The incidence and prevalence of SD associated with medications and substances of abuse differ significantly depending on the specific medication, group of medications and substances of abuse. There are also gender differences in estimates of prevalence of SD associated with medications and illicit substances. SD associated with medications if frequently underreported. It is well known that patients, especially in earlier clinical studies, underreport or do not report SD spontaneously. Several studies demonstrated differences between spontaneous reporting of SD and reports of SD when patients were actively asked by investigators—the frequency yielded during active questioning by investigators was always higher. The difference between spontaneous and actively obtained frequency of SD probably explains the originally low incidence of SD associated with fluoxetine mentioned in Physician’s Desk Reference [3]—1.9%—and much higher frequencies in later studies (e.g., 52.9% [4]).

Various articles summarized the evidence of SD associated with antidepressants. Serretti and Chiesa [5] in their meta-analysis reported significantly higher rate of total and specific treatment-emergent SD and specific phases of dysfunction compared with placebo for the following drugs in decreasing order of impact; sertraline, venlafaxine, citalopram, paroxetine, fluoxetine, imipramine, phenelzine, duloxetine, escitalopram, and fluvoxamine; while no significant difference compared to placebo was found for agomelatine, amineptine, bupropion, moclobemide, mirtazapine, and nefazodone . The frequency of SD in their analysis ranged from 25.8 to 80.3%. The widespread differences in reporting SD with antidepressants and the fact that most studies lacked using a validated sexual functioning rating scale and a baseline evaluation of SD or a placebo control or both, lead Montgomery, Baldwin and Riley [6] to the conclusion that the existing literature confirms sexual dysfunction as a possible adverse event of all antidepressants. They also pointed out the occurrence of sexual dysfunction in various mental disorders (e.g., mood disorders, anxiety disorders, schizophrenia) which also varies significantly and may impact the reporting of SD associated with treatments for these disorders. However, the evidence is not sufficiently robust to support most claims for differences in the incidence of SD between existing antidepressant therapies, especially since most studies reporting SD with antidepressants were not comparative. The DSM-5 ([7], p. 449) concluded that approximately 25–80% of individuals taking monoamine oxidase inhibitors (MAOIs) , TCAs, SSRIs, and combined serotonergic-adrenergic antidepressants (SNRIs) report sexual side effects.

It is probably prudent to expect SD in 40–50% of patients treated with antidepressants, if carefully evaluated.

Approximately 50% of patients taking antipsychotics will experience SD, including problems with sexual desire (mostly), erection, lubrication, ejaculation, orgasm, priapism, retrograde ejaculation [7, 8]. There are probably individual differences among various antipsychotics and it seems that the prevalence of SD with second generation (atypical) antipsychotics may be lower than that with the first generation (typical) antipsychotics. However, as with antidepressants, there are no good comparative studies and many studies are marred by methodological issues such as lack of baseline evaluation, and lack of validated rating tools. The evidence of SD associated with other psychotropic drugs such as anxiolytics and mood stabilizers is scarce and not providing data to estimate prevalence. It seems that buspirone may be associated with less SD than other medications used to treat anxiety disorders.

The exact prevalence and incidence of SD associated with non-psychotropic medications such as cardiovascular, gastrointestinal, hormonal, and cytotoxic agents are unknown [7, 8]. Some of these medications seem to have a high incidence of specific SD (e.g., erectile dysfunction associated with cimetidine is estimated to be 40–60%). Estimating the prevalence of SD associated with some of these medications may be difficult due to intrinsic patient and medication factors. Examples include some antihypertensives and some anticancer drugs. Hypertension is a well-known risk factor for erectile dysfunction (vascular damage) and thus untangling what part of SD is due to vascular disease and what part is due to medication may be difficult. Similarly, cancer is associated with psychological problems which may lead to SD, and cytotoxic medications may cause general fatigue and damage to nerves and gonads—thus, it may be again difficult to determine what part of SD is due to a direct medication effect, indirect effect (fatigue) or the illness itself. The situation in estimating SD associated with medications used in obstetrics and gynecology, namely hormones, is similar.

There are many reports on SD associated with illicit drugs [7–9]. However, the estimates of incidence and prevalence are rare or nonexistent. In addition to previously mentioned methodological problems, the estimates of prevalence of SD associated with illicit drugs is complicated by the fact that some of these drugs may acutely help with sexual functioning, but later lead to deterioration of it (e.g., alcohol may decrease anxiety; cocaine may increase libido, cannabis may increase sexual pleasure and satisfaction and enhance orgasm).

