Doxycycline is a broad-spectrum tetracycline antibiotic that kills bacteria and protozoa by inhibiting protein synthesis (aminoacyl-tRNA to the mRNA-ribosome complex). The drug was patented in 1957, introduced as a pharmaceutical in 1967, and has received medical approval as a treatment for conditions such as: acne, bacterial pneumonia, chlamydia, cholera, Lyme disease, Rocky Mountain spotted fever, and syphilis.
Although many find doxycycline to be an effective treatment of various medical conditions, select users experience debilitating side effects and/or adverse reactions. A specific adverse reaction reported among doxycycline users is the unexpected onset of severe depression, suicidal thoughts, and/or anxiety.
According to medical sources, the frequency of depression among doxycycline users is unknown due to lack of reporting. However, the side effect of anxiety is estimated to occur in 1% to 10% of all doxycycline users.
Doxycycline & Depression, Suicide (Medical Literature)
As of current, there’s a paucity of data suggesting that doxycycline provokes adverse neuropsychiatric reactions such as: depression, suicidality, and/or anxiety. Nevertheless, it’s possible that adverse neuropsychiatric reactions are underreported by doxycycline users and/or underacknowledged by medical doctors.
Perhaps adverse neuropsychiatric reactions of depression, suicidality, and/or anxiety are more common and/or debilitating among doxycycline users than originally suspected. Included below are case reports and/or studies in which depression, suicidality, and/or anxiety were documented as adverse reactions to doxycycline.
2013: Doxycycline and suicidality.
Although doxycycline has been in pharmaceutical use since 1967, adverse neuropsychiatric reactions to the medication are considered uncommon. Historically, anxiety is the sole adverse neuropsychiatric reaction associated with doxycycline treatment in medical literature.
Furthermore, anxiety is the only adverse neuropsychiatric reaction cited by the British National Formulary for doxycycline. (Estimates suggest that between 1% and 10% of doxycycline users experience anxiety). Despite the fact that anxiety is historically the only adverse neuropsychiatric reaction to doxycycline cited in medical literature, emerging evidence suggests that additional adverse neuropsychiatric reactions to the medication can occur.
A series of case reports presented by Atigari, Hogan, and Healy (2013) document the unexpected onset of depression and suicidality among 3 doxycycline users with no history of neuropsychiatric disorders or symptoms. After initiation of doxycycline treatment, all 3 users became depressed and suicidal, followed by suicidal actions and death in 2 of the 3 patients.
Case A: (Patient A)
- Age: 19
- Sex: Male
- Dose: 50 mg (b.i.d.)
- Condition: Perioral dermatitis
The first case presented by Atigari, Hogan, and Healy (2013) was that of a 19-year-old male reportedly from a happy home with a stable social life, easy-going personality, and noteworthy intelligence who commit suicide following doxycycline treatment. The patient, referred to as “Patient A” by authors, had no history of neuropsychiatric disorders, alcohol misuse, or substance misuse.
Examination of the patient’s medical history revealed: mild asthma, allergic rhinitis, giardiasis, hives, and allergic reactions with swelling of the extremities – all during childhood. Evaluation of the patient’s family medical history revealed that the patient’s eldest brother experienced “severe anxiety” while taking doxycycline as a malaria prophylactic.
Additionally, another of the patient’s brothers experienced an unpleasant anxious reaction while taking doxycycline for dermatitis. However, in each of the patient’s brothers, the aforementioned adverse anxiety reactions abated following cessation of doxycycline.
In the case of Patient A, doxycycline was prescribed at a dosage of 50 mg (b.i.d.) for the treatment of perioral dermatitis. Authors reported that doxycycline was utilized by Patient A as a monotherapy – no other medications and/or substances were administered during his treatment.
Approximately 4 days after the initiation of doxycycline treatment, the patient went out with friends to socialize, yet no atypical behavior was noticed by his social group. On the night before his death, the patient participated in sports with his friends and exhibited no apparent signs of depression.
Later, the patient discussed his future with his parents – and his parents mentioned that they thought the patient was spending too much time on social media (e.g. Facebook). Patient A accepted the feedback from his parents and declared that he would restrict his social media usage in the upcoming academic year.
(It was further noted that his parents had similar conversations with his siblings regarding excessive social media usage – so this conversation regarding social media usage wasn’t unique to the patient). Although the patient was noted as having been a “little bit” more quiet than usual leading up to his death, the quietude wasn’t considered significant.
Six days after doxycycline treatment, the patient reportedly had a typical morning at home with his family – and exchanged seemingly normal text messages with his friends. Approximately 17 minutes prior to his death, Patient A texted a friend to bring some whites for him to the cricket match – and thereafter, texted “wake up it’s nearly midday” to a girl he liked.
In less than 5 minutes of sending the aforementioned text message, Patient A jumped off a school building near his home which resulted in death. No warning signs of suicide (e.g. abnormal behaviors, statements, etc.) were noticed by Patient A’s family and friends leading up to his death.
In the aftermath of Patient A’s death, it was suspected that doxycycline treatment may have provoked suicidal ideation, ultimately leading to his death. Neither alcohol nor illicit substances were detected in an autopsy of Patient A’s body following his death.
Moreover, a genetic evaluation of Patient A revealed decreased CYP450 enzyme activation as a result of the patient carrying the CYP2C19*2 heterozygote genotype. Because doxycycline is metabolized in the liver, it’s possible that a genetically-mediated reduction in CYP450 enzyme activity could alter the metabolism of doxycycline such that risk of a severe adverse reaction might increase.
Since there wasn’t a reliable method available to assess doxycycline levels in the body following Patient A’s death, it remained unclear as to whether abnormally high concentrations of doxycycline may have been culpable for unexpected suicidality. Nevertheless, even if doxycycline concentrations weren’t abnormal [as a result of the patient’s abnormal CYP450 metabolism], this case supports the idea that doxycycline may cause depression and suicidality.
Case B (Patient B)
- Age: 33
- Sex: Female
- Dose: 100 mg/day
- Condition: Acne
The second case presented by Atigari, Hogan, and Healy (2013) was that of a 33-year-old female referred to as “Patient B.” Patient B was a health professional with no history of neuropsychiatric disorders, alcohol misuse, or substance misuse – who had a stable relationship with family (sisters and mother).
Examination of the patient’s medical history revealed mild acne for 9 years – with no other conditions. Because the patient had experienced a resurgence of acne, she sought medical care and was prescribed doxycycline (200 mg for the first day, followed by 100 mg/day thereafter).
It was reported that doxycycline effectively attenuated Patient B’s acne, however, she experienced a few unwanted side effects on Day 2 of treatment such as: nausea and headache. The patient also experienced social disinhibition which she subjectively found “liberating,” but this social disinhibition led to the onset of neuropsychiatric symptoms such as: irritability, anxiety, and depression.
As a result of these neuropsychiatric symptoms, Patient B became socially withdrawn, detached, and ruminated over minor things. On Day 3 of doxycycline treatment, Patient B experienced suicidal ideation such that she considered suicide as a potential solution to her problems.
Patient B continued doxycycline treatment for several days following the onset of suicidal ideation, however, the suicidal thoughts worsened – including one thought that involved crashing her car. Due to worsening of suicidal ideation, Patient B discontinued treatment.
Approximately 10 days after cessation of doxycycline treatment, Patient B’s adverse neuropsychiatric symptoms subsided and her mental status returned to normal (pre-treatment status) without any intervention. At a follow-up appointment around 3 months after doxycycline cessation, the patient remained mentally stable.
With assistance of family and friends, Patient B later attempted to identify occupational, social, and familial stressors that may have contributed to her unexpected neuropsychiatric symptoms while using doxycycline – yet none were identified. The patient suggested that her stopping of doxycycline was merely “luck.” This is yet another case suggestive of the fact that doxycycline may cause depression and suicidality in healthy adults.
Case C: (Patient C)
- Age: 18
- Sex: Male
- Doses: 50 mg/day & 100 mg/day
- Condition: Acne
The third case presented by Atigari, Hogan, and Healy (2013) was that of an 18-year-old male referred to as “Patient C.” Patient C was prescribed doxycycline at a dosage of 50 mg per day for the management of mild acne.
Although Patient C had no history of neuropsychiatric symptoms, his sister had a history of social anxiety disorder for which she was receiving treatment. Prior to initiation of doxycycline treatment (50 mg/day), Patient C was employed part-time after having completed a mechanics pre-apprenticeship.
