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Benadryl (Diphenhydramine) For Anxiety: A Makeshift, Last-Resort Option?

Benadryl is a widely-recognized brand name for popular over-the-counter (OTC) antihistaminergic products containing diphenhydramine (U.S. & Canada), a chemical of the ethanolamine classification.  Diphenhydramine was initially discovered in 1943 by professor and chemist George Rieveschl while attempting to synthesize alternatives to scopolamine.  Just several years after its synthesis, diphenhydramine received FDA approval in 1946 as a prescription pharmaceutical for the management of allergy, common cold, and cough-related symptoms.

After decades of usage as a prescription-only (Rx-only) medication and evidence to support its favorable safety profile, diphenhydramine received FDA authorization in 1985 to be sold over-the-counter.  Not long after its approval for over-the-counter retail, Pfizer Consumer Healthcare began marketing diphenhydramine under the brand name “Benadryl.”  Rights to the name Benadryl were eventually transferred in 2007 to Johnson & Johnson, a subsidiary of McNeil Consumer Healthcare.

These days, Benadryl remains a frequently utilized intervention for a host of medical conditions including: allergies, common colds, coughs, extrapyramidal symptoms, itchiness, insomnia, motion sickness, nausea, vertigo, and vomiting.  Due to the fact that Benadryl can induce a sedative and/or hypnotic effect, and has been suggested to facilitate an anxiolytic effect, some have questioned whether it could be effective for the treatment of anxiety.  Though diphenhydramine’s anxiolytic efficacy hasn’t been formally evaluated, when considering its pharmacodynamics and anecdotal testimonials documenting its anxiolytic effect, there’s reason to believe that Benadryl may serve as a makeshift intervention in a subset of anxiety sufferers.

How Benadryl May Treat Anxiety (Mechanisms of Action)

At low doses, the mechanism of action associated with Benadryl’s anxiolytic effect isn’t very complex.  Diphenhydramine primarily acts as an inverse agonist at central and peripheral H1 (histamine) receptor sites, whereby it simultaneously blocks activation of H1 receptors and exerts an opposite effect upon H1 receptors than endogenous ligands (e.g. histamine).  As a result of this inverse agonism, Benadryl users may report feeling predictably drowsy, sedated, and in some cases, less anxious.

At higher doses, Benadryl users may derive additional [yet less substantial] anxiolytic effects via modulation of: acetylcholine, norepinephrine, and serotonin.  This is because, in hierarchy of binding affinity after its chief H1 receptor target, diphenhydramine exhibits affinities for other targets including: M1 receptors, NETs (norepinephrine transporters), alpha-1 receptors, and SERTs (serotonin transporters).  In other words, diphenhydramine’s blockade of H1 receptors generates a majority of its anxiolytic effect, however at higher doses, the combination of:  M1 antagonism, NET inhibition, alpha-1 antagonism, and SERT inhibition – may be somewhat implicated in the anxiety reduction.  Below are descriptions of each mechanism of diphenhydramine’s action in regards to how they may reduce anxiety.

H1 receptor (inverse agonist):  Among those who claim to experience lower anxiety after taking Benadryl, action of diphenhydramine upon central H1 (histamine) receptors should be regarded as generating most of the [perceived] anxiolytic effect.  Inverse agonism at the H1 receptor implies that diphenhydramine not only blocks the H1 receptor from the stimulation of endogenous ligands (e.g. histamine), but also that it exerts an opposing effect upon (i.e. inversely agonizes) the receptor [as compared to histamine].  Though evidence from human trials is lacking to substantiate H1 receptor inverse agonism as a legitimate anxiolytic mechanism in humans, animal model research indicates that it may be effective.

For example, a study by Kumar, Krishna, and Palit (2007) discovered that H1 receptor activation induced anxiety in animal models.  Specifically, when researchers administered L-histidine to increase central concentrations of histamine, anxiety-like behavior was observed among mice in an elevated plus maze.  In effort to determine the specific histamine receptors implicated in the anxiogenic response, researchers administered antagonists of H1, H2, and H3 receptors prior to L-histidine and recorded behavioral changes of the mice in the elevated plus maze.

It was documented that only the H1 receptor antagonist (pyrilamine) effectively prevented anxiety-like behaviors in the mice, suggestive of the fact that H1 receptor activation can directly cause anxiety.  Other research by Imaizumi, Miyazaki, and Onodera (1996) reported similar findings such that, agonism of H1 receptors with betahistine increased anxiety-like behavior in mice.  What’s more, like the other study, administration of H1 receptor antagonists (pyrilamine and ketotifen) counteracted the betahistine-induced anxiety, leading researchers to conclude that H1 receptors may regulate aspects of anxiety.

More evidence linking the H1 receptor to anxiety is derived from a study by Hasenöhrl, Weth, and Huston (1999).  In this study, researchers examined the effect of an H1 receptor antagonist (chlorpheniramine) on the performance of aged Norway rats in various testing paradigms.  Not only did chlorpheniramine administration enhance overall maze performance of the rats, but it decreased fear-related behaviors in open field and black-and-white box tests, indicating that degree of H1 receptor activation influences fear-related processes.

Other experiments by Privou, Knoche, Hasenöhrl, and Huston (1998) analyzed the effect of the H1 receptor blocker chlorpheniramine on rats.  Researchers administered chlorpheniramine via injection to the nucleus basalis magnocellularis region of rat brains and recorded performance of the rats in multiple experiments.  In the second experiment, it was noted that chlorpheniramine administration reduced anxiety-like behavior, as was evidenced by increased scanning and open arm times in an elevated plus maze.

Overall, numerous studies in animal models support the idea that activation of H1 receptors can induce anxiety in animals, and that deactivation of H1 receptors can attenuate anxiety and/or generate an anxiolytic effect.  Though we cannot assume these animal model data are neurochemically-relevant to humans, potential similarities cannot be blatantly dismissed.  One possibility is that a subset of humans exhibit excessive H1 receptor activation as a predominant or partial cause of their anxiety disorders.

It is logical to assume that administration of an H1 receptor inverse agonist to persons with overactive H1 receptors would markedly reduce symptoms of anxiety.  That said, there’s no compelling data to suggest that a majority of individuals with an anxiety disorder exhibit dysregulated histamine transmission.  Nonetheless, even among those devoid of preexisting histaminergic irregularities as a cause of anxiety, inverse agonism of diphenhydramine upon the H1 receptor could mitigate anxious symptoms in humans analogous to, or perhaps more effectively than, the H1 antagonists did in animal models.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/17426485
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M1 receptor (competitive antagonist): Though the binding affinity of diphenhydramine to the M1 (muscarinic) receptor is less than 10-fold its affinity for the H1 receptor, at moderate or high doses, M1 receptor antagonism may contribute to the overall anxiolytic effect.  Evidence from animal and human studies supports the idea that modulation of M1 receptor activity can affect anxiety levels.  For example, a study by Fogaça, Fedoce, Ferreira-Junior, et al. (2016) tested activation of M1 receptors and CB1 receptors in rats to determine whether they influenced anxiety.

The study utilized rats and assigned them to received injections of the acetylcholinesterase inhibitor neostigmine within the prelimbic medial prefrontal cortex, a region associated with emotional regulation through cholinergic and endocannabinoid transmission.  That said, prior to the injections of neostigmine, the rats had been divided into groups and received one of the following: a vehicle (placebo), pirenzepine (an M1 antagonist), AM251 (a CB1 antagonist), or URB597 (an FAAH inhibitor).  After the neostigmine injections, rats were evaluated in an elevated plus maze.

Researchers noted that inhibition of acetylcholinesterase decreased open arm exploration of rats in the elevated plus maze, signifying an anxiogenic-like response.  However, when the M1 antagonist pirezepine or CB1 antagonist AM251 were administered, the anxiogenic-like response never occurred.  Based on these findings, it was concluded that crosstalk between the M1 receptors and CB1 receptors influence anxiety-like behavior.  It was proposed that M1 receptor activation leads to downstream endocannabinoid release whereby CB1 receptors become activated downstream and cause anxiety.

Additional evidence linking the muscarinic acetylcholine receptors (mAChRs) to anxiety comes from a study by Hoeller, Costa, Bicca, et al. (2016) in which the cholinergic system was examined as it relates to emotional processing.  The researchers cited evidence from older studies reporting single-dose injections of pilocarpine, a muscarinic acetylcholine receptor agonist, lead to long-term anxiogenic-like responses in rats for up to 3-months post-injection.  In their study, it was discovered that pilocarpine injections to Wistar rats caused anxiety-like behavior in an elevated plus maze.

It was noted that activation of muscarinic acetylcholine receptors disrupts HPA axis function, which in turn facilitates corticosterone release.  The release of corticosterone decreases expression of hippocampal glucocorticoids and downregulates the expression of NMDA receptor subunits, ultimately causing long-term anxiety.  Although this study didn’t specifically focus on the M1 receptor, it indicates that agonism of muscarinic receptors (including the M1 receptor) may cause unremitting anxiety over an extended duration.

Also worth mentioning is a study by Wall, Flinn, and Messier (2001) in which the cognitive and behavioral effects of muscarinic acetylcholine receptor (MAChR) drugs were assessed in mice.  For this study, researchers administered scopolamine, pirenepine, or McN-A-343 to mice via infusion within the infralimbic (IL) area of the ventromedial prefrontal cortex (vmPFC), and thereafter, documented their performance in elevated plus mazes and Y-tests.  Results indicated that administration of scopolamine (a muscarinic receptor antagonist) lead to some anxiogenic-like behavior, whereas the M1 receptor antagonist pirenzepine yielded anxiolytic-like effects, but compromised working memory.