In several studies the majority of subjects abusing opioids reported SD and the prevalence of SD in those abusing heroin is estimated to be 60–80% [7, 9]. Tobacco smoking is also associated with SD—increased incidence of erectile dysfunction in over 50% smokers has been reported in some studies [10] and in a meta-analysis by Tengs and Osgood [11], 40% of impotent men were current smokers compared with 28% of men in the general population. Tobacco smoking increases the risk of sexual dysfunction . As with other substances and medications, it is difficult to estimate the share of tobacco smoking in SD, as tobacco smoking is associated with poor overall general health and other risks of SD such as cardiovascular disease.

The etiology of SD associated with medications or substances of abuse is clearly related to a specific substance and its impact on various neurotransmitters/receptors and hormones regulating sexual functioning. The regulation of sexual behavior and sexual response is complex and not fully understood. It involves the central nervous system (CNS), peripheral nerves and endocrine glands. Various neurotransmitters that are influenced by psychotropic medications play also an important role in mediating the sexual response. The serotonergic system generally inhibits sexual functioning (e.g., [8, 12])—by actually inhibiting all three major phases of the sexual response cycle, desire, arousal, and orgasm. However, the involvement of the serotonergic system is more complex, as some serotonergic receptors inhibit sexual functioning while others (e.g., 5-HT_1A) stimulate it. It is well known that serotonergic antidepressants are associated with SD, most significantly with delayed orgasm and anorgasmia. However, there are differences among serotonergic antidepressants in their impact, e.g., on ejaculation. For instance, paroxetine delays ejaculation significantly more than sertraline or citalopram [13, 14]. Presumably, strongly serotonergic medication may influence sexual functioning at the CNS (e.g., amygdala, hippocampus) and peripheral level. Dopamine , another neurotransmitter influenced by various medications, plays an important role in regulating sexual desire and arousal (e.g., 12). Dopamine (motor neurotransmitter of the reward system) activates nucleus accumbens and some hypothalamic regions that are important for sexual motivation and desire [12]. Thus medications blocking the dopamine receptors, such as antipsychotics, impact sexual functioning, namely desire and arousal. However, dopamine also regulates the secretion of prolactin from the pituitary gland—D₂ receptor blockage by antipsychotics increases the secretion of prolactin. Prolactin decreases sexual desire and the decreases levels of some sex hormones, such as estrogen and testosterone. On the other hand, prolactin seems to provide the body with sexual gratification after sex. Thus, psychotropic medications blocking the dopamine receptors (especially D₂ receptor) may profoundly impact sexual functioning. As noted before, sexual functioning may be also impacted by mental illness treated with a particular medication (e.g., antidepressant), that may contribute to SD. Further factor complicating the determination of a relationship between the substance and SD include possible multiple diseases, their treatments, marital discord, alcohol abuse and general life stress [8]. Another complicating issue may be the delayed onset of action of the substance implicated in SD (e.g., carbamazepine- and estrogen-induced increases in serum hormone binding globulin, thus decreasing the availability of free testosterone—[8]).

The etiology of SD associated with medications used to treat various physical illnesses is again tied to the specific mechanism of a particular medication. For instance, the erectile dysfunction associated with some beta-blockers, especially the nonselective ones, is due to their direct effect on penile vascular smooth muscle cells causing vasoconstriction from the unopposed alpha-adrenergic stimulation, leading to decreased perfusion in the corpora cavernosa [15]. In addition, some beta blockers (e.g., atenolol, propranolol, pindolol) have been reported to decrease the levels of testosterone and follicle stimulating hormone [15]. The underlying cardiovascular illness may again play an additional role in SD in this case. Quite frequent sexual side effects of cimetidine, an H₂ blocker, have been attributed to its antiandrogenic and estrogenic (increase of estradiol) properties [8, 16], ganglionic blockage, and an effect on central histaminic function [8].

As noted, the etiology of SD associated with substances of abuse again depends on the specific substance. Sexual dysfunction associated with chronic use of stimulants (cocaine) is related to the dopaminergic system . Alcohol related SD seems to be related to alcohol-induced hepatic catabolism of testosterone and its transformation to estradiol, and also possibly to the phytoestrogen content of alcoholic beverages [9]. SD associated with cannabis use is probably related to the disinhibition provided by delta-9-tetrahydrocannabinol [9]. SD associated with tobacco use could be explained by the strong vasoconstrictive effect of nicotine, its effect on the penile endothelium and its increase of sympathetic nervous tone [17]. Finally, SD associated with opioid use is probably related to the inhibition of the hypothalamic–pituitary–gonadal axis and increase in prolactin levels [9]. Sexual functioning during abuse of illicit substances is probably also impacted by poor physical health due to substance abuse (e.g., liver disease).

The physiology/regulation of human sexual response is quite complex. It involves CNS structures (e.g., amygdala, thalamus, paragigantocellularis nucleus), spinal cord and peripheral nerves (e.g., inferior mesenteric plexus, superior hypogastric plexus, pelvic plexus), endocrine glands (gonads, pituitary gland, and “peripheral” other endocrine organs, e.g., neuropathy due to diabetes), blood vessels, and smooth muscles.