Over a 1-year span, Patient C administered doxycycline at the prescribed dosage of 50 mg per day and reportedly felt “unwell” and appeared “down” (i.e. depressed) at times. Subsequently, Patient C walked out of a part time job that he appeared to have been enjoying prior to doxycycline treatment.
The mother of Patient C confronted him to discuss his mental health and actions, but never suspected that his depressed mood was related to doxycycline treatment. In August 2011, Patient C: discontinued doxycycline treatment, experienced considerable mood improvement, began working again, and started saving money for a vacation.
In February 2012, Patient C’s acne returned and he reinitiated doxycycline treatment at a dose of 100 mg – despite the fact that the medication packaging stated 50 mg. During this time, Patient C experienced bouts of depressed mood despite there being no apparent psychosocial stressors in his life that would’ve explained the depression.
Analogous to his prior period of doxycycline treatment, Patient C quit his job after onset of depression. Approximately 8 weeks after reinstatement of doxycycline treatment at 100 mg/day, and 2 days after quitting his job, Patient C commit suicide via hanging. This case further supports the idea that doxycycline can cause severe depression and suicidality in select persons.
Why do researchers suspect that doxycycline may have caused depression and suicidality?
Atigari, Hogan, and Healy state that the mechanism by which doxycycline may lead to suicide as an adverse reaction is unknown. After reviewing each of the aforementioned cases using the Bradford Hill criteria for causation, researchers reflected upon several variables to determine whether doxycycline likely caused adverse neuropsychiatric reactions of depression and suicidality.
Because the adverse neuropsychiatric reactions of depression and suicidality emerged with the onset of doxycycline treatment AND abated with cessation of doxycycline treatment – it’s logical to assume that doxycycline was the underlying cause.
- Treatment initiation: Depression and suicidality emerged as adverse neuropsychiatric reactions following the initiation of doxycycline treatment in all patients.
- Discontinuation: In Patient B and Patient C, discontinuation of doxycycline treatment led to remission of depression and suicidality.
There were no (1) identifiable stressors; (2) additional medications or substances used with doxycycline; or (3) histories of neuropsychiatric symptoms – among the patients that would’ve otherwise accounted for these neuropsychiatric symptoms.
In Patient C, authors state that there’s evidence for a “biological gradient.” Patient C experienced neuropsychiatric symptoms at lower doses (50 mg per day), but did not engage in suicidal actions.
However, at a dosage of 100 mg per day, the patient died via a suicidal action. As was noted, Patient C thought that he was receiving 50 mg per day (based on medication packaging), but was actually administering 100 mg per day.
Although it is unknown as to whether the patient would’ve have engaged in suicidal actions upon reinstatement of a lower 50 mg/day dose, historically no such actions occurred at this dosage. For this reason, authors suspect that the 100 mg/day dosage provoked stronger neuropsychiatric symptoms (e.g. suicidality) – supporting the idea that doxycycline was to blame.
In Patient A, authors state that there’s evidence for “biological plausibility.” This is based upon the findings that: (1) multiple siblings of Patient A had experienced severe anxiety as an adverse neuropsychiatric reaction to doxycycline – and (2) Patient A carried a genotype (CYP2C19*2) that reduced activity of his CYP450 liver enzymes.
In other words, because multiple siblings of Patient A experienced adverse neuropsychiatric reactions while using doxycycline – it’s reasonable to suspect that doxycycline was the cause of these symptoms. Moreover, because doxycycline is metabolized in the liver and Patient A exhibited diminished liver enzyme function (as a result of genetics) – this may have increased his risk of an adverse reaction.
Another reason to authors suspect that doxycycline causes depression and suicidality is patient reports of adverse reactions to the FDA (Food and Drug Administration). A total of 317 adverse reactions have been documented in the U.S. FDA database from patient reporting – some of which involve changes in psychological state.
Of the 317 documented adverse reactions, 16 were suicide attempts. Authors state that the possibility of additional neuropsychiatric symptoms such as: agitation, anxiety, depression, abnormal thinking, and self-injury – should not be overlooked.
Recommendations by researchers
Authors state that there’s a need to further investigate the biochemical basis of suicidality for the sake of identifying possible biochemical triggers. It was further noted that select doxycycline users (particularly persons with a personal and/or family history of adverse neuropsychiatric reactions to doxycycline) may require monitoring during treatment.
Additionally, authors note that any patients experiencing suicidality while using doxycycline should be advised to discontinue treatment, and if necessary, presented with alternative management strategies. Overall, this series of case reports provides evidence to suggest that doxycycline can cause depression and suicidality as adverse neuropsychiatric reactions.
Note: If you know of any additional scientific literature linking doxycycline to depression, link to the study in the comments section.
How Doxycycline causes depression, anxiety, suicidal thoughts (Hypothetical mechanisms)
Included below is a list of possible mechanisms by which the antibiotic “doxycycline” might trigger depression, anxiety, and/or suicidal thoughts – as adverse reactions. Understand that because this list is hypothetical and not substantiated with scientific research – it may be subject to inaccuracies.
Nevertheless, when reflecting upon (1) the mechanism of doxycycline’s action and (2) potential causes of neuropsychiatric symptoms, it’s reasonable to surmise that this list may contain legitimate mechanisms by which doxycycline induces anxiety, depression, and/or suicidality in select users.
Gut bacteria alteration
As a “broad-spectrum” antibiotic, doxycycline kills an array of pathogenic bacteria throughout the body – making it an extremely useful medication among patients with serious bacterial infections. However, an unfortunate byproduct of using doxycycline or any other antibiotic (especially if “broad spectrum”) – is that these medications also obliterate healthy bacteria (i.e. probiotics) throughout the body.
Some speculate that doxycycline might cause depression, anxiety, or other neuropsychiatric symptoms as a result of altering the composition of bacteria within the gastrointestinal tract – colloquially referred to as the “gut.” Doxycycline might trigger adverse neuropsychiatric symptoms via the gut by:
- Depleting “healthy” bacteria
- Reducing bacterial diversity
- Enabling proliferation of pathogenic bacteria
Keep in mind that the aforementioned effects of doxycycline within the gut may vary in magnitude among users. Certain individuals may experience depression solely from the depletion of healthy bacteria, others from a reduction in bacterial diversity, and others from a combination of all the aforementioned potential “gut” alterations in response to doxycycline treatment.
Okay, so how specifically might the effect of doxycycline on gut bacteria provoke depression and/or anxiety? Because doxycycline alters gut bacteria composition, and gut bacteria can influence the signaling of afferent neurons, motor neurons, and glial cells within the enteric nervous system (a peripheral network [with upwards of 500 million neurons] that some experts consider a “second brain”) – any substantial gut bacteria alteration [mediated by doxycycline] might substantially modulate activation of the enteric nervous system.
Since the enteric nervous system engages in multidirectional crosstalk (i.e. signaling) with a host of bodily systems, any significant antinational change within the enteric nervous system (ENS) [due to doxycycline-mediated gut bacteria alterations] could subsequently impact activation within systems such as the: (1) autonomic nervous system (sympathetic and parasympathetic branches); (2) brain (primarily by way of vagal nerve signaling); and/or (3) immune system.
In the event that activation within the autonomic nervous system; brain (e.g. neurochemistry, blood flow, regional activity, etc.); and/or immune system (e.g. cytokine production) is significantly modified (or shifted away from pre-treatment homeostasis) in response to doxycycline-mediated gut bacteria alterations – this could trigger adverse neuropsychiatric reactions such as anxiety, depression, suicidality could emerge (in select “at-risk” persons).
Depleting “healthy” gut bacteria
As a broad-spectrum antibiotic, doxycycline will deplete or decrease healthy species of bacteria in the gastrointestinal tracts of all users. In other words, when you take doxycycline to treat an infection (or for any other reason), it won’t selectively discriminate between killing pathogenic and healthy bacteria – it kills them all.
Healthy gut bacteria are understood to: augment absorption of dietary nutrients; protect against intestinal permeability (i.e. “leaky gut”) by strengthening tight junctions; produce favorable peripheral neurotransmitters; optimize vagal nerve signaling; and decrease inflammation. If large counts of healthy or beneficial gut bacteria are depleted in response to doxycycline treatment, there may be serious deleterious consequences.
Reducing healthy bacteria might: impair nutrient absorption; lead to intestinal permeability; reduce production of favorable neurotransmitters; impair vagal nerve function; increase inflammation; and possibly trigger autoimmunity (such as in the aftermath of “leaky gut”). All of the aforementioned prospective consequences of “healthy” gut bacteria depletion could directly and/or indirectly contribute to the onset of neuropsychiatric symptoms.