It was further mentioned that the M1 receptor agonist McN-A-343 induced anxiogenic-like effects, but enhanced working memory.  Researchers concluded that enhanced activation of the M1 receptors in the vmPFC causes anxiety but bolsters working memory, whereas blocking M1 receptors in the vmPFC reduces anxiety but compromises working memory.  From these results, we might speculate similar outcomes in humans, such that: M1 receptor stimulation (in the vmPFC) exacerbates anxiety and improves working memory, whereas M1 receptor blockade (in the vmPFC) impairs working memory but reduces anxiety.

Though M1 receptor activation in certain regions of the brain such as the vmPFC may influence the severity of anxiety in humans similar to animals, results from the animal studies cannot be extrapolated to humans.  For this reason, a trial in which scopolamine was administered to humans warrants discussing.  A randomized, placebo-controlled, double-blind, crossover trial by Furey, Khanna, Hoffman, and Drevets (2010) recruited 52 outpatients with major depressive disorder OR bipolar disorder to test the therapeutic efficacy of scopolamine, a muscarinic receptor antagonist.

The trial involved patients receiving intravenous infusions of a placebo OR scopolamine (4 mcg/kg).  Measures collected prior to the trial included the severity of a person’s depression based on the MADRS (Montgomery-Asberg Depression Rating Scale) and the HAM-A (Hamilton Anxiety Rating Scale).  A significant antidepressant and anxiolytic response were observed among patients following treatment with the scopolamine, and the effects were greater in women compared to men.

Evidence from this trial supports the idea that muscarinic receptor antagonists such as scopolamine may improve mood and/or decrease symptoms of anxiety in a subset of the population.  Additionally, some believe that scopolamine may exhibit highest binding affinity for the M1 receptors in humans, meaning that M1 receptors may facilitate a bulk of its anxiolytic effect.  Though we cannot assume that diphenhydramine exerts the same magnitude of antagonism upon the M1 receptor as scopolamine, it’s possible that even a smaller degree of M1 antagonism contributes to an anxiolytic effect.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26873081
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NET inhibitor:  The action of diphenhydramine as an inhibitor of the norepinephrine transporter (NET) is significantly lower than its action as an H1 inverse agonist, and nearly 3-fold lower than its action as an M1 competitive antagonist.  Nonetheless, individuals using a moderate-to-high dose of Benadryl will likely experience some degree of NET inhibition.  Although inhibition of the norepinephrine transporter (NET) from diphenhydramine may increase anxiety for some, counterintuitive responses such as reduced anxiety may be observed.

For this reason, the inhibition of diphenhydramine upon the NET should be mentioned as possibly implicated in an anxiolytic response.  It is known that the principal function of the NET is to transport norepinephrine within the synaptic cleft, back into the presynaptic neuron.  Some sources estimate that around 90% of norepinephrine released into the synaptic cleft is subject to reuptake by the NET.

However, when the NET is inhibited, norepinephrine within the synaptic cleft doesn’t reenter the presynaptic neuron, rather, it stimulates postsynaptic noradrenergic receptors to increase signaling.  Noradrenergic signaling is understood to influence a person’s arousal, mood, learning, memory, and pain perception.  When noradrenergic signaling is dysregulated, neuropsychiatric disorders may occur, particularly depression, but anxiety (although less likely) is another possibility.

In their paper “The Noradrenergic Paradox,” researchers Montoya, Bruins, Katzman, and Blier (2016) note that inhibitors of the NET may not cause anxiety in the majority of users.  The paradox is that NET inhibition may even reduce stress responses and anxiety through elevation of basal norepinephrine from a deficit to increase inhibitory tone.  Researchers document the finding that reboxetine, a selective NRI (norepinephrine reuptake inhibitor), appears effective for the treatment of panic disorder, phobias, anticipation anxiety, and social deficits.

In some studies, reboxetine is also effective for the treatment of comorbid anxiety, agitation, and insomnia among persons with major depression – indicating an anxiolytic effect.  The paper concluded that inhibition of the NET does not increase likelihood of anxiety, and may paradoxically decrease it.  Considering this evidence, it’s possible that moderate-to-high dose diphenhydramine’s modest action as an NET inhibitor might slightly help with alleviation of anxiety.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/27042068

Alpha-1 receptor (antagonist):  When taken at low doses, the alpha-1 receptor antagonism exerted by diphenhydramine is probably too insignificant to facilitate anxiety reduction.  On the other hand, when Benadryl is taken at high doses, the alpha-1 antagonism of diphenhydramine may be substantial enough to slightly alleviate anxious symptoms of some users.  Animal model studies support the idea that alpha-1 receptor antagonists can affect fear-related behavior.

Cecchi, Khoshbouei, and Morilak (2002) report that the central nucleus of the amygdala (CeA) is a component of fear-anxiety circuitry within the limbic system and can influence activity of the HPA axis.  When noradrenergic transmission is upregulated in the CeA as a result of immobilization stress, alpha-1 adrenergic receptors are stimulated, which appears to cause fear and anxiety-like behaviors among rats in social interaction (SI) and elevated plus maze (EPM) tests.  Microinjections of benoxathian (an alpha-1 receptor antagonist) within the CeA of rats was shown to dose-dependently prevent anxiety on the social interaction test after immobilization stress.

It was concluded that modulation of alpha-1 receptor activation in the CeA could protect against certain aspects of anxiety.  Though it is unknown as to whether antagonism of alpha-1 receptors could be used to treat anxiety in humans, a report by Miller (2008) suggests that they could be helpful.  Miller noted that the alpha-1 adrenergic receptors are implicated in startle and sleep responses.

Specifically, it seems as though activation of alpha-1 receptors in humans can trigger PTSD-related traumatic memories and nightmares.  Oppositely, deactivation of the alpha-1 receptors with administration of the drug Prazosin can attenuate the trauma and nightmares.  Since diphenhydramine (at high doses) can antagonize the alpha-1 receptors, it’s possible that it could slightly mitigate certain aspects of anxiety in certain people.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/12504920
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/18447662

SERT inhibitor: To a slightly lesser extent than it’s alpha-1 receptor antagonism, diphenhydramine can function as a serotonin transporter (SERT) inhibitor, which might contribute negligibly to anxiety reduction among those using a high dose.  Inhibition of the serotonin transporter prevents the reuptake of extracellular serotonin into the presynaptic neuron.  As a result, more serotonin remains within the synaptic cleft and binds frequently to postsynaptic receptors, thereby increasing serotonin signaling.

It is thoroughly established that the increased serotonin signaling can induce relaxation and improve mood, hence the reason SSRIs (selective-serotonin reuptake inhibitors) are commonly prescribed as first-line agents for the treatment of anxiety disorders.  Though pharmacodynamics differ slightly based on the specific drug administered, all SSRIs enhance postsynaptic receptor stimulation through inhibiting serotonin reuptake.  Older agents such as TCAs and MAOIs also prevent the reuptake of serotonin and increase postsynaptic receptor stimulation to attenuate symptoms of anxiety.

Not everyone with anxiety will derive benefit from SERT inhibition, but many will, as evidenced by clinically relevant anxiety reductions following administration of serotonergic antidepressants.  That said, unless you’re using a relatively outrageous dose of Benadryl, SERT inhibition won’t occur and this mechanism will be irrelevant in regards to treating anxiety.  On the other hand, using an extreme quantity of Benadryl should provide some SERT inhibition that contributes to the overall anxiolytic effect.

  • Source: https://www.ncbi.nlm.nih.gov/pubmed/10511010
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In summary, anyone claiming that Benadryl works well for their anxiety at standard dosages is likely experiencing an anxiolytic effect mediated by H1 receptor inverse agonism and M1 receptor competitive antagonism.  In other words, the antihistaminergic and anticholinergic properties of standard-dose Benadryl can be sedating enough to alleviate some aspects of anxiety or reduce sympathetic tone.  A small percentage of persons utilizing moderate-to-high doses could potentially derive an anxiolytic effect from inhibition of the norepinephrine transporter (NET), although most would consider this unlikely.

At more extreme and/or higher doses of diphenhydramine, users will experience blockade of alpha-1 receptors and inhibition of the serotonin transporter (SERT).  The alpha-1 receptor blockade may help with aspects of fear or anxiety such as startle, nightmares, or traumatic memories, and the SERT inhibition is a proven treatment for anxiety.  Overall, the degree to which an individual derives anxiolytic benefit from diphenhydramine will be subject to significant individual variation and contingent upon the neurochemical underpinnings of the user’s anxiety.

Note:  Benadryl sold in the United Kingdom (UK) does not contain diphenhydramine, instead it’s comprised of acrivastine, a different antihistamine.  Acrivastine functions primarily as an H1 receptor antagonist, making it similar to diphenhydramine in its primary mechanism of action, however, it may differ in secondary and tertiary targets at higher doses.

Other Possible Anxiolytic Mechanisms of Benadryl

Besides the direct CNS targets such as the H1 and M1 receptors, there are other possible means by which diphenhydramine may generate and/or contribute to an anxiolytic effect in some users.  In other words, the effect of its central actions within the brain upon H1 receptors and M1 receptors may not always directly reduce anxiety.  It’s possible that some individuals derive an anxiolytic benefit from its modulatory influence over the autonomic nervous system, its ability to enhance sleep, and/or the fact that it may decrease inflammation.

ANS modulation: Another possible mode by which diphenhydramine might attenuate symptoms of anxiety is through modulation of the autonomic nervous system (ANS).  It is understood that diphenhydramine’s H1 inverse agonism and M1 competitive antagonism facilitate respective antihistaminergic and anticholinergic effects.  The downstream outcome of antihistaminergic and anticholinergic action is downregulated tone of the sympathetic nervous system, a branch of the autonomic nervous system (ANS) implicated in arousal, anxiety, and stress.