Each phase of the sexual cycle is regulated by a complex interplay of biological, psychological, and environmental factors. For instance, the core of the excitatory system involved in sexual desire appears to be formed by the brain dopamine systems (incertohypothalamic and mesolimbic) that link the hypothalamus and the limbic system [18]. This system also includes melanocortins, oxytocin, and norepinephrine [18]. Brain opioid, endocannabinoid, and serotonin systems are activated during periods of sexual inhibition and blunt the ability of excitatory systems to be activated [18]. Thus, as Pfaus wrote [18], drugs (medications and drugs of abuse) that stimulate the activation of hypothalamic dopamine or that blunt endocannabinoid or serotonin release and/or postsynaptic binding may be effective in stimulating sexual desire. On the other hand, substances that inhibit or block dopamine or stimulate serotonin or endocannabinoid release seem to decrease or suppress desire. In addition, plasma testosterone is necessary for desire or interest in both men and women [12], as it influences specific brain regions sensitive to internal and external cues. Testosterone release is directly inhibited by, among others, prolactin. Substances that reduce dopamine or thyroid dysfunction may thus indirectly decrease testosterone availability.

Dopamine receptor activation may also be associated with penile erection, which also involves the inhibition of alpha-adrenergic influences and beta-adrenergic stimulation plus the release of a noncholinergic vasodilator substance and possibly vasoactive peptide [19]. Substances inhibiting the dopamine pathways or substances with alpha-adrenergic stimulation properties may impair erection centrally (the alpha-adrenergic influence could impair erection also on the peripheral level, e.g., in the regulation of vasoconstriction of peripheral vessels). Arousal regulation in both men and women involves the autonomic nervous system (e.g., acetylcholine is involved in parasympathetic activation which leads to vasodilatation in the penis, clitoris and vaginal wall). There are also intracellular mechanisms involved in medicating erection, e.g., cyclic guanosine monophosphate (c-GMP) and adenosine monophosphate (AMP) . As explained e.g., by McVary [20] and many others, increased concentration of nitric oxide (NO) in smooth muscles (e.g., by nonadrenergic noncholinergic fibers; release is connected to sexual desire) leads to relaxation of cavernous sinusoids of penis through a complex way. The increase of NO leads to activation of guanylate cyclase which produces cGMP , and to a decrease in intracellular calcium through a pathway mediated by cGMP and that leads to muscle relaxation (cAMP may also decrease the intracellular calcium). Relaxation of smooth muscles leads to increased blood flow into corpora cavernosa. Substances that affect the cGMP pathway (e.g., drugs blocking phosphodiesterase-5 which metabolizes cGMP) or the cAMP pathway (alprostadil), or both pathways (papaverine) thus prolong muscle relaxation and inflow of blood into corpora cavernosa. Phosphodiesterase-5 inhibitors are medications used to treat erectile dysfunction through this complex mechanism. However, impairment of these pathways via various substances or due to physical illnesses (e.g., cardiovascular—endothelial damage) may lead to SD. It is hypothesized that similar mechanisms are involved in women [8]. Many of the same neurotransmitters involved in the regulation of erection have been identified in clitoris and/or vaginal wall [8].

Ejaculation involves the sympathetic nervous system (alpha-adrenergic fibers) [19]. The activation of this system leads to contraction of the smooth muscles in the epididymis, vas deferens and seminal vesicles, thus propelling the ejaculate to the posterior urethra [12]. Then spasms of the surrounding muscles lead to propulsion of the ejaculate from the urethra. Activation of dopamine or 5-HT_1A receptors promotes ejaculation. Serotonergic stimulation appears to inhibit the ejaculatory reflex. Opioids (endogenous and exogenous) inhibit ejaculation. Norepinephrine (primary messenger in the sympathetic nervous system) and prolactin also influence ejaculation. Finally, oxytocin seems also involved in regulating ejaculation/orgasm., especially the pleasant sensations experienced during orgasm and the affiliative feelings. All nerves and neurotransmitter/hormone systems could be impacted by medications or substances of abuse at various stages. The detailed physiology of female orgasm (beyond spasms of orgasmic platform, uterus, and anal sphincter) is less well understood and involves the coordination of sympathetic, parasympathetic, and somatic efferent system innervating the genital organs [21]. The reflexive cascade of contractions may be modulated by serotonin and dopamine; however, other neurotransmitters, hormones, and other substances are involved, too.

Clayton and colleagues [12] summarized the possible genetic/pharmacogenetic predisposition to SD associated with SSRIs. There are studies (e.g., [22]) reporting a higher incidence of SD associated with paroxetine in poor metabolizers of cytochrome CYP450 2D6. The role of genetics SD associated with medications or substances of abuse is not clear. Clayton and colleagues [12] noted that there is a lot of ongoing research into the pharmacogenetics affecting liver metabolism, the blood–brain barrier, serotonin receptor subunits, neurotropic factors, and glutamate receptor subunits.