For example, if a noteworthy reduction in healthy bacteria occurs in response to doxycycline treatment, and this reduction in healthy bacteria interferes with nutrient absorption – depression could ensue as a result of a nutrient deficiency. Another example might involve overactivation of the sympathetic nervous system (i.e. the stress response) in response to changes in peripheral neurotransmitter production – stemming from depletion of healthy gut bacteria.
Reducing bacterial diversity within the gut
Research suggests that treatment with broad-spectrum antibiotics like doxycycline substantially reduces bacterial diversity within the gut. Although this effect is generally transient for most individuals (such that bacterial diversity is eventually recovered in the aftermath of antibiotic discontinuation), the reduction in bacterial diversity may be [partially] culpable for the onset of adverse neuropsychiatric reactions like anxiety, depression, and suicidal thinking.
Preexisting evidence indicates that healthy adults [devoid of disease] typically exhibit significantly greater bacterial diversity within the gut – relative to adults with diseases such as: obesity, Chron’s disease, ulcerative colitis, and irritable bowel syndrome (IBS). Although it’s scientifically unknown as to whether reduced gut bacteria diversity is: (1) a cause (or partial cause) of diseased states; (2) byproduct of diseased states; or (3) both a cause and a byproduct of diseased states – some suspect that reductions in the diversity of gut bacteria can negatively impact health.
Any notable reduction in bacterial diversity throughout the gut might yield unfavorable changes in: peripheral neurotransmission; vagal innervation; immune function; gastrointestinal permeability; and/or nutrient absorption. Assuming any of the aforementioned unfavorable changes occur during treatment (as a result of decreased diversity of gut bacteria) – it’s reasonable to suspect that problematic neuropsychiatric symptoms could ensue.
- Source: https://www.nature.com/articles/nature11550
- Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191029/
Pathogenic gut bacteria proliferation
Doxycycline may enable various species of pathogenic bacteria to proliferate and/or thrive within the gastrointestinal tract during treatment. Studies involving mice have shown that administration of antibiotics increases the availability of host-derived free sialic acid throughout the gastrointestinal tract.
Because pathogenic bacteria like Salmonella typhimurium and Clostridium difficile readily use free sialic acid as a fuel source, the populations of these bacteria substantially increase in the mouse gastrointestinal tract during antibiotic treatment. If the aforestated findings from mice studies can be extrapolated to humans, it’s reasonable to hypothesize that doxycycline treatment might bolster the growth of pathogenic microbes in the human gastrointestinal tract.
Additionally, an upregulation of pathogenic gut microbes (attributable to antibiotic-mediated changes in acid production) might yield a simultaneous downregulation of healthy gut microbes – due to the fact that pathogens and healthy microbes are competing with each other for gastrointestinal space (i.e. real estate). In the event that populations of pathogenic gut microbes significantly increase during treatment with doxycycline – this might provoke adverse neuropsychiatric reactions of anxiety, depression, and/or suicidality (in select persons).
Proliferation in pathogenic gut microbes could: damage the gastrointestinal tract (potentially inducing “leaky gut,” impaired absorption, nutrient deficits, etc.); cause cravings for unhealthy foods (associated with weight gain, inflammation, depression, etc.); distort peripheral neurotransmission; and/or trigger a stress response (via the sympathetic nervous system). For this reason, it’s not farfetched to hypothesize that negative changes in mood during doxycycline treatment might be attributable to the proliferation of pathogenic microbes.
It’s also worth noting that treatment with doxycycline not only might augment the proliferation of pathogenic microbes, but it could lead to (1) bacterial resistance and/or (2) strengthen gut pathogens that are already resistant to doxycycline. According to Francino (2016) the human gut microbiota is a known reservoir of antibiotic resistances and cumulative exposure to antibiotics increases likelihood of harboring antibiotic-resistant pathogens within the gut.
If doxycycline treatment leads to antibiotic resistance within the gastrointestinal tract, this could further bolster the proliferation of pathogenic microbes – as well as their overall presence. If pathogenic microbes within the gut are related to the medical condition for which you were prescribed doxycycline, this might eventually provoke a heightened immune response (e.g. due to an untreated infection) with inflammation that could induce anxiety, depression, or suicidality.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/22825498
- Source: https://www.ncbi.nlm.nih.gov/pubmed/26793178
Effects of Doxycycline on Gut Bacteria
A study by Angelakis et al. (2014) examined the respective effects of long-term doxycycline and hydroxychloroquine administration on human gut bacteria. To evaluate the effect of doxycycline and hydroxychloroquine treatment on gut bacteria, researchers collected fecal samples from 82 participants: 48 with Q fever endocarditis (treatment group) and 34 healthy adults (controls).
The collected fecal samples were molecularly analyzed to elucidate total bacteria levels and specific concentrations of: Methanobrevibacter smithii, Bacteroidetes, Firmicutes, Escherichia coli, Lactobacillus, and Lactobacillus reuteri. Results of the study suggest that doxycycline and hydroxychloroquine treatment can significantly reduce total gut bacteria and populations of specific gut bacteria at the phylum level.
Bacteroidetes: Patients using doxycycline exhibited significant reductions in the populations of Bacteroidetes bacteria relative to healthy controls – regardless of whether treatment was short-term (under 3 months) or longer-term (over 3 months). Longer-term antibiotic treatment was associated with a greater reduction in total Bacteroidetes than shorter-term antibiotic treatment.
Firmicutes: All persons treated with doxycycline for over 3 months exhibited significant reductions in the concentrations of Firmicutes bacteria relative to healthy controls. Additionally, there was an association between treatment duration and magnitude of Firmicutes reduction. Specifically, it was discovered that the longer the duration of doxycycline treatment, the more substantial the reduction in Firmicutes.
Lactobacillus: The concentrations of Lactobacillus bacteria significantly decreased among patients treated with doxycycline relative to healthy controls – regardless of whether treatment was short-term (under 3 months) or longer-term (over 3 months). There were no significant differences in Lactobacillus reductions between short-term and long-term doxycycline users.
Lactobacillus reuteri: Among 53 patients tested, Lactobacillus reuteri was only detected in 2 (4% of the sample). Both patients that tested positive for Lactobacillus reuteri had been using doxycycline for less than 3 months. Based on this finding, it’s reasonable to suspect that doxycycline use depletes Lactobacillus reuteri and that longer-term use increases the magnitude of depletion.
Total bacteria: Researchers reported that total gut bacteria were reduced in response to doxycycline treatment, however, this reduction wasn’t of statistical significance. The Mann-Whitney test revealed a significant reduction in total bacteria concentrations among patients using doxycycline for more than 3 months relative to healthy controls, however, this result wasn’t confirmed with Dunn’s multiple-comparison test.
Moreover, doxycycline treatment for more than 3 months significantly reduced total bacteria relative to doxycycline treatment for less than 3 months. Based on this finding, it seems as though long-term antibiotic use has a more substantial effect on gut bacteria than short-term antibiotic use.
- (Recommended: “10 Best Probiotics for Depression & Anxiety“)
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What does this study suggest?
This study suggests that doxycycline and hydroxychloroquine treatment significantly reduces levels of specific gut bacteria such as: Bacteroidetes, Firmicutes, and Lactobacillus. Additionally, this study suggests that longer-term doxycycline and hydroxychloroquine treatment is associated with greater reductions in total bacteria, Bacteroidetes, and Firmicutes – than shorter-term treatment.
Authors noted that antibiotic-mediated alterations in gut microbiota at the phylum level could yield deleterious health effects such as weight gain. It’s also possible that the specific aforementioned alterations in gut bacteria [in response to antibiotic treatment] cause adverse neuropsychiatric reactions – directly and/or indirectly.
Assuming significant weight gain occurs in response to these antibiotic-mediated gut bacteria alterations, this weight gain might: (1) increase systemic inflammation; (2) compromise self-esteem; (3) result in poor dietary choices; (4) alter brain activity – all of which could induce anxiety and/or depression.
Nevertheless, it is important to underscore the limitations of this study including: Q fever endocarditis in the treatment group (a condition which could directly impact gut bacteria); small sample size (reducing the strength of results); the use of hydroxychloroquine (making it difficult to distinguish its effect on the gut versus doxycycline); and side effects such as weight gain (which might’ve been partially culpable for the gut bacteria changes – rather than vice-versa).
Inflammatory response (Jarisch–Herxheimer reaction)
Another potential means by which doxycycline treatment might provoke adverse neuropsychiatric reactions (anxiety, depression, suicidality, etc.) is through bacterial “die off.” When doxycycline is administered for the treatment of bacterial infections, it inhibits protein synthesis to kill pathogenic bacteria.
