Bipolar disorder, lithium, & erectile dysfunction

Erectile dysfunction (ED) is a common side effect of lithium carbonate medication, often prescribed for bipolar disorder. Yet, very little information is available for those struggling with this frustrating side effect.

In this blog, we’ll cover all areas of this important topic, including:

How common is ED in people taking lithium?
Why lithium affects erectile function
The link between ED, bipolar, and cardiovascular risk
What can be done to improve ED
What can be done to improve cardiovascular health for those with BD

Lithium is an effective and safe medication for bipolar disorder and has been a preferred treatment since the 1970s. Since that time, there have been numerous documented cases of sexual dysfunction as a side effect of lithium (1).

Despite this, studies have found that people with bipolar disorder on lithium therapy who experience ED do not report dissatisfaction (2), probably because the benefits of lithium outweigh the side effects, and bipolar patients on lithium therapy report improved quality of life, including more satisfying interpersonal, relationship, and sexual experiences (3).

Additionally, while sexual dysfunction is common in those on lithium therapy, people with bipolar disorder who discontinued treatment due to side effects rarely cited sexual dysfunction as a reason for discontinuation (4).

More simply put, the benefits of lithium seem to outweigh the experience of ED for most people. Nonetheless, it is essential to note that declining erectile function is an early warning sign of metabolic disease and cardiovascular disease (5, 6).

Erectile dysfunction may be a difficult topic for healthcare practitioners to raise with their patients, but because it’s a common early warning sign of cardiovascular complications (6), it’s an important topic to discuss with your patients. Addressing erectile dysfunction as early as possible can help prevent cardiovascular complications later on (6).

How common is ED in people taking lithium medication?

Based on the available literature, around 14-30% of those on lithium experience some form of erectile dysfunction. In addition to ED, side effects such as sexual dysfunction and reduced frequency of sexual thoughts have also been reported (2, 7).

Despite these findings, pleasure during sexual activity and satisfaction with sexual performance may not be diminished (7).

Additionally, it’s worth noting that the studies above are small, and the incidence may be more or less common than reported.

How does lithium affect erectile function?

Researchers have sought to understand why lithium affects erectile function through animal studies. There are several plausible mechanisms, including lithium’s interactions with neurotransmitters involved in sexual processes, including dopamine, serotonin, and glutamate/NDMA, as well as the HPA-axis (1). Lithium’s effects on the nitric oxide pathway likely affect erectile function.

“It has been shown that chronic lithium treatment can cause erectile dysfunction through impairment of the nitric oxide (NO) pathway. Importantly, this effect of lithium seems to be present at concentrations below the therapeutic range of the drug ” (8).

Nitric oxide is essential for blood vessel dilation, optimal blood flow throughout the body, and healthy erectile function.

“NO is believed to be the main vasoactive NANC [nonadrenergic noncholinergic] neurotransmitter of erectile action in the corpora cavernosa…The erectile response is triggered with the initial release of NO by the autonomic NANC dilator nerve fibers supplying the corpora cavernosa and the vascular and sinusoidal endothelium. Further, NO release from the endothelium results from blood flow shear forces. NO then diffuses across the smooth muscle membrane and activates soluble guanylate cyclase (sGC), which catalyzes the production of 3′,5′‐cyclic guanosine monophosphate (cGMP). The increased cGMP activates a protein kinase that phosphorylates specific proteins and ion channels, resulting in the opening of potassium channels and hyperpolarization of the muscle cell membrane… the erectile actions of NO have been demonstrated in human penile tissue samples and in a range of experimental in vitro and in vivo animal studies” (9).

What can help with ED caused by lithium medication?

There is a stark lack of research examining how to combat ED as a side effect of lithium therapy. However, a research review led to two promising options—aerobic exercise and aspirin.

Aerobic exercise

Aerobic exercise has a significant and clinically meaningful improvement in erectile function (10).

In a recently published meta-analysis and systematic review of randomized controlled trials, aerobic exercise was found to be effective for the treatment of erectile dysfunction (10). The study was not specific to people with bipolar disorder on lithium but more generally focused on people with erectile dysfunction. The improvement in ED was measured by the IIEF-EF (International Index of Erectile Function), a scale where a lower score corresponds with more severe ED.

Regular aerobic exercise (30-60 minutes, 3-5 times per week) resulted in a noticeable improvement in erectile function, and this was the most pronounced for those with more severe dysfunction.

For example, those with severe ED saw an average improvement of nearly 5 points, which could move them from a category of severe ED (6-10) to moderate or mild ED (11-16 and 17-25, respectively) (10).

Comparing these results with other ED therapies helps emphasize the therapeutic benefits of aerobic exercise. Testosterone replacement therapy usually provides a 2-point improvement in ED, and phosphodiesterase-5 inhibitors result in a 4 to 8-point improvement (10).

Regardless of the category of ED, the results of this study suggest that aerobic exercise has a clinically meaningful impact on all ranges of ED. Even those with mild ED experience a clinically relevant improvement in ED.