While sympathetic tone is downregulated, we should expect and upregulated tone of the parasympathetic nervous system, a branch of the autonomic nervous system (ANS) implicated in rest, relaxation, and digestion.  There’s reason to believe that modulation in the ratio of sympathetic to parasympathetic activation (SNS:PNS) could help persons with anxiety disorders.  Evidence supporting the concept of autonomic nervous system dysfunction among a subset of patients with psychiatric disorders, including anxiety, is documented in a systematic review by Alvares, Quintana, Hickie, and Guastella (2016).

A study by Sharma, Sagar, Deepak, et al. (2011) reported autonomic rigidity or diminished ANS flexibility among pediatrics with anxiety disorders, also supporting the idea that autonomic dysfunction may play a causal role in anxiety.  It is general knowledge that excessive activation of the sympathetic nervous system is associated with release of catecholamines and stress hormones, each of which can cause anxiety.  Since individuals with anxiety disorders often exhibit hyperactivation of the sympathetic nervous system, pharmacological interventions capable of decreasing sympathetic and/or increasing parasympathetic tone, could yield marked anxiolytic effects.

Research by Hou, Langley, Szabadi, and Bradshaw (2007) suggests that diphenhydramine modulates ANS activation by increasing decreasing sympathetic activation, whereby it likely reduces mental and physical symptoms of anxiety.  In their research, the effect of diphenhydramine was compared to the drug modafinil on ANS function in healthy volunteers.  It was discovered that diphenhydramine reduced sympathetic tone (speculatively mediated by H1 inverse agonism) whereas modafinil increased it (speculatively mediated by activation of the locus coeruleus).  Overall, autonomic nervous system modulation necessitates consideration as an anxiolytic mechanism of diphenhydramine.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/26447819
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Inflammation reduction: Benadryl may also reduce aspects of anxiety by decreasing systemic inflammation and/or neuroinflammation resulting from allergies.  Though diphenhydramine will not reduce all types of inflammation, it is known to counteract allergy-related inflammation through its antihistaminergic effect, which could generate an anxiolytic response, especially among persons with chronic and/or unremitting allergies and corresponding high inflammation.  Several reports have suggested links between allergy-related disorders and anxiety disorders.

Research by Ponarovsky, Amital, Lazarov, et al. (2011) discovered considerably higher rates of anxiety and depression among patients with chronic allergic skin conditions than those without.  Though correlation doesn’t equal causation, one reasonable speculation is that allergic reactions lead to inflammation, which in turn, contributes [partially or extensively – depending on the person] to the pathogenesis of anxiety.  Worth mentioning is a study by Sarlus, Höglund, Karshikoff, et al. (2012) concluding that ongoing allergy can cause chronic peripheral inflammation which leads to increased expression of Alzheimer’s disease-related proteins in the brain, accompanied by significant neuroinflammation.

There is also no shortage of reports indicating that inflammation could be a causal mechanism of anxiety disorders, at least of a subset of individuals.  A study by Yang, Wang, Guo, et al. (2016) discussed the fact that systemic inflammation directly causes anxiety disorders and induces glutamatergic dysfunction in the CNS.  In fact, researchers went as far as to pinpoint a specific pathway by which systemic inflammation induces anxiety in mice.

They noted that the CXCL12/CXCR4 pathway mediated the inflammation-induced anxiety-like behaviors in mice.  Administration of a CXCL12 receptor CXCR4 antagonist prevented the anxiety, as did knockdown of CXCR4 receptor expression using short hairpin RNAs.  A report by Michopoulos, Powers, Gillespie, et al. (2016) highlights a relationship between inflammation and many types of anxiety disorders, including GAD, panic disorder, phobias, and PTSD.

It was noted that anxiety disorders are associated with increased proinflammatory biomarkers (e.g. C-reactive protein) and inflammatory signaling.  In short, the stress response can trigger cytokine release from central and peripheral immune cells, whereby the inflammation modulates biological processes to potentiate and prolong this stress until it becomes a chronic anxiety disorder.  These researchers believe that targeting inflammation may effectively alleviate anxious symptoms.

Although diphenhydramine is unlikely to mediate peripheral inflammation of all causes, it may help minimize allergy-related inflammatory responses by blocking histamine.  Results from a study by Siegel, Giri, Scheinholtz, and Schwartz (1980) noted that administration of diphenhydramine blocked the first phase of adriamycin-induced inflammation in the mouse paw, suggesting that it may prevent and/or reverse inflammatory responses.  It’s possible that diphenhydramine may help with more types of systemic inflammation beyond just allergy-induced.

Nonetheless, it is reasonable to suspect that a subset of anxiety sufferers may be dealing with chronic allergy-induced inflammation.  For these individuals, Benadryl may prove surprisingly effective as a result of reversing and/or attenuating peripheral inflammatory responses and downstream neuroinflammation.

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Sleep enhancement: Based on the fact that there’s more evidence to substantiate the usefulness of diphenhydramine as a sleep aid than as an anxiolytic, it’s reasonable to consider that sleep enhancement (especially over a long-term), may reduce unremitting anxiety.  It is known that ongoing lack of sleep and/or poor quality sleep can contribute directly or indirectly to symptoms of anxiety.  Most would acknowledge that a bidirectional relationship between sleep and anxiety exists such that: poor sleep can increase anxiety and high anxiety can disturb sleep.

Research by Papadimitriou and Linkowski (2005) mentions that panic disorder is characterized by longer sleep latency, increased time awake, and poorer sleep efficiency.  Among persons with generalized anxiety disorder, research shows increased sleep latency and decreased sleep continuity.  Other evidence suggests additional abnormalities of sleep among patients with anxiety disorders including: REM dysregulation, decreased REM latency, and decreased slow-wave sleep.

There’s some evidence to suggest that diphenhydramine may improve certain sleep problems (e.g. insomnia), which could help with the attenuation of anxiety.  For example, a randomized controlled crossover trial by Rickels, Morris, Newman, et al. (1983) evaluated the efficacy of diphenhydramine for the treatment of insomnia.  A total of 111 patients with mild-to-moderate insomnia were assigned to receive either diphenhydramine (50 mg) or a placebo for one week at bedtime, then were crossed over to the opposite intervention.

The results indicated that administration of diphenhydramine significantly improved sleep parameters including sleep latency compared to the placebo.  What’s more, recipients of diphenhydramine reported feeling better rested after diphenhydramine compared to the placebo.  For individuals with anxiety caused by insomnia, perhaps administration of diphenhydramine improves anxiety indirectly by managing the insomnia.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/16194794
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Benefits of Benadryl (Diphenhydramine) for Anxiety (Possibilities)

There are potential benefits associated with using Benadryl to manage anxiety.  Perhaps the most obvious benefit is that Benadryl can be purchased over-the-counter (without a doctor’s prescription) at a low-cost and administered in a pinch or as a last resort if a person has no access to other anxiolytics options.  Other possible advantages associated with using Benadryl for anxiety include its: ability to treat symptoms of comorbid conditions (e.g. allergies, insomnia, etc.), fast onset of action, and safety.