As pathogenic bacteria are killed [from doxycycline treatment], some may secrete endotoxin-like compounds (e.g. toxins, proteins, oxidizing agents) just prior to their death. The secretion of these endotoxin-like compounds can trigger an inflammatory response within the body whereby the immune system upregulates its production of cytokines such as: TNF-alpha; interleukin-6; and interleukin-8.
One possibility is that these endotoxin-like compounds (secreted by dying bacteria) circulate throughout the body to impair aspects of peripheral and central neurotransmission – directly causing adverse neuropsychiatric reactions. However, what’s most likely is that an immune-mediated increase in production of proinflammatory cytokines [in response to circulating endotoxin-like compounds] triggers neuropsychiatric symptoms like anxiety, depression, and/or suicidality (in select persons experiencing this reaction).
In the medical literature, the aforementioned inflammatory response to lipoproteins or endotoxin-like compounds (secreted by bacteria prior to their death) is referred to as a “Jarisch–Herxheimer reaction.” Medical conditions in which the Jarisch–Herxheimer reaction is most likely to occur during antibiotic treatment include: syphilis, Lyme disease, relapsing fever, leptospirosis, Q fever, bartonellosis, brucellosis, trichinellosis, and African trypanosomiasis.
Common symptoms associated with a Jarisch–Herxheimer reaction include: fever, chills, hypotension, headache, tachycardia, hyperventilation, vasodilation with flushing, myalgia, exacerbation of skin lesions and anxiety. Moreover, a Jarisch–Herxheimer reaction typically occurs within hours of the first antibiotic dose and its severity is associated with the level of inflammation; higher inflammation causes harsher symptoms.
Note: Although some individuals may experience adverse neuropsychiatric reactions to doxycycline as a result of one of the aforementioned potential effects of doxycycline on gut bacteria (e.g. depletion of healthy bacteria; reduced bacterial diversity; proliferation of pathogenic microbes) – others might be affected by a combination of these effects plus the inflammatory Jarisch–Herxheimer reaction.
Modulation of neurotransmission
Although doxycycline exerts a potent peripheral effect, only a small percentage of ingested doxycycline penetrates the blood-brain barrier (BBB). One study reported that approximately 26% of ingested doxycycline enters the cerebrospinal fluid (CSF), whereas a second study reported that approximately 15% of ingested doxycycline enters the cerebrospinal fluid (CSF).
This means that only a small amount of doxycycline is entering the brain and central nervous system (CNS). Nevertheless, even if there’s just a small amount of doxycycline that crosses the blood-brain barrier and acts within the central nervous system, it could still have a substantial effect upon the user’s neurotransmission whereby it could affect mood.
5-HT1A receptor modulation: One way that doxycycline may cause adverse neuropsychiatric reactions in select persons is through interacting with and/or modulating concentrations of 5-HT1A receptors. In a study by Valdez, Shakti Regmi, et al. (2010), the administration of doxycycline for 26 weeks significantly altered the extracellular density of 5-HT1A receptors.
Immunofluorescence measurements revealed an increase in 5-HT1A receptor density significantly increased. Although the effect of doxycycline on 5-HT1A receptor densities in humans hasn’t been evaluated, it’s possible that a similar effect could occur.
In the event that doxycycline substantially modulates 5-HT1A receptor concentrations and/or activity, this could be the principal mechanism by which doxycycline provokes neuropsychiatric reactions of anxiety, depression, and/or suicidality [in select users] during treatment. After all, a plethora of human studies have linked 5-HT1A receptor abnormalities to anxiety disorders, major depression, and suicide.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/19428959
- Source: https://www.ncbi.nlm.nih.gov/pubmed/24337875
Although there’s evidence indicating that doxycycline can affect concentrations of 5-HT1A receptors in mice, it’s unclear as to whether it further interacts with other receptor sites and/or neurotransmitter systems. A study by Jantzie, Rauw, and Todd (2006) reported significant modulation of neurotransmitters in rat models of neonatal hypoxia-ischemia – following the administration of doxycycline (relative to untreated rats).
Rats that received doxycycline exhibited significantly lower concentrations of alanine and serine (within the cortex and striatum) than controls. Because this study involved rats (rather than humans) and the induction of neonatal hypoxia-ischemia (which substantially alters neurotransmission), it is unclear as to whether doxycycline actually alters levels of alanine and serine in healthy humans.
In the event that doxycycline reduces serine in humans, this could be another neurochemical mechanism by which it triggers adverse neuropsychiatric reactions. Low plasma serine concentrations have been linked by Mitani et al. (2006) to the severity of depression (as measured by the Hamilton Depression Rating Scale).
Though everyone may be prone to some degree of neurochemical modulation from doxycycline, the dosage of doxycycline administered and baseline (i.e. pre-treatment) neurochemistry of the specific user (as determined by genes and environment) may determine risk of adverse neuropsychiatric reactions during treatment.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/16919849
- Source: https://www.ncbi.nlm.nih.gov/pubmed/16707201
Other mechanisms by which doxycycline might cause neuropsychiatric reactions
There may be additional mechanisms by which doxycycline could cause adverse neuropsychiatric reactions such as by: interfering with nutrient absorption; modulating epigenetics; and/or inducing mitochondrial dysfunction.
Micronutrient deficits: Research by Akimova and Shteĭngardt (1992) suggests that antibiotics can interfere with the absorption of basic nutrients in the small intestine. Specifically, antibiotics have been shown to inhibit the absorption of fat, protein, and carbohydrates (likely via their effect on gut bacteria). If doxycycline treatment significantly impairs nutrient absorption, this could yield nutrient deficits which lead to anxiety, depression, and/or suicidality.
Epigenetic modulation: Treatment with doxycycline might directly alter epigenetic expression of users in ways that could induce unwanted adverse neuropsychiatric reactions. Furthermore, even if doxycycline doesn’t directly alter epigenetic expression, it might indirectly alter epigenetic expression via depleting gut bacteria – to cause adverse neuropsychiatric effects.
Mitochondrial dysfunction: Research has linked mitochondrial dysfunction to an array of neuropsychiatric disorders (including depression and anxiety) and some experts believe that it may be possible to treat these disorders by normalizing or enhancing mitochondrial function. According to research by Chatzispyrou et al. (2015), doxycycline (and other tetracycline antibiotics) target mitochondrial translation and impair mitochondrial function. It’s possible that this is yet another contributing mechanism by which doxycycline induces adverse neuropsychiatric reactions in a subset of users.
In summary, it’s important to underscore that the specific mechanism(s) by which doxycycline triggers adverse neuropsychiatric reactions such as anxiety, depression, and/or suicidality might be subject to interindividual variation. For example, a subset of doxycycline users might be prone to depression as a result of doxycycline-mediated gut bacteria depletion – whereas others might experience depression as a result of doxycycline-mediated neurochemical changes.
Other doxycycline users might become depressed and/or anxious as a result of multiple contributing mechanisms such as doxycycline-mediated: gut bacteria modulation; neurochemical changes; impairment of nutrient absorption; etc.). More research is necessary to pinpoint the specific mechanisms by which doxycycline (and other antibiotics) cause adverse neuropsychiatric reactions.
Note: The hypothesized mechanisms by which doxycycline might induce adverse neuropsychiatric reactions may not differ significantly from those of other antibiotics.
Did doxycycline cause depression and anxiety – or did a preexisting medical condition (e.g. an infection)?
Although doxycycline is capable of causing adverse neuropsychiatric reactions such as depression and anxiety, it’s possible that (in a subset of persons), these neuropsychiatric reactions are caused by the condition for which doxycycline was prescribed. Numerous bacterial infections can: modify immune function; increase inflammation and oxidative stress; impair nutrient absorption; alter gut bacteria; induce metabolic changes; and cause mitochondrial dysfunction – to cause adverse neuropsychiatric symptoms.
For example, Lyme disease (caused by Borrelia burgdorferi and spread by ticks), a condition that’s regularly treated with doxycycline – can cause symptoms such as anxiety, depression, panic attacks, and suicidality. This considered, it’s reasonable to suspect that certain doxycycline users might endure neuropsychiatric symptoms during treatment due to the ongoing or lingering presence of an infection.
Perhaps once the infection is fully eliminated from the body (irrespective of whether doxycycline is still being administered), the unwanted neuropsychiatric symptoms abate. This could explain why some doxycycline users only experience depression in the early stages of treatment (as the infection hasn’t been eliminated) and mood improvement thereafter (despite continued doxycycline administration).