Multiple factors are responsible for the benefits of aerobic exercise on ED, including improved metabolic health and nitric oxide function.

“Physical activity positively affects cardiovascular health, which is closely associated with erectile function. Additionally, regular aerobic exercise helps reduce body weight in overweight or obese individuals, lower blood pressure, and improve glycemic control in people with diabetes—all risk factors for ED that could be mitigated through aerobic activity. Aerobic exercise also improves endothelial function through increased nitric oxide production and endothelial progenitor cell growth, which regulate vascular function and maintain normal erectile function. Testosterone concentration is augmented with aerobic training by activating the hypothalamic-pituitary-gonadal axis and reducing sex hormone–binding globulin. Finally, regular aerobic exercise reduces oxidative stress and inflammation, additional factors associated with ED development” (10).

Aerobic exercise includes jogging, running, hiking, swimming, and cycling.

Although the study above wasn’t specific to bipolar patients, it’s still a worthwhile strategy, and aerobic exercise likely has other benefits for those with bipolar. Strangely, the effect of aerobic exercise on bipolar symptoms hasn’t been studied (11, 12), but evidence shows that aerobic exercise benefits other mental illnesses such as major depressive disorder and schizophrenia (12).

Aspirin

Beyond exercise, A 2013 RCT demonstrated the effectiveness of aspirin for improved erectile function in those with bipolar disorder (13). In fact, according to the study authors, this is the only study to date that has looked at treatment for lithium-related sexual dysfunction.

In the small randomized placebo-controlled study of 30 patients with bipolar disorder on lithium therapy, 15 were randomly assigned to take 80 mg of aspirin three times a day (240 mg/day of aspirin) for six weeks. The aspirin group experienced an 85.4% improvement over baseline scores for erectile function at completion of the 6-week study period, and overall sexual function in the aspirin group improved by 63.9% (13)!

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Cardiovascular issues, bipolar disorder, and how ED symptoms fit into the picture

Cardiovascular disease and cardiovascular mortality are higher in people with bipolar disorder than in the general population. This increased risk is independent of what medications are used for bipolar disorder.

Those with bipolar disorder may have poorer measurements of endothelial function compared to healthy controls, as measured by reactive hyperemia index (RHI) (14).

Fascinatingly, endothelial function varies depending on mood polarity. Kennedy et al. (2023) showed that RHI in youth bipolar patients was lowest in those with a depressed mood and highest in those experiencing hypomanic/mixed symptoms. These findings indicate endothelial dysfunction in bipolar patients with depression but improved endothelial function in those with hypomania (14).

Why does this matter?

Endothelial dysfunction is an early predictor of cardiovascular risk and may appear many years before symptoms. Lower RHI is associated with worse endothelial function and greater cardiovascular risk.

“Youth with BD have elevated levels of pro-inflammatory markers like C-reactive protein (CRP) and traditional CVRFs [cardiovascular risk factors], including obesity, hyperglycemia, hypertension, and dyslipidemia). Additionally, CRP and CVRFs are associated with worse mood symptoms, neurocognition, and brain structure in youth with BD. Given that poorer endothelial function is associated with greater CRP and CVRF, it is important to assess whether endothelial function is independently associated with mood states/symptoms among youth with BD” (14).

Let’s quickly address an interesting finding from that study—hypomania is associated with better endothelial function in youths with bipolar. Why would that be?

The study authors provide a thoughtful answer to this:

“There may be several mechanisms underlying the observation that greater manic symptom severity is associated with higher endothelial function. From a psychological perspective, as summarized in a recent American Heart Association scientific statement, positive psychological health has been associated with indices of positive cardiovascular health, whereby positive psychological health can improve cardiovascular health through behavioral factors (i.e., greater exercise) or biologically by positively influencing the autonomic nervous system. Indeed, prior research has demonstrated that positive affect, such as joy and laughter, is associated with increased endothelial function in normative samples. Hypomanic symptoms in this outpatient sample, including elation, may have similar beneficial associations with endothelial function.”

It’s important to note that while the study on youth with bipolar disorder indicated the correlation with reduced endothelial dysfunction in certain mood states, the studies are more mixed in adults with BD. For example, a 2018 study on adults with bipolar found no association between BD and endothelial function for any mood states when compared to healthy controls (15).

Despite the mixed findings, the American Heart Association expert panel has recognized bipolar disorder as a tier II moderate risk factor for atherosclerosis and early onset CVD in youth patients (16).

With this in mind, erectile dysfunction may be the canary in the coal mine for early atherosclerosis and endothelial dysfunction. Atherosclerosis affects all of the blood vessels in the body, but because of the small size of the blood vessels in the penis, they are often the first affected. According to Schwartz & Kloner (2011), “…the first stage of atherosclerosis, endothelial dysfunction, usually affects the penis first, ED can be a warning sign that a heart attack or a stroke may follow, often in the next 3 to 5 years. This warning sign can be a good thing if it alerts you and your doctor that you have atherosclerosis because then you can take steps to treat the atherosclerosis and prevent a heart attack or stroke” (17).