  • Adjunct potential: Multiple trials imply that diphenhydramine, the active ingredient within Benadryl, can be safely administered with benzodiazepines like lorazepam. In these trials, diphenhydramine (25 mg) and lorazepam (1 mg) were co-administered as a combination drug called “Somnium” to treat anxiety and comorbid insomnia.  The Somnium appeared to treat measures of anxiety and insomnia better than standalone lorazepam (1 mg) and a placebo.  Not only was there synergistic benefit from diphenhydramine plus lorazepam, but the combination somehow prevented cognitive deficits associated with standalone lorazepam.  Preliminary results indicate that diphenhydramine (25 mg) augmentation of a benzodiazepine may facilitate greater anxiety reduction with fewer unwanted side effects compared to a standalone benzodiazepine.
  • Alternative intervention: While Benadryl cannot be recommended over FDA approved anxiolytics or even evidence-based off-label anxiolytics for the treatment of anxiety, a rare subset of individuals may [unexpectedly] discover that Benadryl is the single most effective anxiolytic they’ve ever used. If Benadryl somehow ends up reducing your symptoms of anxiety to a significantly greater extent than all other evidence-based anxiolytics you’ve tested, it’s possible that diphenhydramine is a superior or optimal fit for your neurochemical abnormalities compared to other agents.  For this reason, some may consider Benadryl’s antihistaminergic (H1 receptor inverse agonism) and anticholinergic (M1 receptor competitive antagonism) mechanism of action as a possibly-useful anxiolytic alternative among persons who don’t respond to serotonergic or GABAergic medications.
  • Anecdotal accounts: It’s generally not a smart idea to administer a substance for anxiety based on a few random anecdotal accounts. Some people could report that eating one blue gummy bear before bed significantly reduces anxiety, yet this may be nothing more than a placebo effect or some odd individual-specific effect.  That said, there’s more than just a few random anecdotal reports suggesting that Benadryl is helpful for anxiety.  When considering the sheer number of anecdotal reports documenting that Benadryl reduces anxiety, plus the lack of financial incentive to do so and its sedating pharmacodynamics – it seems reasonable that Benadryl facilitates an anxiolytic effect in some individuals.  The fact that there are supportive anecdotal testimonials claiming that Benadryl decreases anxiety is encouraging.
  • Anxiety subtypes: Most experts know that not all types of anxiety are the same in terms of symptoms and underlying causes. Even among individuals with the same psychiatric diagnoses (e.g. generalized anxiety disorder), neurochemical underpinnings may be subject to significant individual variation.  In other words, two individuals with generalized anxiety disorder may have the same set of symptoms, yet one person exhibits dysregulated norepinephrine in the locus coeruleus as the chief cause, and another exhibits dysregulated serotonin in the raphe nucleus as the root cause.  These individual-specific variations explain why a single medication is not universally effective for everyone with the same diagnosis.  Assuming someone exhibits a neurochemical signature in which there are signaling abnormalities stemming from the H1 receptor and/or M1 receptor, Benadryl may work extremely well because it targets both.  Even if the neurochemical targets of Benadryl are not causally implicated in anxiety disorders, research may find that Benadryl works better for certain anxiety diagnoses (e.g. GAD) better than others (e.g. phobia).
  • “As-needed” administration: Some consider Benadryl an appealing anxiolytic because it can be taken on an “as-needed” basis for acute bouts of anxiety. After oral administration, Benadryl delivers a sedating effect within 10 to 30 minutes and the effect lasts anywhere from 4 to 6 hours.  For someone with unpredictable, intermittent anxiety attacks who doesn’t have access to pharmaceutical anxiolytics, taking Benadryl “as necessary” may seem like a lifesaver.  By comparison, many serotonergic antidepressants (SSRIs, SNRIs, TCAs, MAOIs) don’t work very well for anxiety when administered “as needed,” possibly making Benadryl a more attractive option.
  • Fast onset of action: Though the effect of diphenhydramine is not instantaneous, it’s relatively quick compared to many medications. Most Benadryl report that the diphenhydramine constituent elicits a noticeable sedative effect within 10 to 30 minutes of oral ingestion.  Some even claim to feel diphenhydramine’s sedative effect faster than most in less than 10 minutes post-ingestion.  This rapid onset of action may be advantageous over other medications such as serotonergic antidepressants that can take long to work, sometimes requiring up to 8 weeks for peak anxiolytic effect.  Individuals with extreme forms of anxiety and/or panic attacks may be unable to wait nearly 2 months for symptom reduction, ultimately perceiving the rapid-acting Benadryl as more useful.
  • Low cost: Another alluring attribute of Benadryl is that it can be acquired for an extremely low cost. Most stores sell a 100-count pack of 25 mg diphenhydramine tablets within the price range of $5 to $15, making it a highly-affordable medication.  Assuming you were charged $15 for 100 tablets, this equates to just $0.15 per tablet.  If you use 20 tablets per month on an as-needed basis as a last-resort anxiolytic, you’ll have spent a whopping $3.  The low cost of diphenhydramine might be perceived as favorable to newer non-generic anxiolytic medications that cost hundreds of dollars per month without insurance.
  • Mechanism of action: The mechanism of diphenhydramine’s action may be considered slightly unique when compared to conventional anxiolytics. It inversely agonizes the H1 receptor and competitively antagonizes the M1 receptor, simultaneously yielding an antihistaminergic and anticholinergic effects.  Additionally, diphenhydramine can affect the neurotransmission of norepinephrine and serotonin, which might be useful for some, yet a disservice to others.  In any regard, it’s possible that some individuals may somehow derive more sufficient symptomatic reduction from diphenhydramine’s action than drugs with pharmacodynamic similarities.
  • Medical comorbidities: There are medical conditions for which Benadryl is known to be useful, including: allergies, the common cold, itchiness, insomnia, motion sickness, movement disorders, and nausea. Assuming you’re struggling with a condition for which Benadryl is indicated to treat plus comorbid anxiety, you may like the fact that a single tablet of Benadryl might effectively alleviate all of your symptoms simultaneously.  In other words, rather than taking one medication for your allergies, another for your insomnia, and an entirely different drug for your anxiety (all of which could cause a disastrous interaction effect), just one diphenhydramine tablet may help you cope with all conditions.
  • Over-the-counter: Another perceived benefit associated with Benadryl by individuals who use it for anxiety is its over-the-counter availability. As an over-the-counter medication, Benadryl can be purchased at local convenience stores and/or even online for a low cost without a doctor’s prescription.  In fact, many stores that sell Benadryl are open 24/7, making it an accessible option for whenever a person [who finds it effective for anxiety] needs last-resort or unexpected relief.  Furthermore, some individuals have such extreme anxiety that they cannot bring themselves to leave their homes, let alone visit a doctor, so they like the convenience of being able to purchase Benadryl online.  Others may prefer using makeshift anxiolytics like Benadryl over prescriptions because they can save money on [potentially unaffordable] doctor visits.  More advantages associated with over-the-counter sale of Benadryl include: saving time on doctor visits and pharmacy pick-ups and avoiding fear of being judged by a doctor or pharmacist for your respective diagnosis and medication.
  • Safety: When utilized on an acute basis at recommended dosages (25 mg to 50 mg taken once every 4 to 6 hours for adults), diphenhydramine is generally regarded as safe. As is known, diphenhydramine first emerged for pharmaceutical sale in the 1940s and has been subject to extensive human testing ever since to verify its safety.  A major reason the FDA approved diphenhydramine as an over-the-counter medication in the 1980s is related to its proven track-record of being safe and/or lower risk when compared to many other prescription drugs.
  • Systemic elimination: Some individuals prefer to use medications with short half-lives because they won’t linger in the body for weeks after administration.  If for whatever reason you are concerned about medication elimination speed, you may perceive the ~8.5-hour half-life of diphenhydramine as being beneficial compared to other anxiolytics with longer half-lives.  An 8.5-hour half-life signifies that, on average, Benadryl stays in your system for approximately 2 days after your final dose.  Moreover, even if the half-life were to exceed ~8.5 hours based on individual factors, Benadryl should be completely excreted within 4 days post-cessation.
  • Tolerability: Yet another benefit of using Benadryl as a treatment for anxiety is that, when administered at standard recommended doses, it is very well-tolerated. Assuming you don’t take too high of a dose (e.g. above 50 mg) and are in good health, you shouldn’t struggle to tolerate Benadryl.  Though some side effects such as sedation and drowsiness can occur, most users wouldn’t consider them overwhelming or unmanageable.  Moreover, the fact that the FDA considers diphenhydramine fit for over-the-counter retail suggests that it should be tolerable for a bulk of the population.

Drawbacks of Benadryl (Diphenhydramine) for Anxiety (Possibilities)

Though some claim to derive therapeutic benefit from Benadryl for anxiety, there are some serious drawbacks to contemplate before even considering its anxiolytic potential.  Among the most substantial of drawbacks associated with using Benadryl as an anxiolytic is that it impairs cognitive function and motor abilities.  Other notable drawbacks associated with Benadryl usage include: dependence potential, depression or mood swings, exacerbation of anxiety, unwanted long-term effects, tolerance onset, and withdrawal symptoms after discontinuation.