In select persons, it could also be possible that both an infection and doxycycline treatment contribute to adverse neuropsychiatric reactions. That said, most individuals with neuropsychiatric symptoms from an infection will likely have experienced those symptoms prior to the initiation of doxycycline treatment.
If neuropsychiatric symptoms were not present prior to doxycycline use, and an infection is successfully treated with doxycycline, then it’s likely that doxycycline was more culpable for the neuropsychiatric symptoms than the infection. Moreover, many people use doxycycline for conditions other than infection (e.g. acne) and still become depressed, anxious, suicidal, etc. – suggesting that the medication can substantially alter mood irrespective of a preexisting infection.
How long will depression and/or anxiety last after stopping doxycycline?
There’s no exact timeline that can be recommended to all doxycycline users to explain how long depression, anxiety, and/or other neuropsychiatric symptoms will persist following doxycycline discontinuation. In a single case report, adverse neuropsychiatric symptoms (e.g. depression and suicidality) subsided within 10 days of doxycycline discontinuation.
That said, it remains unknown as to whether the “10 day” timeline derived from a standalone case report accurately represents how long adverse neuropsychiatric reactions will persist following doxycycline cessation. It is understood that doxycycline exhibits an elimination half-life within the range of 15 to 25 hours.
Knowing this, we can determine that doxycycline stays in the system (i.e. body) between 3.45 and 5.73 days (on average). If neuropsychiatric symptoms significantly diminish once doxycycline exits the body, then a significant improvement in neuropsychiatric status should be evident in most users within 5 days of discontinuation.
However, one must consider the possibility that doxycycline-mediated physiologic modulations linger even after doxycycline is completely eliminated from the body. Examples of potential physiologic modulations that might linger after doxycycline is eliminated include: gut abnormalities and atypical neurotransmission.
If these physiologic modulations linger, then unwanted neuropsychiatric symptoms might remain in the aftermath of doxycycline cessation. Research suggests that broad-spectrum antibiotics (e.g. doxycycline) tend to have the longest-lasting effect on gut composition.
Although the amount of time it takes for the gut microbiome to completely recover following doxycycline treatment is unknown, researchers have documented recovery times for other antibiotics. For example, a study by Dethlefsen et al. (2008) reported that 5 days of treatment with the antibiotic ciprofloxacin altered approximately one-third of bacterial taxa within the gut and reduced taxonomic richness.
In the aforementioned study, “nearly complete” recovery in gut microbiome composition occurred approximately 4 weeks following discontinuation (for most users) – but some compositional changes persisted for up to 6 months. What’s more, a second exposure to ciprofloxacin around 6 months after the initial exposure impaired gut microbiota recovery to a greater degree.
Based on this finding, it’s reasonable to suggest that multiple doxycycline treatments within a short-term or moderate-term (e.g. 6 months) could yield longer-lasting (potentially permanent) effects on gut microbiota – relative to a standalone treatment. Moreover, a study by Jakobsson et al. (2010) assessed the effect of clarithromycin, metronidazole, and omeprazole administered over 7 days – on the pharyngeal and fecal taxonomic composition of the gut.
Researchers in the aforementioned study reported that the medications broadly altered taxonomic composition of gut bacteria, but gut bacteria recovery occurred rapid following discontinuation. However, in select persons only partial recovery was observed – such that treatment-mediated gut bacteria alterations persisted for at least 4 years post-exposure.
If doxycycline-mediated gut bacteria alterations are culpable for the onset of anxiety, depression, and/or suicidality – then symptoms will persist until the gut fully recovers post-treatment. Considering the aforementioned studies, it’s reasonable to surmise that “nearly complete” gut microbiota recovery will occur within 4 weeks (in most persons), however, recovery may require additional time for select users (particularly long-term users and/or those who’ve endured multiple consecutive treatments within a short-term or moderate-term window).
Moreover, understand that there may be additional physiologic effects (in addition to gut microbiota alterations) that are culpable for adverse neuropsychiatric reactions that also linger following doxycycline cessation. For example, doxycycline might significantly modulate neurochemistry during treatment such that the brain requires time to reestablish homeostasis (or transition to pre-treatment neurochemistry).
Recovery times from neuropsychiatric symptoms will likely vary among doxycycline users and be contingent upon user-specific variables such as the severities of doxycycline-mediated physiologic changes (during treatment) and/or recovery efforts (e.g. diet, stress reduction, supplementation). In the event that you’re struggling with depression, anxiety, and/or suicidality after you’ve discontinued doxycycline – seek immediate medical attention.
- Source: https://www.ncbi.nlm.nih.gov/pubmed/19018661/
- Source: https://www.ncbi.nlm.nih.gov/pubmed/20352091/
Variables that may influence doxycycline-induced depression and/or anxiety
There are a multitude of variables that could influence whether adverse neuropsychiatric reactions are likely to occur during treatment and the severities of these reactions if they occur. Such influential variables might include: (1) the specific user; (2) dosage of doxycycline; (3) duration of doxycycline use; (4) concurrent substance use; and/or (5) amount of time since previous antibiotic treatment.
Specific doxycycline user
The specific doxycycline user is likely the biggest determinant in whether adverse neuropsychiatric reactions occur during treatment. Research suggests that only 1% to 10% of doxycycline users experience anxiety as an adverse reaction – meaning a majority of users (90%) won’t have this reaction.
Additionally, because depression and suicidality are not even documented as potential adverse reactions in most medical literature – their occurrences may be rare. User-specific factors like: genetics/epigenetics; neurochemistry; and bacterial composition within the gut – might increase risk and/or severity of adverse neuropsychiatric reactions.
Gene expression: The genetics of a doxycycline user might influence whether adverse neuropsychiatric reactions emerge during treatment. Genetics can influence how efficiently doxycycline is metabolized (and thus plasma concentrations) and the expression of neurochemical targets with which doxycycline might interact.
Metabolism (CYP450): Because doxycycline is metabolized within the liver, any persons with poor CYP450 metabolism (as is determined by genetics) – are probably at increased risk of experiencing adverse neuropsychiatric reactions to treatment. When CYP450 function is poor, doxycycline won’t be metabolized as efficiently by CYP3A enzymes as it is in extensive metabolizers.
As a result, a standard dose of doxycycline may accumulate within the bloodstream and reach much higher plasma concentrations than expected. The higher plasma concentrations of doxycycline among poor metabolizers could modulate aspects of physiology (e.g. gut bacteria, neurochemistry, etc.) to a greater extent than expected – possibly triggering adverse neuropsychiatric reactions.
5-HT1A receptors: There’s some evidence suggesting that doxycycline may interact with 5-HT1A receptors in the brain. Because 5-HT1A receptors can influence mood and anxiety – it’s reasonable to suspect that an interaction between doxycycline and 5-HT1A receptors might provoke adverse neuropsychiatric reactions such as depression, anxiety, and suicidality.
It is understood that the expression of 5-HT1A receptors is largely determined by genetics. Persons with atypical gene expression might have different concentrations and/or activations of 5-HT1A receptors than most, which could increase their risk for adverse reactions while using doxycycline.
Baseline neurochemistry: The baseline neurochemistry of a doxycycline user (irrespective of gene expression) might also determine risk of adverse neuropsychiatric reactions to treatment – and the severities of those reactions (should they occur). Certain brain activity and/or neurochemical signatures at baseline (pre-doxycycline) might be at greater risk of experiencing severe adverse neuropsychiatric reactions than others.
For example, someone with HPA axis dysregulation and serotonergic abnormalities prior to treatment (as a result of excessive stress, poor sleep, and/or recent substance use) might be at greater risk of experiencing adverse neuropsychiatric reactions while using doxycycline than most. On the other hand, someone with normative HPA axis function and serotonergic neurotransmission prior to treatment (as a result of living a low stress lifestyle) might be at reduced risk of experiencing adverse neuropsychiatric reactions.
Gut bacteria: The bacterial composition of your gut at baseline could influence risk of adverse neuropsychiatric reactions to doxycycline – and the severities of those reactions (if they occur). Gut bacteria composition is usually determined by: diet, activity levels, stress, gene expression, supplement use (e.g. probiotics), and/or history of antibiotic use.
Persons with specific combinations and/or concentrations of gut bacteria prior to using doxycycline may be at lower risk for experiencing anxiety, depression, and/or suicidality – than those with other combinations and/or concentrations of gut bacteria at baseline.
The dosage of doxycycline administered probably influences risk of adverse neuropsychiatric events throughout treatment. Generally, it is believed that high doses of doxycycline are more likely to trigger adverse reactions (including neuropsychiatric events) – than lower doses.
