Kitchener 2005 Malaria Prophylaxis Adult Australian Doxycycline (Dose 180+ 388 245* 78* 7* 1
(37) soldiers soldiers not reported)
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settled in
East Timor
at risk for
malaria

Kus (66) 2005 Acne Treatment 18–30 Turkey Doxycycline 100mg 90 26 NR NR NR NR

years old BID for one month
Chan et al.

and then once daily

for the next two
months

Layton (20) 1993 Acne Treatment 13–49 United Doxycycline 150 or 183 106 NR NR NR 37
years old Kingdom 200 mg/day

Lee (50)** 2004 Chronic periodontitis Adults South Korea Doxycycline hyclate 274 24 NR NR NR NR
treatment 20mg twice daily

Leijtens (67) 2019 Suppression of Prosthetic 40–88 Netherlands Doxycycline 100– 1157 14 NR NR NR 1
Joint Infection years old 200mg once daily

Leyden 2013 Acne Treatment 12–45 United Doxycycline calcium 84 190 NR NR NR 1

(42)** years old States 40–160mg (weight
based)

Lin (45) 2015 Graves Disease Treatment 18–60 China Doxycycline 50mg 84 16 2 0 0 0
years old once daily

Makunde 2006 Wuchereria Bancrofti 14–68 Tanzania Doxycycline 200mg 60 19 7 0 0 0

(46) Treatment years old once daily

Maleszka 2011 Acne Treatment 14+ years Poland and Doxycycline 100mg 84 120 NR NR NR 0
(68) old Croatia once daily

Molina (3) 2017 STI Prophylaxis Adult France Single dose 261+ 116 102 (Mild 102 (Mild 4 8
Males doxycycline 200mg or or
within 24 hrs after sex Moderate) Moderate)
and no later than 72
hrs

Moore (32)** 2015 Acne Treatment 12–59 United Doxycycline 40– 112 440 NR NR 2 2
years old States 100mg once daily

Naini (69) 2007 Diabetic Proteinuria 49–77 Iran Doxycycline 100mg 61 35 NR NR 0 3

Treatment years old once daily

Sex Transm Dis. Author manuscript; available in PMC 2024 November 01.
Novak (70) 2002 Chronic periodontitis 29–45 United Doxycycline hyclate 183 10 NR NR NR NR
treatment years old States 20mg twice daily

Ohrt (38)** 1997 Malaria Prophylaxis Adult Indonesia Doxycycline 100mg 91 67 NR NR NR 0

soldiers once daily

Pagès (71) 2002 Malaria Prophylaxis Adult French Doxycycline 120 275 NR NR NR 15
soldiers soldiers monohydrate 100mg
deployed in once daily
Gabon and
Chad

Pan (72)** 2022 Thyroid Disease Adults China Doxycycline 50mg 84 50 1 0 0 0

once daily
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Pang (73)** 1998 Malaria Prophylaxis 10–16 Thailand Doxycycline 25– 105 144 NR NR NR 0
years old 100mg daily
depending on weight

Pang (74) 1987 Malaria Prophylaxis 10–15 Thailand Doxycycline 100mg 63 95 NR 0 0 0

years old once daily for
Chan et al.

those over 40kg;

Doxycycline 50mg
once daily for those
less than 40kg

Parish (75) 2005 Acne Treatment 14–36 United Doxycycline hyclate 56 12 NR NR NR NR

years old States 100mg twice a day

Park (76) 2015 Rosacea Treatment 18+ years South Korea Doxycycline 100mg 770 15 NR NR NR 0
old twice a day

Pfeffer (77) 2011 Rosacea Treatment Adults Germany Doxycycline 40mg 60+ 7 0 0 0 0
once daily (slow-
release form)

Pimenta (78) 2011 Lymphangioleiomyomatosis Adult Brazil Doxycycline 100mg 180 41 NR NR NR 0

Treatment Females once daily

Pimenta (79) 2013 Lymphangioleiomyomatosis Adults Brazil Doxycycline 100mg 365 41 NR NR NR 3

Treatment once daily

Popa (51) 2022 Colorectal Cancer Treatment Adults Romania Doxycycline (Dose 56 10 NR NR NR NR
not reported)

Pradier (80) 2017 Suppression of Prosthetic Adults France Doxycycline 200mg 508+ 39 NR NR NR 3
Joint Infection once daily

Pradier (81) 2018 Suppression of Prosthetic 18–91 France Doxycycline 200mg 668 72 NR NR NR 6
Joint Infection years old once daily

Preshaw 2008 Chronic periodontitis 24–81 United Doxycycline 274 133 79 (Mild 79 (Mild 9 7
(31)** treatment years old States monohydrate 40mg or or
once daily (modified Moderate) Moderate)
release)

Putschky (82) 2006 Reactive Arthritis Treatment 18–65 Germany Doxycycline 100mg 122 15 NR NR NR 0
years old twice a day