  • Cognitive impairment: Despite the fact that the antihistaminergic and anticholinergic properties of diphenhydramine can reduce anxiety in a subset of persons, these properties are also understood to impair cognitive function. Aspects of cognition that may be impaired after taking Benadryl include:  attention, critical thinking, impulse control, learning, memory, planning, problem solving, and reasoning.  Assuming the diphenhydramine-induced cognitive impairment is significant, there’s a chance that it might compromise your occupational and/or academic performance whereby underperformance jeopardizes your career, earning potential, and/or job security.  Moreover, even if you aren’t working a cognitively-demanding job or attending school at an elite academic institution, you may still dislike the “brain fog” and/or mental spaciness that occurs each time you pop a Benadryl.
  • Contraindications: Like any drug, Benadryl is contraindicated with various medical conditions, meaning that not everyone will be able to safely use it to help with their anxiety.  Though diphenhydramine is not contraindicated with as many medical conditions as most pharmaceuticals, it may be a risky intervention and/or downright unsafe for a subset of the population to administer.  For this reason, some may perceive certain contraindications as being a drawback of Benadryl.  Examples of various medical conditions with which diphenhydramine is contraindicated include:  bladder dysfunction, bowel disorders, closed angle glaucoma, enlarged prostate, high blood pressure, peptic ulcers, and thyroid dysfunction.
  • Dependence: Most would not consider diphenhydramine as being among the most addictive drugs on the planet, however, regular diphenhydramine administration can lead to [mild] psychological dependence in a subset of users. When Benadryl is utilized on a frequent basis to alleviate symptoms of anxiety, the brain adapts [via neuroadaptation] to the ongoing presence of diphenhydramine.  As a result of neuroadaptation, receptors and neurotransmitter systems are modified to the extent that a person’s psychological health becomes dependent upon regular dosing of diphenhydramine.  Some users may feel as though they cannot function and/or make it through the day without another dose.  Once dependence has been established, attempting to cease usage may lead to a backlash of discontinuation effects.  To avoid this backlash, many individuals will continue their regular use of Benadryl whereby the dependence is overtly obvious to others.  If you dislike the potential of becoming psychologically dependent upon a drug to reduce anxiety, Benadryl may be perceived as a poor anxiolytic option.
  • Depression: Even if Benadryl works well for your anxiety, there’s a chance that it could induce depression and/or aggravate preexisting depressive symptoms. In a subset of users, diphenhydramine can provoke depressive thoughts, unpredictable mood swings, and in extreme cases – suicidal ideation.  It’s not difficult to understand why certain people might become depressed after taking Benadryl.  One reason depression may occur as a result of the antihistaminergic and anticholinergic effects, and possibly modulation of noradrenergic and serotonergic systems at higher doses.  Modifying these neurotransmitter systems could lead to unfavorable signaling (i.e. “a chemical imbalance”) in select persons to cause depression.  Some Benadryl users may also end up depressed as a result of treatment-related side effects such as:  cognitive impairment, depersonalization/dissociation, low arousal, and/or slowed thinking.  While persons at highest risk for experiencing Benadryl-induced depression are those with a history of major depressive disorder (MDD), nobody is completely immune to this side effect.
  • Drug-induced psychosis: Another reason some may want to think twice about using Benadryl for anxiety is based on the potential occurrence of “drug-induced psychosis.” Drug-induced psychosis is loosely defined as a perceptual break with reality, often accompanied by delusions and/or hallucinations – as a result of using a drug.  In 1997, Sexton and Pronchik published a report documenting that Benadryl can induce psychosis at therapeutically-relevant doses.  In other words, a subset of the population may experience transient psychosis from taking standard amounts of Benadryl (e.g. 25-50 mg).  Additional research indicates that risk of psychosis increases when administering doses above 50 mg due to an excessive anticholinergic effect.  Although risk of psychosis isn’t something most should be concerned with at normative doses, it is a potentially disastrous adverse effect for someone with anxiety or any other neuropsychiatric conditions.  (Source: https://www.ncbi.nlm.nih.gov/pubmed/9270406).
  • Impaired motor skills: Benadryl is known to decrease CNS activity whereby users experience impaired motor skills. Though impaired motor skills may not be a big deal for certain individuals, anyone who operates a vehicle, heavy machinery, and/or engages in athletic events should be concerned with the impairment.  Even modestly-impaired motor skills can significantly increase risk of injury, death, or equipment damage – among vehicle and/or machinery operators.  If your job requires you to drive a vehicle and/or operate machinery, taking Benadryl is dangerous.  Research suggests that a standard dose of Benadryl is analogous to a blood-alcohol concentration of 0.10 – an amount that exceeds the drunk driving limit of 0.08.  Additionally, athletes who uses Benadryl may exhibit increased proneness to injury and/or poorer performance as a result of the motor impairment.  Moreover, elderly individuals with age-related motor dysfunction may be susceptible to falling and corresponding injury from Benadryl-related motor impairment.
  • Ineffective: Not everyone taking Benadryl will find it helpful as a treatment for anxiety.  Many individuals experiment with Benadryl as an anxiolytic and discover that their anxiety level remains unchanged even after the drug has fully kicked in.  Certain people may try taking Benadryl at a low dose (25 mg to 50 mg) and find that it makes them slightly sedated, yet fails to attenuate anxiety.  Others may increase their dose beyond the 50 mg limit and end up feeling intoxicated, dissociated, and/or “buzzed” without much change in the severity of their anxiety.  It’s also possible that the high-dose users might feel more anxious from the dissociation that occurs at larger doses.  Moreover, as of current, there are no substantial data to support the efficacy of Benadryl (diphenhydramine) as an anxiolytic.
  • Interactions: Another notable drawback associated with using Benadryl for anxiety is that it might interact with a co-administered substance (e.g. drug or dietary supplement).  A pharmacokinetic interaction could occur as a result of diphenhydramine sharing similar hepatic isoenzymes with a co-administered substance.  This could lead to accelerated or prolonged metabolism of either the diphenhydramine or the co-administered substance whereby a person may experience a serious adverse reaction such as toxicity, intoxication, CNS suppression, fainting, or even death.  Another possibility of altered metabolism is that the medically-necessary effects of a co-administered substances are negated, ultimately endangering a user’s health.  Benadryl may also interact with co-administered substances through potentiation of neurochemical changes.  For example, if Benadryl is taken with an anticholinergic medication, users may experience “anticholinergic toxicity.”  Similarly, if administered with a serotonergic medication (e.g. SSRI), users may experience “serotonin syndrome.”  Moreover, any agent that downregulates CNS activity could provoke interaction effects.  Various medications that may interact with Benadryl include: alcohol, antidepressants, antihypertensive agents, benzodiazepines, muscle relaxants, opioids, other antihistamines, sleep aids, and tranquilizers.
  • Long-term effects: Though Benadryl is widely regarded as safe when administered acutely on an as-needed basis for allergies, individuals who use it regularly over an extended duration may experience deleterious long-term effects. Potential long-term effects resulting from diphenhydramine usage might include: cognitive dysfunction, motor dysfunction, neurodegeneration, and neuropsychiatric symptoms.  Perhaps the most noteworthy long-term effect associated with diphenhydramine is neurodegeneration.  Preliminary data suggest that anticholinergics and antihistamines may cause dementia when used over a long-term, especially at high doses.  (Benadryl is both an antihistamine and anticholinergic).
  • Neurodevelopmental issues: Although hypothetical, some surmise that regular administration of Benadryl to young persons (pediatrics) may interfere with brain development. This hypothesis is based upon the fact that the brains of young individuals are highly plastic and may be subject to detrimental modification from frequent usage of any drug [including Benadryl] during critical developmental periods.  Furthermore, the implications of altering neurochemistry and/or neural connectivity through Benadryl administration among are unknown, however, they may include suboptimal and/or abnormal developmental outcomes (e.g. failure to reach peak cognitive potential).  Due to the neurodevelopmental risks, pediatrics and even young adults should be encouraged to avoid using diphenhydramine as an anxiolytic.
  • Non-evidence-based: As of current, there are zero published studies to substantiate the monotherapeutic efficacy of diphenhydramine for anxiety disorders, hence the reason Benadryl is considered a non-evidence-based anxiolytic. Since Benadryl is a non-evidence-based anxiolytic, it is unclear as to whether it is any better at reducing anxious symptoms in a majority of users compared to a placebo.  As a non-evidence-based intervention, no medical professional can recommend or support the decision to use Benadryl for anxiety.  Moreover, the fact that Benadryl’s usage to treat anxiety is not supported by research means that there are plenty of anxiolytic medications [and even supplements] that should be tried ahead of Benadryl.
  • Side effects: As was already mentioned, standard dosages of Benadryl commonly cause unwanted side effects such as sedation and drowsiness. The sedation and drowsiness usually induce cognitive deficits, impaired motor skills, and a depressed mood.  Other side effects that a person may experience after taking recommended dosages of Benadryl include:  abnormal breathing, blurred vision, body temperature changes, constipation, dilation of pupils, dizziness, dry mouth, flushed skin, increased heart rate, irritability, sensory sensitivity, sexual dysfunction, and urinary difficulties.  When taking high doses, users may experience side effects such as:  delirium, depersonalization, dissociation, drug-induced psychosis (with hallucinations), torsades de pointes, and vomiting.  Overall, most would consider the antihistaminergic and anticholinergic side effects of Benadryl as worse than many prescription anxiolytics.
  • Superior anxiolytics: An obvious drawback of using Benadryl to treat anxiety is that countless superior anxiolytic interventions exist. Any medication that has received FDA approval as an anxiolytic has proven itself to be safe, effective, and tolerable in large-scale randomized controlled trials (RCTs) for the treatment of anxiety.  Since diphenhydramine hasn’t undergone a single randomized controlled trial, we don’t know whether it’s legitimately effective as an anxiolytic.  Most would agree that if you’re suffering from anxiety, it’s better to pursue a drug that’s supported by evidence to alleviate symptoms rather than opting for an unproven, speculative intervention (e.g. Benadryl).  Additionally, a majority of FDA approved anxiolytics are more tolerable than Benadryl with fewer unwanted side effects and long-term effects.  If for whatever reason you respond poorly to conventional anxiolytics but find Benadryl effective for your anxiety, chances are there are still superior interventions such as hydroxyzine and tricyclic antidepressants.  Moreover, if you’re concerned about costs, most similarly-acting FDA approved medications are manufactured as generics and are equally as cheap as, or cheaper than, Benadryl.
  • Tolerance: Although Benadryl may work well for your anxiety when you first start using it, eventually you may become tolerant to its effects. After weeks or months of usage, the anxiolytic benefit that you got from 25 mg to 50 mg dosages may dwindle and the drug might feel as though it stopped working.  When the anxiolytic effect completely dwindles, it’s because your body has become tolerant to the drug, or adapted to expect diphenhydramine.  Tolerance to any drug is caused via numerous mechanisms, a some of which may include neuroadaptation (receptor upregulation/downregulation) and hepatic adaptation (the body becomes more efficient at metabolizing diphenhydramine).  To continue reaping the anxiolytic effects from Benadryl, some may increase their dosage beyond 50 mg.  Even if the larger dose helps with anxiety, eventually the frequent Benadryl user will become tolerant to the larger dose and it will stop working.  Moreover, at higher dosages, side effects will become increasingly severe, putting the user’s health and safety at risk.
  • Toxicity: Among the most serious drawbacks associated with Benadryl is that it can induce anticholinergic toxicity, especially at high doses, possibly leading to death. Though no cases of death from diphenhydramine toxicity have been documented, most professionals acknowledge the possibility.  It is believed that diphenhydramine induces toxicity through blockade of the delayed rectifier potassium channel whereby QT interval is prolonged, and cardiac arrhythmias occur.  An acute episode of diphenhydramine poisoning is hypothesized to cause cardiovascular collapse and death within 2 to 18 hours.  While toxicity does not generally occur if administered at standard dosages to a healthy adult, persons using high-dose diphenhydramine and/or with other drugs may experience a disastrous toxic outcome.  Toxicity management usually entails hospitalization and administration of physostigmine.
  • Unestablished dosing guidelines: Another significant drawback associated with taking Benadryl for anxiety is that there are no established dosing guidelines for its usage as an anxiolytic. It is known that diphenhydramine is safe for most adults when administered at a dose between 25 mg and 50 mg once every 4 to 6 hours, however, it remains unknown as to whether this quantity would be effective for the attenuation of anxiety.  It’s possible that only larger doses of Benadryl exceeding 50 mg once every 4 to 6 hours would alleviate anxiety, however, exceeding the 50 mg dosage increases likelihood of adverse reactions and could be unsafe.
  • Withdrawal symptoms: If Benadryl is administered intermittently over a short-term, there aren’t usually any significant discontinuation effects. Most people revert back to homeostatic normalcy within one to several days after their final diphenhydramine tablet.  That said, someone who resorts to taking Benadryl for his/her anxiety may be administering it on a more frequent basis and/or over a longer-term.  Frequent administration and long-term usage of diphenhydramine can lead to adaptations in the body, such that when discontinued, persons experience Benadryl withdrawal symptoms.  These symptoms may be difficult to cope with and might include things like: rebound anxiety, insomnia, nausea, itching, diarrhea, restlessness, runny nose, and sweating.
  • Worsening of anxiety: Not everyone will find Benadryl helpful as an intervention for their anxiety. Some may experience a significant worsening of their anxiety while taking Benadryl.  The worsening of anxiety from Benadryl may be partly due to the neurochemical action of diphenhydramine exacerbating preexisting neurochemical irregularities of the user.  In some animal studies, H1 antagonists (at certain dosages) induce anxiogenic-like behavior, suggesting that a subset of humans may have similar experiences to the H1 inverse agonism of diphenhydramine.  Additionally, it is known that diphenhydramine inhibits NET, which might also increase anxiety in a subset of users.  Another possibility is that some people feel so depersonalized or dissociated when taking Benadryl, that this causes them to feel anxious.  It’s also plausible that some may feel excessively relaxed such that they experience “relaxation-induced anxiety” from diphenhydramine.  Moreover, anyone with a genetic polymorphism that makes them a CYP2D6 ultrarapid metabolizer (UM) may end up feeling jittery, wired, and/or excited – rather than relaxed due to the accelerated metabolism and distribution of diphenhydramine whereby it likely inhibits NET to a significant extent.  (Source: https://www.ncbi.nlm.nih.gov/pubmed/18227744).