In one case report, a patient had developed depression at a 50 mg dose, but never engaged in self-harm. The patient randomly discontinued doxycycline for around 6 months and eventually reinstated doxycycline at 100 mg (as a result of a dosing error) – and became so depressed and suicidal, that he took his own life.
Authors of the case report stated that high doses of doxycycline appear to increase risk and severities of his adverse psychiatric symptoms. It makes logical sense that high doses of doxycycline would increase risk and/or severities of adverse neuropsychiatric reactions (relative to lower doses) because high doses exert a stronger effect upon aspects of the user’s physiology.
More specifically, high doses of doxycycline likely alter gut bacteria and neurotransmission to a greater extent than lower doses – making neuropsychiatric symptoms more likely to occur. If neuropsychiatric symptoms emerge with low doses of doxycycline, these symptoms may intensify at increased dosages.
Note: Persons with suboptimal CYP450 metabolism (as a result of gene expression) may be at even greater risk of experiencing adverse neuropsychiatric symptoms at high doses – due to the fact that poor CYP450 metabolism leads to antibiotic accumulation (and potentially toxicity).
Duration of doxycycline treatment
The total duration over which doxycycline is used could impact one’s risk of experiencing adverse neuropsychiatric reactions and/or the severities of those reactions during treatment. Although duration of doxycycline use might impact the severities of neuropsychiatric symptoms in affected persons, duration of use might impact neuropsychiatric symptoms uniquely among users.
According to case report data (from 3 patients), adverse neuropsychiatric reactions to doxycycline become noticeable within the first two weeks of treatment and persist and/or worsen with continued administration. That said, other doxycycline users might experience adverse neuropsychiatric symptoms shortly after treatment initiation followed by a gradual reduction in their severities and/or complete resolution with longer-term administration.
Another possibility is that certain doxycycline users will experience zero adverse neuropsychiatric reactions in the early days or weeks of treatment – followed by a delayed onset (e.g. weeks after treatment initiation). Nevertheless, because long-term doxycycline treatment might modify aspects of physiology more substantially than shorter-term treatment (e.g. due to a cumulative effect), it’s reasonable to speculate that long-term doxycycline use would (on average) increase risk of, severities of, and/or durations of adverse neuropsychiatric reactions.
Concurrent substance use
Although available case reports documented adverse neuropsychiatric reactions in persons who used doxycycline as a standalone (i.e. monotherapy) – it’s reasonable to suspect that concurrent administration of substances (e.g. supplements, medications, etc.) during treatment could influence risk of experiencing adverse neuropsychiatric events – and/or the severities of those events (among affected persons).
Certain concurrently-administered substances might increase risk of adverse neuropsychiatric reactions – whereas other concurrently-administered substances might decrease risk of, or attenuate the severities of, adverse neuropsychiatric events. For example, concurrently-administered substances that interact with CYP3A enzymes might impair the metabolism of doxycycline (or vice-versa) – leading to increased plasma concentrations of doxycycline.
If plasma concentrations of doxycycline are elevated as a result of a pharmacokinetic interaction, doxycycline will modulate physiology more substantially than it otherwise would – whereby risk of adverse reactions (including neuropsychiatric events) increases. Furthermore, some substances (e.g. additional antibiotics) might enhance certain physiologic effects exerted by doxycycline (e.g. gut bacteria depletion) to amplify anxiety and/or depression symptoms.
That said, other concurrently-administered substances might protect against doxycycline-mediated physiologic changes to protect against and/or reduce the severities of adverse neuropsychiatric reactions during treatment. For example, concurrent administration of a high-potency probiotic and/or a 5-HT1A receptor modulator might help maintain healthy gut bacteria and serotonergic neurotransmission during treatment whereby anxiety and/or depression are prevented.
Moreover, it’s necessary to underscore that some concurrently-administered substances with doxycycline may have no impact whatsoever on its propensity to induce adverse neuropsychiatric reactions – and other concurrently-administered substances might provoke adverse neuropsychiatric reactions (irrespective of doxycycline). In brief, if you’re experiencing adverse neuropsychiatric events while using doxycycline – evaluate the potential influence of concurrently-administered substances.
Time since previous antibiotic treatment
Evidence suggests that multiple antibiotic treatments administered within a short-term or moderate-term can modulate aspects of physiology (especially the gut) to a greater extent multiple antibiotic treatments administered over a long-term with significant time gaps between treatments. Specifically, research has shown that multiple rounds of antibiotic treatment within a 6-month window can have longer-lasting deleterious effects on the composition of gut bacteria than usual.
It’s also possible that multiple rounds of antibiotic treatment within a 6-month window can have longer-lasting deleterious effects on aspects of physiology besides the gut (e.g. brain function, neurochemistry, autonomic nervous system activation, etc.). Hypothetically assuming that doxycycline is administered multiple times (or following treatment with another antibiotic) within a 6-month period – risk of adverse neuropsychiatric reactions might substantially increase.
Nevertheless, it’s also possible that infrequent or first-time doxycycline (or antibiotic) users could be at increased risk of experiencing significant bacterial “die off” and a Herxheimer-like reaction (associated with inflammation in response to secretion of endotoxin-like compounds by dying microbes) – due to the fact that more bacteria may exist in their gut (because antibiotics are seldom administered). In summary, realize that the amount of time since your previous antibiotic use could impact the likelihood of experiencing neuropsychiatric events (plus their severities if they occur).
Risk factors for doxycycline-induced anxiety, depression, suicidality
Highlighted below are prospective factors that may increase one’s risk of experiencing adverse neuropsychiatric events (anxiety, depression, suicidality, etc.) while using doxycycline. These risk factors were determined based upon existing case reports and deductive reasoning.
- Prior adverse reaction to doxycycline: Anyone who has previously experienced an adverse neuropsychiatric reaction (anxiety, depression, etc.) while using doxycycline is at highest risk of experiencing an adverse neuropsychiatric reaction with future doxycycline treatment. Additionally, anyone with a first-degree family member who has previously experienced an adverse neuropsychiatric reaction while using doxycycline is at greater risk of experiencing an adverse neuropsychiatric reaction (likely due to genetically-mediated similarities in cytochrome P450 metabolism, neurochemistry, and/or the gut microbiota).
- History of neuropsychiatric disorders: A relatively obvious risk factor for experiencing adverse neuropsychiatric reactions while using doxycycline is a history of neuropsychiatric disorders and/or symptoms. In other words, if you’ve been diagnosed with major depressive disorder, generalized anxiety disorder, or another psychiatric condition – this could increase your risk of experiencing adverse neuropsychiatric events during doxycycline treatment.
- Poor CYP450 metabolism: Individuals with suboptimal or poor CYP450 metabolism might be at increased risk of experiencing adverse neuropsychiatric reactions while using doxycycline. More specifically, poor expression and function of CYP3A enzymes (implicated in doxycycline metabolism) might result in elevated plasma concentrations of doxycycline and possibly even toxicity (among a subset of high dose users). Elevated plasma concentrations of doxycycline will amplify its effect thereby increasing risk of adverse neuropsychiatric reactions.
- High doses: The greater the dosage of doxycycline administered, the more substantially it’ll modulate aspects of physiology in ways that could affect mood. For example, high doses of doxycycline exert a more substantial effect on gut bacteria and within the brain (than lower doses). In one case report, a patient was suspected to have experienced harsher depression and suicidality at 100 mg doses – relative to 50 mg doses. High dose doxycycline users are probably at greater risk of experiencing depression and anxiety – than lower dose users.
- Atypical gene expression: As was mentioned, poor CYP450 (cytochrome P450) metabolism as a result of atypical gene expression could yield elevated plasma concentrations of doxycycline and increase risk of adverse neuropsychiatric reactions. Additionally, atypical expression of genes encoding for 5-HT1A receptors in the brain (neurochemical receptors that might also be affected by doxycycline) – could increase risk of adverse neuropsychiatric reactions.
- Long-term treatment: It is hypothesized that long-term doxycycline administration may increase risk of anxiety, depression, and/or suicidality – relative to short-term administration. This might be due to the fact that the magnitude and/or quantity of physiologic modulations (e.g. gut bacteria depletion) induced by doxycycline might increase or compound over time. Moreover, if adverse neuropsychiatric reactions emerge over a short-term, it’s possible that deleterious thought patterns (and feedback loops) might be strengthened over a longer-term whereby adverse neuropsychiatric reactions increase in severity.