Of course, many other factors may contribute to endothelial dysfunction and ED as well, including smoking, metabolic disease, and diabetes. However, healthy endothelium is vital to erectile function (18), so regardless of the individual risk factors, ED is a red flag that should not be overlooked.

Strategies for improving cardiovascular health include hydrogen-rich water, dietary fiber, and supporting a healthy oral microbiome (19, 20, 21).

Hydrogen-rich water improves the endothelial function of the arteries and arterioles (16).

This beneficial effect was recently demonstrated in a placebo-controlled study where volunteers consumed 3.5 mg of H2 in water (7 ppm hydrogen). Twenty-four hours after first drinking hydrogen water, RHI improved by 22%, increasing to 25% after daily consumption for two weeks (19).

Molecular hydrogen has anti-inflammatory and antioxidant effects, and its therapeutic benefits are a growing area of research. Laeberon et al. (2019) found that daily consumption of hydrogen-rich water significantly improved redox homeostasis, inflammatory biomarkers, and metabolic markers in adults with metabolic syndrome (22).

Fiber-rich diets are a beneficial strategy for improving cardiovascular health, and high-fiber diets have been shown to significantly reduce the incidence of CVD and death from CVD (23).

The protective effects of fiber have been attributed to lowering cholesterol and glucose and the beneficial consequences of fiber-containing foods on the gut microbiota, leading to systemic anti-inflammatory effects (20). Additionally, increasing fiber intake means increasing the intake of polyphenol-rich plant foods. These polyphenols regulate transcription factors—such as nuclear factor kappa beta—and can turn off genes that increase the overproduction of inflammatory compounds (23).

A high-fiber diet may sound extreme, but it is really not excessive; getting in just 30-35 grams of fiber daily can help improve endothelial function by 30% (24)!

A daily goal of 30 grams of fiber can be easily achievable by including fiber-rich plant foods with each meal. Certain plant foods are higher in fiber than others. Some of my favorite fiber-rich foods include skin-on pears, raspberries, pumpkin seeds, chia seeds, apples, beans and lentils, sunchokes, artichokes, blueberries, skin-on white potatoes, and pumpkin.

Finally, emerging evidence has shown that dysbiosis of the oral microbiome may contribute to cardiovascular disease (25).

“The oral microbiota induces inflammatory and immune responses in oral tissues, which in turn affects cardiometabolic health and promotes the onset of cardiovascular disease. The microbial invasion of the bloodstream and alterations in gut microbiota caused by oral-gut microbiota transfer may also exacerbate systemic inflammation. Oral dysbiosis ultimately manifests as systemic inflammation, immunoreaction, oxidative stress, and thrombosis. Systemic inflammation may also disrupt the balance of the oral microbiota, as the relationship is bi-directional” (25).

Additionally, the oral microbiome contributes to the synthesis of nitric oxide, which, as you recall, is essential for cardiovascular health and erectile function.

“The oral microbiome may also be important in maintaining systemic health, including the maintenance of a lower blood pressure. NO, for example, is naturally formed either through the NO synthase-dependent pathway or by the enterosalivary nitrate-nitrite-NO pathway involving bacteria. This pathway is important for homeostasis via oral facultative anaerobic bacteria concentrated on the posterior part of the tongue, which can reduce nitrate (from diet or excreted by salivary glands) to nitrite. Thereafter, nitrite and remaining nitrate are ingested, where nitrite is further reduced to NO either under the influence of gastric acidity or in the systemic circulation by further enzymatic and nonenzymatic pathways” (25).

Although I am not an oral health expert, below are my suggestions to improve oral health and the oral microbiome based on the research.

Practice excellent oral hygiene: brush and floss regularly, but be cautious with antibacterial mouthwash.

A 2023 longitudinal study found that good oral hygiene over 18 years was associated with a 51% decrease in the risk of death from CVD (HR: 0.49 [0.28-0.85]; p = 0.01) (28).

Some researchers have suggested a link between antibacterial mouthwash and cardiovascular disease, although research is conflicting. For instance, the above study found no notable connection between mouthwash use and cardiovascular health or disease.

However, a 2020 study of 520 participants found that those who used mouthwash twice daily or more had an 85% higher risk of hypertension (28). Another study supported these findings, specifically looking at chlorhexidine mouthwash. The results showed that regular antibacterial mouthwash disrupted the oral microbiota, reduced nitrate production, and increased systolic blood pressure (29). Alarmingly, these effects occurred after only seven days of use.

Use food to support your oral microbiome.

Just like your food affects your gut microbiota, the same applies to oral microbiota (30).

Consuming a diet low in ultra-processed foods and added sugar and focusing on the abundant micronutrients available in nutrient-dense foods may effectively support the good microbes in your mouth.

References