Benadryl (Diphenhydramine) for Anxiety Disorders (Review of the Research)

Although diphenhydramine hit the market as a pharmaceutical in the 1940s, and has been available as an over-the-counter medication since the 1980s, it never underwent evaluation for the treatment of anxiety disorders.  Its lack of evaluation as an anxiolytic may seem surprising when considering that discovery of diphenhydramine’s serotonergic action in the 1960s lead to the development of SSRIs like fluoxetine.  To determine whether diphenhydramine may be useful as an intervention for anxiety, it’s necessary to examine the available scientific literature assessing its anxiolytic efficacy.  Overall, there doesn’t appear to be any strong evidence in support of using diphenhydramine to treat anxiety.

2002: Cocaine-induced anxiety: alleviation by diazepam, but not buspirone, dimenhydrinate or diphenhydramine.

Paine, Jackman, and Olmstead (2002) discussed the fact that cocaine withdrawal and administration can induce symptoms of anxiety and organized a study to determine whether putatively effective anxiolytic agents could reduce the anxious symptoms.  The study involved administering cocaine to rats at a dose of 20 mg/kg OR a saline (placebo) approximately 40 minutes prior to testing with an elevated plus maze (EPM).  Other rats were assigned to be part of a withdrawal condition in which they received cocaine OR a placebo for 14 consecutive days.

The rats in the withdrawal condition were evaluated 48 hours after cessation of cocaine or saline administration.  To determine the efficacies of the putative anxiolytics in preventing cocaine-related anxiety, various agents were administered intraperitoneally prior to the cocaine, including: diazepam, buspirone, dimenhydrinate or diphenhydramine, OR a saline placebo.  It was discovered that diazepam effectively reduced anxiety in the withdrawal condition, whereas the remaining interventions (buspirone, dimenhydrinate, diphenhydramine) did not.

None of the putative anxiolytics effectively reduced cocaine-induced anxiety.  Though this is an animal model study and the data cannot be generalized to humans, it indicates that diphenhydramine may be ineffective as a treatment for psychostimulant-induced anxiety and/or withdrawal-related anxiety.  While cocaine-induced anxiety and withdrawal-related anxiety may not accurately model human anxiety disorders, this provide some evidence to suggest that diphenhydramine may be unequipped to manage prominent symptoms of anxiety.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/12409990

1997: Nonorganic insomnia in generalized anxiety disorder. 2. Comparative studies on sleep, awakening, daytime vigilance and anxiety under lorazepam plus diphenhydramine (Somnium) versus lorazepam alone, utilizing clinical, polysomnographic and EEG mapping methods.

Saletu, Saletu-Zyhlarz, Anderer, et al. (1997) discussed previous research suggesting therapeutic advantage associated with using the combination drug Somnium (1 mg lorazepam plus 25 mg diphenhydramine) over standalone lorazepam.  Researchers noted that the lorazepam and diphenhydramine appeared synergistic in the facilitation of a hypnotic effect.  For this reason, they organized a subsequent double-blind, parallel-group trial to assess the respective efficacies of Somnium and lorazepam for the treatment of insomnia and anxiety among 44 individuals with generalized anxiety disorder and comorbid nonorganic insomnia.

Commencement of the trial involved a run-in phase in which all participants received a placebo for 1-week.  Next, participants were assigned to receive either Somnium (1 tablet) or lorazepam (1 mg) for a 4-week duration, followed by a 1-week placebo run-out phase.  Prior to the active treatment phase of the trial, researchers had collected measures of anxiety with the Hamilton Anxiety Rating Scale (HAM-A), Zung Self-Rating Anxiety and Depression Scale, and the Withdrawal Symptom Scale (WSS).

Measures of insomnia were also collected prior to the active treatment phase through sleep laboratory evaluations and included:  objective/subjective sleep and awakening quality (via polysomnography), self-ratings of sleep and awakening quality, results from a psychometric test battery (given in the morning), and daytime brain function (based on EEG mapping).  Other pre-treatment evaluations included: a hematology and blood chemistry tests and a physician’s assessment of efficacy, tolerance, and adverse effects.  The physician’s assessments of insomnia revealed moderate symptomatic improvement in the active treatment phase compared to pre/post-treatment placebo phases.

Each of the treatments facilitated significant reductions in HAM-A scores, however, the Zung Self-Rating Anxiety measures indicated improvement only among those receiving Somnium.  During treatment with each intervention, no significant improvements were observed on Zung Self-Rating Depression measures nor on the Withdrawal Symptom Scale (WSS).  There appeared to be no rebound anxiety and both interventions were well-tolerated.

Polysomnography recordings indicated significantly reduced latency of stage 2 sleep onset after receiving Somnium compared to lorazepam and each of the placebo phases.  Somnium also appeared to significantly improve sleep efficiency, total sleep time morning drowsiness, and total sleep scores compared to lorazepam and the placebo.  Both interventions decreased number of awakenings during sleep, increased wakefulness time, and improved subjective sleep quality compared to the placebo phases.

It was noted that lorazepam was more effective than Somnium for the attenuation of somatic symptoms, however, users of lorazepam were thought to have developed tolerance by the end of the 4-week trial due to an observable increase in movement time.  Interestingly, awakening quality was favorable among users of Somnium as evidenced by improved reaction times on psychometric testing compared to users of lorazepam.

The results from this study suggest that diphenhydramine (25 mg) can effectively treat symptoms of generalized anxiety disorder and insomnia when co-administered with lorazepam (1 mg) over a short-term.  Though the anxiolytic efficacy of standalone diphenhydramine wasn’t evaluated in this trial, the fact that diphenhydramine plus lorazepam was superior in efficacy to standalone lorazepam provides reason to believe that it generates a relevant anxiolytic effect.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9313245

1997: Comparative studies on the effects of the combination drug lorazepam plus diphenhydramine (Somnium) versus lorazepam on the noopsyche, thymopsyche and psychophysiology in nonorganic insomnia related to generalized anxiety disorder.

Grünberger, Saletu, Linzmayer, et al. (1997) compared the efficacy of Somnium (a combination drug comprised of 1 mg lorazepam plus 25 mg diphenhydramine) to that of standalone lorazepam (1 mg) for the treatment of insomnia related to generalized anxiety disorder (GAD).  Researchers recruited 44 patients with nonorganic insomnia associated with generalized anxiety disorder (GAD) to participate in a double-blind, parallel-group trial.  After a 1-week placebo run-in phase, participants were assigned to receive either: Somnium OR standalone lorazepam– for a 4-week duration.

The efficacy of each intervention was determined based upon degree of symptomatic change from pre-treatment baseline through the fourth week.  Symptoms were measured and grouped into the following categories:  thymopsychic dysfunction (somatic, state anxiety, trait anxiety, self-rating anxiety, etc.), noopsychic dysfunction (aspects of memory), pupillary responses, and skin conductance.  Results indicated that symptoms of thymopsychic dysfunction significantly decreased after administration of the Somnium and lorazepam.

That said, the Somnium (lorazepam plus diphenhydramine) was statistically superior to standalone lorazepam in treating the thymopsychic dysfunction.  Another finding was that on measures of noopsychic dysfunction, Somnium appeared to significantly improve verbal memory from baseline, whereas standalone lorazepam significantly impaired verbal memory from baseline.  No differences on pupillary responses were observed between recipients of Somnium and recipients of standalone lorazepam.

Recipients of Somnium exhibited significant changes on measures of skin conductance as compared to recipients of standalone lorazepam.  The finding of altered skin conductance lead researchers to speculate that Somnium facilitated an anxiolytic effect through the autonomic nervous system (ANS), whereas standalone lorazepam did not.  To recap, this study found that Somnium treated symptoms of anxiety more effectively than lorazepam; Somnium exerted favorable effects upon verbal memory whereas lorazepam impaired it; and Somnium mediated an anxiolytic effect through the ANS yet lorazepam did not.

The finding that Somnium attenuated symptoms of anxiety to a greater extent than standalone lorazepam is not farfetched.  Combining lorazepam (1 mg) with another sedating agent (25 mg diphenhydramine) should yield a greater effect than standalone lorazepam (1 mg).  That said, it’s possible that the dosage of standalone lorazepam may have been an unfair comparison to the combination drug of Somnium.