- Recent antibiotic use: If you’ve used antibiotics within 6 months of administering doxycycline, you might be at increased risk of experiencing adverse neuropsychiatric reactions during treatment – relative to persons who’ve never used antibiotics and/or those with longer time-gaps between their previous course of antibiotics and doxycycline administration. Recent antibiotic use (prior to doxycycline treatment) increases risk of deleterious physiologic changes lingering within the body. If any deleterious physiologic changes are still lingering from a prior course of antibiotics (e.g. gut dysbiosis) – this might substantially increase odds of an adverse reaction to doxycycline.
Recovering from doxycycline-induced depression and/or anxiety (Recommendations)
Included below are recommendations to ensure that you recover as quickly as possible from doxycycline-induced adverse neuropsychiatric reactions. Such recommendations include: receiving medical support; seeking psychological support; focusing on health; considering supplements; and letting time pass.
- Professional medical support: If you experience any adverse reaction while using doxycycline (regardless of whether neuropsychiatric), it is recommended to seek immediate medical attention. A medical doctor will be qualified to: (1) determining why doxycycline might’ve caused an adverse reaction; (2) prescribe an alternative medication (if necessary – such as if there’s still an infection); and/or (3) recommend strategies and/or medications to treat the adverse reactions.
- Professional psychological support: In addition to seeking immediate medical attention, you may want to seek professional psychological support. Although depression, anxiety, and/or suicidality from doxycycline treatment may be short-lived and abate following discontinuation – having support from a psychologist while experiencing these adverse neuropsychiatric reactions may prove to be immensely helpful.
- Focus on your health: To recover from adverse neuropsychiatric reactions to doxycycline, it is recommended to focus on your health as much as possible. This means eating a nutritious diet (high fiber, vegetables, fruits, fermented foods, no excess sugar, etc.); maintaining a healthy circadian rhythm (with adequate sleep); getting plenty of sunshine; practicing stress reduction; exercising regularly; and staying socially engaged with family and friends. All of these activities should augment gut microbiome recovery after doxycycline cessation – and may counteract depression and/or anxiety.
- Let time pass: Even if you’re working with a medical doctor; seeing a psychologist; and living the healthiest lifestyle you’re capable of – you may still experience some unwanted lingering neuropsychiatric symptoms following doxycycline cessation. This could be due to the fact that aspects of physiology (e.g. gut bacteria composition, neurochemistry, etc.) haven’t transitioned back to pre-doxycycline homeostasis. Assuming your neuropsychiatric symptoms were legitimately attributable to doxycycline, an effective recovery strategy is often to “let time pass.” The physiology of most individuals will recover with enough time off of doxycycline.
Supplements to Manage Doxycycline-induced Depression & Anxiety
Included below is a list of supplements that may help reduce the severities of adverse neuropsychiatric symptoms associated with doxycycline treatment. Prior to using any supplement – always consult a medical doctor to ensure that it’s safe in accordance with your current medical status and medication usage.
Additionally, because certain supplements on this list may interact with others – do not administer multiple supplements simultaneously unless deemed safe by a medical doctor. Moreover, realize that certain individuals may derive more benefit from supplementation in the management of adverse neuropsychiatric reactions to doxycycline than others.
Affiliate link disclosure: The supplements listed above contain affiliate links which help MentalHealthDaily.com earn money. If you want to support the site, buying products through affiliate links is appreciated. I did my best to select products that I thought were reasonably priced and potentially therapeutic for persons attempting to counteract doxycycline-induced depression and/or anxiety.
- PRO-15 (Probiotic): Because doxycycline may trigger depressive and/or anxious symptoms by depleting healthy gut bacteria, it is strongly recommended to consider supplementing with a probiotic during doxycycline treatment – and post-treatment. I personally like the supplement “PRO-15” which contains many bacterial strains in a favorably-formatted “bead” (such that bacteria won’t be killed by stomach acid before colonizing within the gut).
- Visbiome (High-potency probiotic): A stronger probiotic supplement to consider if your gut needs greater microbial replenishment following doxycycline treatment is “Visbiome.” Because Visbiome is a more powerful probiotic than PRO-15, users should be cognizant of potential side effects. (Read: “Probiotics Side Effects” & “How Long Does It Take for Probiotics to Work?”)
- Curcumin: Potentially one of the best supplements for restoring gut health in the aftermath of doxycycline (or antibiotic) administration is curcumin. Curcumin is a spice that has been shown to regulate intestinal barrier function and bolster intestinal integrity. Additionally, curcumin supplementation in animals has been shown to improve gut microbe diversity. Other research suggests that curcumin might reduce systemic inflammation, improve brain function, and mental health. (Read: “Curcumin Side Effects”)
- Magnesium citrate: If you’re experiencing severe anxiety, insomnia, or feel irritable from doxycycline – consider supplementing with magnesium citrate. Magnesium citrate is understood to decrease excitatory transmission and generally has a calming effect whereby it reduces anxiety, insomnia, and irritability. (Read: “Magnesium for Depression“)
- Krill oil: This is a supplement that contains omega-3 fatty acids (DHA and EPA) in a highly-bioavailable form. The omega-3 fatty acids in krill oil are believed to stabilize irregular neurochemistry and promote healthy brain function. Some animal studies also suggest that krill oil improves gut bacteria composition. (Read: “Krill Oil Side Effects”)
- L-theanine: If you’re experiencing heightened anxiety or irritability as a result of doxycycline treatment, you may want to consider supplementing with L-theanine. (Read: “L-theanine for Anxiety“) L-theanine modulates a variety of neurotransmitter systems to induce an anxiolytic effect whereby stress and anxiety levels generally decrease. (Read: “L-theanine Side Effects”)
- B complex: Some individuals find vitamin B complex supplements to be effective for anxiety, muscle tension, insomnia, and depression. If you’re experiencing any severe neuropsychiatric reactions while using doxycycline (or in the aftermath of discontinuation) – consider testing the effect of a vitamin B complex supplement.
- Multivitamin: Ongoing treatment with doxycycline (or other antibiotics) might impair dietary nutrient absorption (in a subset of the population). If nutrient absorption is impaired as a result of treatment, a nutrient deficit (even if modest) could cause adverse reactions like depression and anxiety. To ensure that a nutrient deficit isn’t causing these adverse reactions – you may want to supplement with a multivitamin.
- Glutathione: Glutathione is arguably the single most potent antioxidant within the body. If your glutathione production is suboptimal and/or you have high levels of oxidative stress (as a result of doxycycline treatment) – this could be contributing to adverse neuropsychiatric symptoms such as depression and anxiety. Supplementation with glutathione should help decrease oxidative stress and may counteract lingering adverse symptoms.
- Lemon balm: Assuming none of the aforementioned supplements were effective in attenuating anxiety, insomnia, depression, or an overactive stress response caused by doxycycline – the herbal supplement known as “lemon balm” might be worth trying. Preliminary research suggests that lemon balm exerts a combination of anxiolytic and antidepressant effects.
- Electrolyte formula: It’s reasonable to suspect that doxycycline use might alter concentrations of electrolytes throughout the body. If electrolyte levels are imbalanced within the body and/or brain – this could affect neurotransmission and prompt adverse neuropsychiatric symptoms. Supplementation with an electrolyte formula may help restore or optimize electrolyte levels after discontinuation of doxycycline.
- Rhodiola rosea: Rhodiola rosea is an adaptogenic herb that many suspect can help balance autonomic nervous system activation – and increase concentrations of monoamines (serotonin, norepinephrine, dopamine) within the brain. If you think doxycycline might’ve altered your autonomic nervous system activity and/or monoamine levels – Rhodiola might be beneficial. (Read: “Rhodiola Rosea Side Effects“)
- Epsom salts: Although the therapeutic efficacy of Epsom salts remains scientifically unclear, many individuals claim that adding Epsom salts to a warm bath significantly reduces feelings of anxiety and stress. If you’re experiencing significant anxiety and/or are struggling to remain calm while using doxycycline – Epsom salts may be worth trying.
Can doxycycline ever treat depression and/or anxiety?
Although the purpose of this article was to underscore the fact that doxycycline can cause adverse neuropsychiatric reactions such as anxiety, depression, and suicidality – not all users have this experience. In fact, a subset of users with preexisting anxiety disorders and/or major depressive disorder might experience a substantial subjective improvement in anxious or depressive symptoms while using doxycycline.
There are numerous hypothetical reasons as to why a subset of doxycycline users experience a noticeable reduction in preexisting anxiety and/or depression during treatment. Prospective mechanisms by which doxycycline might enhance mood and reduce anxiety include: (1) eliminating pathogenic gut bacteria; (2) reducing systemic inflammation; (3) decreasing oxidative stress; (4) modulating neurotransmission; and/or (5) eradicating a lingering infection that was culpable for the anxiety and/or depression.