Sex Transm Dis. Author manuscript; available in PMC 2024 November 01.
Quarterman 1997 Rosacea Treatment 31–66 Georgia Doxycycline 100mg 84 39 NR NR NR NR
(83) years old once daily

Sanchez 2005 Rosacea Treatment 18+ year United Doxycycline hyclate 112 20 NR NR 0 0
(84)** old States and 20mg twice daily
females Puerto Rico for 12 weeks
(with metronidazole
0.75% topical lotion)
followed by 4 weeks
of monotherapy with
doxycycline hyclate
20mg
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Schlagenhauf 2003 Malaria Prophylaxis 18–70 Travel Doxycycline 66 153 128 51 9 5

(34) years old clinics in monohydrate 100mg
Switzerland, once daily
Germany,
and Israel
Chan et al.

Sehgal (85) 2000 Leptospirosis prophylaxis 10+ years India Doxycycline 200mg/ 84 386 NR NR NR 3
old week

Smith (35) 2011 Rheumatoid Arthritis Adults United Doxycycline 200mg 90 484 31 53 26 35
Treatment States once daily

Snijders 2011 Knee Osteoarthritis Adults Netherlands Doxycycline 168 116 NR NR NR 19

(86)** Treatment monohydrate 100mg
twice a day

Sonmez (87) 2005 Malaria Prophylaxis Adult Turkish Doxycycline 100mg 84 506 395 32 0 NR
soldiers soldiers in once daily
Kabul,
Afghanistan

Tan (47) 2014 Acne Treatment 12–35 Canada Doxycycline hyclate 140 133 NR NR 0 6
years old 200mg once
daily (with
adapalene 0.1%/
benzoyl peroxide
2.5% gel)

Taylor (88)** 1999 Malaria Prophylaxis 18–55 Indonesia Doxycycline 100mg 140 75 NR NR NR 1
years old once daily

Taylor (89) 2005 Wuchereria Bancrofti 15–68 year Tanzania Doxycycline 200mg 56 34 8 NR NR 0
Treatment old males once daily

Thiboutot 2005 Acne Treatment 12–36 United Doxycycline 100mg 84 467 NR NR 0 5

(90) years old States once daily
(Multiple
sites)

Thiboutot 2009 Rosacea Treatment 19–83 United Doxycycline 28–84 172 19 8 4 12

(40) years old States monohydrate 100mg
twice daily (with
topical azelaic acid

Sex Transm Dis. Author manuscript; available in PMC 2024 November 01.
15% gel)

Ullah (91) 2014 Acne Treatment 14–30 Pakistan Doxycycline 100mg 90 193 NR NR NR 0
years old once daily

Ullah (92) 2022 Acne Treatment 12–24 Pakistan Doxycycline 100mg 84 37 NR NR NR NR

years old once daily

van der 2016 Rosacea Treatment 18+ years Netherlands Doxycycline 40mg 112 40 23 (Mild 23 (Mild 0 3
Linden (41) old once daily or or
Moderate) Moderate)

Weiss (93) 1995 Malaria Prophylaxis 9–14 years Kenya Doxycycline 50mg 77 32 NR NR NR 2
old once daily
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NR=Not reported
1
Longer term was defined as 8+ weeks
*
Events (not individuals)
**
Included in the meta-analysis (N=18)
Chan et al.

Sex Transm Dis. Author manuscript; available in PMC 2024 November 01.
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TABLE 2:

Relative risk of adverse events between doxycycline and placebo arms of randomized controlled trials
Author Manuscript

Outcome κ Relative risk (95% CI) I2% P-value

Included RCT studies

Any AE 9 1.03 (0.89, 1.21) 59.6 0.66

Severe AE 12 0.83 (0.59, 1.16) 2.20 0.28

Neurological AE 11 0.88 (0.73, 1.05) 0.90 0.15

Gastrointestinal AE 12 1.68 (1.19, 2.38) 72.2 <0.01

Dermatological AE 9 3.55 (1.39, 9.01) 45.9 0.01

Dropped due to AE 18 1.62 (1.12, 2.34) 7.50 0.01

100 – 200 mg dosages

Any AE 3 1.35 (0.69, 2.64) 74.7 0.38

Severe AE 6 0.94 (0.65, 1.34) 0.00 0.73

Author Manuscript

Neurological AE 5 0.99 (0.97, 1.02) 0.17 0.68

Gastrointestinal AE 6 1.78 (1.16, 2.74) 81.9 0.01

Dermatological AE 4 5.52 (1.75, 17.42) 68.3 <0.01

Dropped due to AE 10 1.82 (1.06, 3.11) 20.9 0.03

κ = number of studies; AE = adverse event; I2 variation across studies because of heterogeneity rather than chance; CI = confidence interval; RCT
= randomized controlled trial
Author Manuscript
Author Manuscript

Sex Transm Dis. Author manuscript; available in PMC 2024 November 01.