Perhaps increasing the lorazepam dose to 1.5 mg or 2 mg would’ve proven equally as effective as Somnium in reducing symptoms across all measures.  It’s also somewhat difficult to believe that the combination intervention managed to improve verbal memory over a 4-week duration, yet standalone lorazepam worsened it.  This suggests that the H1 inverse agonism and M1 competitive antagonism provided by the diphenhydramine constituent of Somnium significantly enhanced aspects of verbal memory and simultaneously offset lorazepam-induced impairment.

The only other plausible explanations to explain a verbal memory improvement with Somnium include: a counterintuitive synergistic verbal memory-enhancement effect generated by diphenhydramine and lorazepam AND/OR such greater symptomatic relief with Somnium, that the symptom reduction resulted in an improved verbal memory.  It is also necessary to note that since diphenhydramine was only administered as a Somnium constituent, we cannot know whether standalone diphenhydramine may have also been an effective treatment.  Nonetheless, this study provides evidence that low-dose diphenhydramine can effectively augment benzodiazepines to reduce symptoms of mild generalized anxiety disorder (GAD) and comorbid insomnia.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9500129

1982: Effect of diphenhydramine on stress-induced changes in brain histidine decarboxylase activity, histamine and plasma corticosterone levels.

Mazurkiewicz-Kwilecki and Bielkiewicz (1982) conducted a study in which they exposed rats to various stressors and monitored stress-induced biomarker changes within the brain.  When exposed to platform stress, rats exhibited significantly increased histaminergic transmission within the hypothalamus.  When exposed to air blast stress, rats exhibited significantly increased histaminergic transmission within the hypothalamus, as well as increased activity of histidine decarboxylase, an enzyme necessary to catalyze the conversion of histidine to histamine.

After stress-related biomarker changes were recorded, researchers sought to determine whether administration of diphenhydramine (an H1 receptor inverse agonist) prior to stress exposure would have any effect upon stress-related biomarkers.  Initially, researchers monitored biomarkers of rats after administration of diphenhydramine at a dosage of 7.5 mg/kg.  Results indicated that diphenhydramine administration had no effect upon histaminergic transmission or histidine decarboxylase activity.

When diphenhydramine (7.5 mg/kg) was administered to rats before air blast-induced stress, it significantly inhibited corresponding increases in histidine decarboxylase activity.  Additionally, among the rats that weren’t treated with diphenhydramine, exposure to platform stress and air blast-induced stress lead to 4.5-fold and 7.8-fold increases in corticosterone, a hormone implicated in the rodent stress response.  Comparatively, rats receiving diphenhydramine prior to stress exposure exhibited significantly lower corticosterone spikes than the untreated group.

Based on the findings of this study, it appears as though diphenhydramine may attenuate physiological changes associated with exposure to acute anxiety and stress among animals.  It’s possible that administration of diphenhydramine prior to an anxiety-provoking or stressful event would prove effective as an acute anxiolytic.  That said, more research is needed to determine whether diphenhydramine is effective for the acute management of anxiety in humans.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/7071092

Limitations associated with Research of Benadryl for Anxiety

There are some serious limitations associated with the research of diphenhydramine as an intervention for anxiety, ultimately making it difficult to determine whether Benadryl would prove therapeutically effective as an anxiolytic.  Arguably the most significant limitation is the overall lack of studies examining the efficacy of diphenhydramine monotherapy for the treatment of anxiety in humans.  Other limitations to consider associated with existing trials include: participant diagnoses, outcome measures, and duration of the trials.

  • Animal studies: Of the 4 studies discussed above, 2 were conducted in animals. As most know, animal data is sometimes useful, but the results from these studies cannot be extrapolated to humans.  One animal study assessed the efficacy of diphenhydramine for the treatment of anxiety-related symptoms following cocaine administration and withdrawal, discovering that it was ineffective as an anxiolytic.  The second animal study assessed the effect of diphenhydramine on stress-induced biomarker changes within the brain, discovering that it prevented histaminergic alterations following stress exposure.  That said, the prevention of stress-induced biomarker changes does not guarantee an anxiolytic effect.  The efficacy of diphenhydramine as an anxiolytic, even in animals, remains uninvestigated.
  • Adjunct-only: Multiple trials have tested the combination drug Somnium (diphenhydramine plus lorazepam) for the treatment of anxiety plus comorbid insomnia. Results showed that the combination drug Somnium decreased symptoms of anxiety plus insomnia to a significantly greater extent than lorazepam and a placebo.  Although it’s helpful to know that co-administered diphenhydramine and lorazepam (i.e. Somnium) facilitate a significant anxiolytic effect, the monotherapeutic efficacy of diphenhydramine remains unknown.
  • Dosage: Another limitation of research associated with diphenhydramine for anxiety is that it hasn’t been evaluated at multiple doses. As was already mentioned, 25 mg diphenhydramine has only been evaluated as an anxiolytic with 1 mg lorazepam as part of the combination drug Somnium.  It is unknown as to whether 50 mg would have induced a more robust anxiolytic effect when administered with the 1 mg lorazepam and/or whether this dosage increase would’ve compromised safety.  Since no studies have evaluated diphenhydramine as a monotherapy for anxiety, no putative dosing recommendations can be made.  Perhaps much larger doses would be more effective for managing symptoms of anxiety than the 25 mg to 50 mg recommended for allergy relief, however, these may be unsafe.
  • Incentive: Most would agree that there’s not much incentive to test the efficacy of diphenhydramine as a treatment for anxiety. Conducting a randomized controlled trial with a reasonable sample size is not only expensive, but time consuming.  Financial resources and time spent evaluating the anxiolytic efficacy of diphenhydramine would be better allocated to other interventions.  While some manufacturers may gain a few more customers if diphenhydramine proved useful as an anxiolytic, the numbers probably wouldn’t be significant.  Moreover, since any drug company can manufacture diphenhydramine, if its demand skyrocketed, the number of manufacturers would increase, making it unprofitable for a single company to fund trials of diphenhydramine for anxiety.
  • Lack of human trials: There are only 2 human trials that have tested the efficacy of diphenhydramine for the treatment of mild generalized anxiety disorder and comorbid insomnia. That said, diphenhydramine was not tested as a monotherapy, only as part of a combination treatment called Somnium.  Though the combination drug with diphenhydramine reduced symptoms of insomnia and anxiety compared to lorazepam and a placebo, these trials were of short-duration with possible methodological flaws.  More human trials are needed to determine if diphenhydramine generates a significant anxiolytic effect.
  • Outcome measures: In one animal study testing the effect of diphenhydramine for the treatment of psychostimulant-related anxiety, reliable measures were used to track anxiety-like behavior. Of the 2 human studies in which diphenhydramine was administered as part of a combination drug, only one study utilized the HAM-A (Hamilton Anxiety Rating Scale) as a measure.  The other study utilized thymopsychic measures to track anxiety, which may have been less accurate than the HAM-A in determining the anxiolytic efficacy of the diphenhydramine as part of a combination drug.
  • Participants: The participants in trials evaluating the efficacy of diphenhydramine plus lorazepam (i.e. Somnium) were individuals that had been diagnosed with nonorganic insomnia and mild generalized anxiety disorder. It’s possible that participants with more extreme (moderate-to-severe) cases of generalized anxiety disorder and/or other forms of anxiety (e.g. panic disorder) may not have responded well to the combination treatment.  Since diphenhydramine hasn’t been tested in persons with other forms of anxiety, it’s unclear as to whether it’s effective.
  • Sample sizes: In studies investigating the anxiolytic effect of diphenhydramine plus lorazepam as the combination drug Somnium, there were 44 participants. Although 44 participants in a trial is a moderate sample, it may be too small to derive accurate data.  Larger trials are still needed to confirm the preliminary efficacy of Somnium for the treatment of anxiety and insomnia.
  • Study duration: The duration of each human trial testing diphenhydramine plus lorazepam (i.e. Somnium) for the treatment of insomnia and anxiety – was 4 weeks. While 4 weeks is a reasonable length of time to test an anxiolytic intervention, longer-term trials are needed to determine whether anxiolytic efficacy is maintained over an extended duration.  It’s possible that patients would’ve developed tolerance to both constituents in Somnium (diphenhydramine and lorazepam) if administered for another month or two.
  • Study designs: To gather accurate data regarding the efficacy of diphenhydramine plus lorazepam in the form of Somnium, randomized controlled trials are necessary. Each of the already-published studies incorporated a placebo “run-in” phase, and one utilized a placebo “run-out” phase among participants to compare the effect of the placebo to that of the active treatment.  Though this strategy may have been appropriate, some may argue that utilizing a placebo throughout the entire 4-week trial would’ve generated better quality data.

Verdict: Benadryl (Diphenhydramine) possibly effective for acute anxiety in a subset of users

Due to the paucity of research investigating the therapeutic potential of diphenhydramine as a treatment for anxiety, there’s insufficient evidence to determine whether it’s an effective anxiolytic.  For this reason, diphenhydramine should not be endorsed or recommended as a treatment for anxiety.  That said, just because there’s inadequate scientific data assessing the anxiolytic efficacy of diphenhydramine does not imply that it should automatically be regarded as ineffective or suggested to definitely “not work.”

Given the limited data from animal and human trials, it’s fairly difficult to predict whether diphenhydramine may facilitate clinically-relevant anxiolytic effects.  A study conducted by Paine, Jackman, and Olmstead (2002) documented that diphenhydramine failed to attenuate cocaine-induced anxiety and cocaine withdrawal-related anxiety among mice, yet diazepam was effective.  Though animal model data cannot be accurately extrapolated to humans, the results suggest that diazepam (a proven anxiolytic) effectively treats anxiety, whereas diphenhydramine does not.