Assuming someone is experiencing neuropsychiatric symptoms from: gut dysbiosis; abnormally high inflammation; heightened oxidative stress; and/or an infection (such as within the brain) – doxycycline treatment has potential to simultaneously counteract all of these causes. That said, the most likely means by which select doxycycline users experience improvement in anxious or depressive symptoms is via its anti-inflammatory action.
Doxycycline is a potent anti-inflammatory agent at both low and high doses whereby it downregulates proinflammatory cytokines and chemokines. Because systemic inflammation can directly cause depression (likely as a result of cytokines and chemokines penetrating the blood-brain barrier and disrupting neurotransmission), counteracting this inflammation with doxycycline would likely improve mood and reduce anxiety.
Nevertheless, doxycycline might also improve gut composition in persons with serious dysbiosis (by killing pathogenic microbes) plus reduce oxidative stress (via its antioxidant effect) among individuals with high concentrations of reactive oxygen and/or nitrogen species – additional mechanisms by which doxycycline could decrease the severities of neuropsychiatric symptoms. Also obvious is that treating an infection like Lyme disease (which causes systemic inflammation and can provoke neuropsychiatric symptoms) with doxycycline can reverse infection-induced neuropsychiatric symptoms (e.g. anxiety and depression).
Note: Antibiotics similar to doxycycline appear to be helpful as antidepressants for some individuals. If you’re interested in learning more, read the article “Minocycline for Depression.”
- Source: https://www.ncbi.nlm.nih.gov/pubmed/21350981
- Source: https://www.ncbi.nlm.nih.gov/pubmed/26711676
- Source: https://www.ncbi.nlm.nih.gov/pubmed/18079991
My personal experiences with doxycycline-induced depression, suicidality
In spring of 2016, I saw a physician’s assistant (PA) who suspected a potential skin infection – and prescribed a 10-day course of doxycycline 100 mg (b.i.d.). The physician’s assistant conducted tests (e.g. bacterial culture) to determine whether an infection was present, however, the results of these tests weren’t available for several days.
For reference, prior to using doxycycline in 2016, it had been over a decade (10 years) since I had been prescribed antibiotics. Although testing eventually revealed that no infection was present, I followed instruction from the physician assistant and administered doxycycline 100 mg (b.i.d.) for the recommended 10-day period.
On the first day of treatment, I experienced some fatigue and noticeable “brain fog” (i.e. unclear thinking) – but no significant anxiety or depression. On the second day of treatment, the brain fog worsened such that I had significant difficulty writing and engaging in conversation.
By the third day of doxycycline treatment, I experienced a mild increase in anxiety and moderate depression. The heightened anxiety was manageable, however, the depression was difficult to bear. On the fourth day of doxycycline treatment I began experiencing a deeper, harsher depression accompanied by suicidal thoughts.
I informed a close relative about the onset of severe depression and suicidal thoughts while using doxycycline. Discussion of how I felt, feedback from the relative, and knowing that I only had 10 days of treatment helped me cope with my adverse neuropsychiatric symptoms.
Though I forced myself to maintain a rigid healthy routine (exercise, diet, sunshine, working, etc.), the depression was unrelenting and at the forefront of my perception. The severe depression with intermittent suicidal thoughts (and crying spells) persisted from the third day through the eighth day of treatment.
Oddly and unexpectedly, the depression lifted on the final two days of treatment and I actually felt good (such that, on days nine and ten of treatment, I wouldn’t have cared if longer-term doxycycline use was necessary). After the 10-day course of doxycycline, I supplemented with probiotics, ate fermented foods, and administered adaptogenic herbs to potentially enhance recovery.
My normative “pre-doxycycline” clarity of thought, mood, anxiety level, and perception – returned within 2 weeks of treatment cessation. Though my deliberate post-treatment consumption of fermented foods and/or probiotics plus adaptogenic herbs may have augmented my recovery – I suspect the biggest factor in recovery was letting adequate time pass for my physiology to transition from a doxycycline-adapted state to homeostasis.
Since my initial use of doxycycline in 2016, I’ve used the medication two additional times: (1) in summer of 2017 for 30 days (100 mg, b.i.d.) to treat arthritis (turned out to be a misdiagnosis) and (2) in spring of 2018 for 10 days (100 mg, b.i.d.) to treat a urinary tract infection (another misdiagnosis). Reflecting upon my 3 series of doxycycline treatments, antibiotic usage could’ve been avoided – as no infections were discovered via testing.
Nevertheless, medical doctors prescribed doxycycline because: (1) it was smarter to err on the side of caution and treat a potential infection and (2) it is a relatively safe antibiotic that’s often used long-term to manage skin conditions (e.g. acne). In all cases, I agree with the prescription of doxycycline and do not “regret” taking it.
Why did I experience depression while using doxycycline? (Possible reasons).
I can only speculate as to why I might’ve experienced depression while using doxycycline. I have: a history of anxiety and depression; atypical 5-HT1A receptor expression (a potential site of interaction for doxycycline); atypical CYP450 metabolism for certain medications (although I’m unsure about doxycycline specifically); and hadn’t used antibiotics for over 10 years prior to 2016 (possibly increasing odds of a Herxheimer-like reaction).
Would I ever use doxycycline again after these reactions?
Yes. Firstly, I’m allergic to many classes of antibiotics – so my options are limited. Secondly, compared to other antibiotics (e.g. fluoroquinolones, macrobid, etc.), I regard doxycycline as safer, more tolerable, and less likely to induce long-term iatrogenic complications (e.g. ototoxicity, tendon ruptures, etc.).
Although doxycycline caused anxiety and moderate-to-severe depression with suicidal thoughts, I’d use it again if necessary. In my experience, the adverse neuropsychiatric reactions resulting from doxycycline were significant but transient (in that they dissipated once doxycycline treatment ended).
Have you experienced depression and/or anxiety from doxycycline?
If you’ve used doxycycline and experienced adverse neuropsychiatric reactions during treatment, share your experience(s) in the comments section below. Document the specific adverse neuropsychiatric reactions that you experienced (e.g. anxiety, depression, suicidality, etc.) – and subjectively rate the severities of these reactions (on a scale from “1” to “10” – with “10” indicating maximum severity).
To help others get a better understanding of your experience(s) with doxycycline-induced adverse neuropsychiatric reactions, provide details such as: (1) doxycycline dosage; (2) treatment duration; (3) concurrent substance use; and (4) the medical condition for which doxycycline was prescribed; (5) whether you used antibiotics in the 6 months prior to doxycycline treatment.
How long after the initiation of doxycycline treatment did it take for adverse neuropsychiatric reactions to emerge? Throughout your course of doxycycline treatment, did you observe any noticeable fluctuations in specific adverse reactions and/or the severities of adverse reactions?
(In other words, did any of the adverse reactions spontaneously resolve, lessen, or intensify during treatment?) If you experienced adverse neuropsychiatric reactions for the entirety of your doxycycline treatment, how long did it take for these reactions to completely resolve following doxycycline cessation?
Could you identify any significant environmental stressors that might’ve either exacerbated your adverse neuropsychiatric reactions to doxycycline OR been fully culpable for these reactions? If you were using other substances with doxycycline such as additional antibiotics, psychiatric medications, etc. – have you considered the possibilities that either: interaction effects (between doxycycline and another agent) might’ve provoked adverse neuropsychiatric reactions OR that concurrently-administered substances might’ve been fully culpable for adverse neuropsychiatric reactions?
If you’ve used multiple doses of doxycycline, did you notice a relationship between dosage and the occurrence and/or severities of adverse neuropsychiatric reactions. In the event that you’ve used doxycycline multiple times (with significant time-gaps between each treatment) – were the adverse neuropsychiatric reactions similar or different between treatments?
For general context, mention whether you’ve ever been diagnosed with a neuropsychiatric disorder; have a history of mild or intermittent neuropsychiatric symptoms; have a first-degree relative with a neuropsychiatric disorder; and/or a chronic medical condition that could cause neuropsychiatric symptoms.
Are there any specific reasons as to why you think you might’ve experienced adverse neuropsychiatric reactions to doxycycline? Examples might include: Herxheimer-like reactions; poor doxycycline metabolism; nutrient deficiencies; neurochemical imbalances; etc.
Lastly, if at some point in the future a medical doctor were to suggest doxycycline as a treatment for a bacterial infection, would you be okay with using doxycycline again (despite a prior adverse neuropsychiatric reaction)? Or would you ask for an alternative antibiotic?