Intact sexual functioning also depends on overall physical health, namely of the cardiovascular and endocrine systems. Medications and substances of abuse could negatively impact these systems.

The physiology of sexual functioning is clearly quite complicated and not fully understood. The pathophysiology of SD is even less well understood. The mechanisms of drug-induced sexual side effects include antiandrogenic, anticholinergic, antiestrogenic, alpha-adrenergic, beta-adrenergic, dopaminergic, and serotonergic effects; and the suppression of gonadotropin release and inhibition of NO synthase [8]. It is obvious that medications and substances of abuse can impact the regulation and physiology of human sexual response at numerous points.

The phenomenology of SD associated with medications and substances of abuse is basically the same as the phenomenology of sexual dysfunction in general. Medications and substances of abuse can be associated with an impairment of a particular phase of the sexual response cycle (decreased desire, impaired arousal, impaired—delayed or suppressed orgasm/ejaculation), or with an overall suppression/impairment of all phases of the sexual response cycle. Some less-known sexual side effects, such as retrograde or painful ejaculations, ejaculatory anhedonia and genital anesthesia may occur with some psychotropic medications (antipsychotics, tricyclic antidepressants).

The DSM-5 [7] diagnostic criteria of substance/medication-induced sexual dysfunction are outlined in Table 23-2.

The DSM-5 ( [7], p. 446) notes that the diagnosis of substance/medication-induced SD should be made instead of a diagnosis of substance intoxication or substance withdrawal only when the symptoms in Criterion A predominate in the clinical picture and are sufficiently severe to warrant clinical attention.

The DSM-5 [7] also delineates the following Specifiers regarding the onset and severity of sexual dysfunction:

With regard to the onset:

With regard to severity:

Of note: The DSM-5 [7] also presents a complicated way of coding substance/medication-induced sexual dysfunction related to use and severity of use of a specific substance. The name of the substance/medication-induced sexual dysfunction should begin with the specific substance, e.g., alcohol or fluoxetine. The coding of medication-induced sexual dysfunction or of substances that do not fit into any of the classes should use the code (DSM or ICD) for “other substance.” If the specific substance is not known but judged to be an etiological factor, the category of “unknown substance” should be used. The diagnosis should be followed by specifiers. The coding seems to be a bit cumbersome from a clinical point of view, but may be useful in future surveillance studies.

In contrast to other sexual dysfunctions , the DSM-5 criteria for substance/medication-induced SD do not specify the duration of this SD. However, the DSM-5 [7] text mentions that the onset of antidepressant-associated SD may occur as early as 8 days after the medication is first taken. It also mentions that about 30% of patients with mild to moderate orgasm delay may experience spontaneous remission within 6 months. SD associated with medications and substances of abuse may increase with age [7]. The question whether the SD persists after the discontinuation of medication/substance of abuse in some individuals remains unresolved. Rare cases of SD associated with SSRIs persisting for 4–24 months after SSRIs discontinuation have been reported [23].

The cornerstone of the best approach to the diagnosis is a thorough clinical interview and questioning. The interview should help to differentiate between SD and sexual complaint. Sexual complaints are almost universal, frequently related to relationship problems or life stress, are transient and inconsistent in symptomatology, and frequently remit spontaneously.

Questioning should be rather specific, with a focus on the character of SD (decreased libido, arousal impairment, orgasm delay or absence), intensity, persistence, and especially the onset of SD and time relationship to the start of a particular medication or taking of a substance of abuse. Baseline evaluation (= prior to starting the medication) of sexual functioning is of utmost importance. It is difficult to rely on the patient’s retrospective interpretation of the relationship/time between the onset of SD and the start of a particular medication. Frequently, the underlying illness treated with a particular medication is also associated with SD (e.g., depression, schizophrenia, diabetes, cardiovascular disease) and it may be difficult to decipher the relationship between the illness, medication, and SD without having the baseline evaluation of SD. Similarly, relationship problems may be a complicating factor. Thus an astute clinician should evaluate sexual functioning at the initial clinical interview, at the start of prescribing any medication and, actually, regularly at follow-up visits. Balon [1] outlined the elements of an evaluation of sexual functioning during baseline evaluation of patients with depression that is applicable to the evaluation of sexual functioning prior to starting any medication. The elements include: (a) pretreatment and, if possible, premorbid sexual functioning ; (b) comorbid psychiatric disorders and substance use (including tobacco and alcohol), (c) physical illnesses; (d) all concurrent medications (including over-the-counter ones); (e) sexual functioning during the recent episode of illness (depression, anxiety, etc.) but before initiation of treatment; (f) potential interpersonal context of the SD (marital conflict etc.).