Another animal study by Mazurkiewicz-Kwilecki and Bielkiewicz (1982) found that stress exposure modifies levels of histidine decarboxylase and histamine in the brain, and also alters levels of corticosterone in the plasma.  Administration of diphenhydramine prior to the stress exposure significantly attenuated stress-induced changes of the aforestated biomarkers, indicating that diphenhydramine may protect against anxiety-related physiology.  Nonetheless, the finding that diphenhydramine attenuated stress-induced biomarker changes does not indicate that it was an effective anxiolytic.

From the animal model data, the only conclusion that can be made is that diphenhydramine may protect against stress-related physiological changes.  The best evidence available to support the theory that diphenhydramine may alleviate symptoms of anxiety is derived from multiple human trials published in 1997.  Each of these trials included 44 participants that had been diagnosed with mild generalized anxiety disorder plus comorbid nonorganic insomnia.  In the trials, diphenhydramine was administered at a dose of 25 mg as part of a combination drug called “Somnium” which also included 1 mg lorazepam.

Each of the trials were conducted over a 4-week duration, and discovered that Somnium was superior to lorazepam (an active control) and placebo for the treatment of mild generalized anxiety disorder and comorbid nonorganic insomnia.  Superior anxiolytic efficacy of Somnium over lorazepam was evidenced by a significantly greater reduction of thymopsychic dysfunction in the first study, and significantly greater improvement on the Zung Self-Rating Anxiety Scale in the second study.  This suggests that diphenhydramine likely generated an anxiolytic effect to make Somnium (diphenhydramine plus lorazepam) more effective than standalone lorazepam.

Considering the aforestated results indicating that co-administration of diphenhydramine with lorazepam was highly effective for the alleviation of anxious symptoms among persons with generalized anxiety disorder, it’s reasonable to surmise that diphenhydramine is an effective anxiolytic adjunct.  Furthermore, the substantially more robust anxiolytic effect derived from Somnium compared to lorazepam leads to speculation that diphenhydramine may be effective as a standalone anxiolytic.  In summary, when considering the preliminary data, diphenhydramine’s sedating mechanism of action, and anecdotal reports suggesting that diphenhydramine reduces anxious symptoms – it’s not a stretch to speculate that Benadryl (diphenhydramine) could be effective as a short-term, as-needed, and/or acute intervention for the treatment of anxiety in a subset of the population.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/7071092
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9313245
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/12409990
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9500129

Who might benefit from Benadryl for anxiety?

As of current, no individuals should be recommended to take Benadryl as a treatment for anxiety because there are superior anxiolytic interventions.  Based on the available literature, it seems as though persons with mild cases of anxiety disorder and/or nonorganic insomnia could derive some degree of anxiety reduction from Benadryl.  It’s also possible that Benadryl be helpful for persons with infrequent/intermittent bouts of panic, allergy-related anxiety, and/or anxiety stemming from H1 or M1 receptor overactivation.  That said, anyone considering Benadryl as an anxiolytic should always confirm its safety and theorized efficacy with a medical professional prior to administration.

  • Generalized anxiety disorder: Multiple studies suggest that the combination drug Somnium effectively reduced symptoms of anxiety among persons with generalized anxiety disorder. To be clear, diphenhydramine (25 mg) is one constituent of Somnium with the other being lorazepam (1 mg).  In both studies, the Somnium was more effective than standalone lorazepam on several measures of anxiety including: thymopsychic dysfunction and the Zung Self-Rating Anxiety Scale.  This finding suggests that the diphenhydramine likely facilitates some degree of anxiolytic benefit of its own, thereby attenuating symptoms among those with generalized anxiety.
  • Insomnia-related anxiety: Most understand that there’s often a bidirectional relationship between insomnia and anxiety such that each of these conditions can cause and/or worsen the other. Two studies tested diphenhydramine plus lorazepam as the combination drug Somnium compared to lorazepam and recruited participants with insomnia and anxiety.  It’s possible that some of these participants experienced anxiety, in part, due to untreated insomnia and/or poor quality sleep.  In the studies, Somnium was a superior intervention to standalone lorazepam for improving sleep of participants, suggesting that diphenhydramine plays a role in sleep enhancement.  Based on this finding, it’s reasonable to speculate that a subset of Benadryl users with insomnia-provoked anxiety may experience anxiety reduction as a result of diphenhydramine mitigating insomnia and/or enhancing sleep quality.
  • Histaminergic or cholinergic: Assuming excessive stimulation of the H1 receptor and/or the M1 receptor by endogenous ligands (histamine and acetylcholine, respectively) was culpable for inducing one’s anxiety, the administration of diphenhydramine (i.e. Benadryl) is likely to prove therapeutically effective in reducing anxious symptoms. This is because the mechanism of diphenhydramine’s action decreases activity at H1 and M1 receptors through respective inverse agonism and competitive antagonism.  As of current, it’s unknown as to whether overactive H1 and/or M1 receptors might cause anxiety in humans.  If overactivity of H1 and/or M1 plays a causal role in a subset of anxiety disorders, administration of diphenhydramine may prove helpful.
  • Allergy-related anxiety: There are established links between chronic allergies and anxiety disorders. Some have theorized that a chronic allergy response increases reactive oxygen species and proinflammatory cytokines, each of which disrupt brain activity to cause neuroinflammation and neuropsychiatric symptoms – one of which might be anxiety.  In animal models, unremitting peripheral allergies lead to expression of Alzheimer’s-like proteins in the brain and neuroinflammation.  If your anxiety emerged after you experienced an allergy and/or allergic reaction, it’s possible that excessive histamine played a causal role in the onset of your anxious symptoms.  Administration of an antihistamine like Benadryl may counteract the excessive histamine associated with your allergy-response and mitigate allergy-related anxiety.
  • Intermittent panic: Benadryl has a fast onset of action and generally takes effect within 10 to 30 minutes in most users. Some claim that it kicks in even faster, with a noticeable effect being generated in less than 10 minutes.  Its total duration of effect is within the range of 4 to 6 hours, meaning you won’t feel under the influence of Benadryl the entire day.  The fast onset of action and moderate duration of effect has lead some to believe that it’s a decent option for persons who are prone to intermittent bouts of panic.  Anecdotal reports from a subset of panic disorder sufferers claim that the sedating effect of Benadryl ameliorates panic attacks, especially if administered just prior to onset of full-blown panic.

What dosage of Benadryl to take for anxiety?

Due to the fact that Benadryl isn’t approved for the treatment of anxiety, no dosing guidelines have been established for its usage as an anxiolytic.  If you plan on taking Benadryl to help with anxiety, it is recommended to first consult a psychiatrist or psychopharmacologist to ensure that it’s safe in accordance with your medical status, medical history, and your medication and/or dietary supplement regimen.  Assuming a medical professional says that you can safely administer Benadryl for your anxiety, it should be recommended to use the minimal effective dose, or lowest quantity necessary to alleviate symptoms.

The minimal effective dose can usually be discovered by starting with the smallest possible amount (e.g. 25 mg) and only increasing the dose until you experience symptomatic relief.  Packaging information on Benadryl products recommends that adults administer 25 mg to 50 mg once every 4 to 6 hours for allergy relief.  Since doses above 50 mg are not recommended by Benadryl manufacturers, it is possible that there are safety concerns associated with larger dosages.

If you mistakenly assume that low doses of Benadryl won’t work well for anxiety and jump on a high dose, you run the risk of experiencing serious adverse medical events such as anticholinergic toxicity.  Unless a psychiatrist verifies your personal safety of exceeding the 50 mg dosage of Benadryl every 4 to 6 hours, larger doses should be avoided.  If Benadryl isn’t decreasing your anxious symptoms within the 25 mg to 50 mg dosage range, you may want to consider that it may have been a poor treatment choice and/or ineffective for your particular type of anxiety.

Have you tried Benadryl (diphenhydramine) for anxiety?

If you’ve taken Benadryl or other diphenhydramine-containing products specifically to help reduce symptoms of anxiety, feel free to document your experience in the comments section below.  Based on personal experience, would you consider Benadryl as being very helpful, slightly helpful, or unhelpful for the treatment of your anxiety?  Assuming you were to rate the anxiolytic efficacy of Benadryl on a scale from 1 to 10 (with “1” = not effective and “10” = extremely effective), what numeric rating would you assign it?

To help others get a better understanding of your situation, provide some additional details regarding your Benadryl usage such as: the dosage you took (e.g. 25 mg), the regularity of its administration (e.g. once daily), and the cumulative duration over which you’ve used it (e.g. 3 months).  Also mention personal details such as the type of anxiety you’re dealing with (e.g. generalized anxiety disorder) and whether you administered Benadryl along with other substances (e.g. drugs or supplements).  For what reason did you initially start taking Benadryl to help manage your anxiety?

Did you confirm with a doctor that it’s safe to take Benadryl with your current medical status and medical history?  Among those that have been using Benadryl regularly and/or over a long-term, have you developed any sort of tolerance and/or become dependent upon its effects?  Have you tested any similar pharmaceutical medications and/or supplements for the treatment of your anxiety instead of Benadryl?

Overall, there’s no compelling evidence to support the usage of Benadryl as a treatment of anxiety.  Furthermore, when considering the fact that there are numerous FDA approved medications [and even dietary supplements] that are superior in efficacy, safety, and tolerability for the treatment of anxiety when compared to Benadryl, it is puzzling as to why anyone might choose Benadryl as a preferred anxiolytic.  Nonetheless, given its sedative-hypnotic mechanism of action, it’s realistic to assume that a subset of users experiences reduced anxiety from its administration.

In closing, Benadryl might be a decent last-resort option for a subset of anxiety sufferers to use in a pinch if they don’t have access to another medication.  That said, before using Benadryl for anxiety (or any other condition), individuals should consult a medical professional to confirm that it’s safe to do so.  Also keep in mind that for some people (e.g. CYP2D6 ultrarapid metabolizers), Benadryl is likely to worsen symptoms of anxiety, making users feel jittery and overly excited.

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