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Marijuana, Alcohol, and ED: Correlations with LUTS/BPH

Benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) is a disease complex with enormous societal burden and yet the pathogenesis of LUTS/BPH is poorly understood. We set out to review the literature on the relationship between depression, marijuana usage, and erectile dysfunction (ED) to LUTS/BPH.

Recent Findings

LUTS/BPH has independent associations with depression as well as with ED. In each case, the causality and mechanistic relationship is unknown. The impact of marijuana, as it increasingly pervades the general population, on the disease complex of LUTS/BPH is not well studied but recent results support short-term benefit and long-term caution.

Summary

Depression, a form of central nervous dysfunction, and ED, which is likely mediated via endothelial dysfunction, are independently associated with LUTS/BPH. The presence of cannabinoid receptors in urologic organs, coupled with recent population studies, supports a modulatory effect of marijuana on voiding although an enormous knowledge gap remains.

Introduction

Benign prostatic hyperplasia (BPH) and BPH-associated lower urinary tract symptoms (LUTS) have a significant impact on men’s health. Globally, BPH carries the highest health burden of any urologic disorder, malignant or benign, and is poised to rise even more rapidly [1]. As the population ages and the societal burden of LUTS/BPH increases, better understanding of its underlying causes and associated disease processes becomes more critical. LUTS/BPH has multiple causative factors and many epidemiologic correlates, but an effective and unifying understanding of this heterogeneous disease has proven elusive.

Specific associations have been investigated in hopes of better understanding how to treat and avoid progression of BPH and LUTS. Metabolic syndrome (MetS) has been linked with the disease process of LUTS/BPH, but evidence has been variable and inconclusive [2•]. Hypertension (HTN), type 2 diabetes (DM), obesity, physical inactivity [3, 4], autonomic nervous system overactivity [5], prostate growth rates, and failure of senescence [6, 7] have all been found to contribute to or correlate with LUTS/BPH. Other community surveys of erectile dysfunction (ED) found that prostatitis and incontinence are strongly associated with LUTS/BPH [8], and a subsequent meta-analysis verified deep interrelationship between these two diseases of the aging male. Implicating central nervous system involvement in the process, depression has been linked with both LUTS and BPH although causality is unknown [9–12]. Furthermore, recent studies have shown a relationship between marijuana usage and LUTS/BPH that suggest short-term improvement in voiding but raise concerns about long-term usage [13–17]. However, we are unaware of any data showing impact on urinary function related to alcohol usage. We set out to review the latest literature on the relationship between LUTS/BPH, and these comorbid conditions and coexisting habits.

Marijuana Use and LUTS

Marijuana is a product derived from the cannabis plant, a flowering member of the family Cannabaceae. The genus is thought to be indigenous to central Asia. Medicinal uses for marijuana date back 5000 years across many cultures for a variety of medical problems. The active ingredients of marijuana include tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is a psychoactive compound which can induce euphoria, relaxation, altered perception of time, increased appetite, and heightened sensory perception [18]. CBD is a non-psychoactive substance that is hypothesized to have an effect on anxiety, cognition, movement disorders, and pain [19]. Suggestive of pharmacologic effect, usage for myriad processes has been reported in the modern medical literature for hundreds of years [20].

THC, the primary identified active agent in marijuana, mediates effect on target tissue via two primary receptors: CB-1 and CB-2. This identification of a direct effect of cannabinoids on the bladder, and the identification of the widespread cannabinoid receptor (CB-1) as a mechanism for the mediation of that effect, has led to studies, primarily in murine models. The second receptor, CB-2, shares 44% homology with CB-1 and is more limited in distribution, being mostly found in brain and testes [21].

Translational Studies of Cannabinoid Effects on Bladder and Voiding

Cannabinoids have been observed to modulate bladder function in animal models including an increase in voided volume, voiding pressure, and prolonged intermicturition intervals [22••]. Direct arterial injection of CB agonist also decreased bladder voiding threshold, both at baseline and in response to irritants [23]. This effect was ameliorated by competitive antagonists of the receptor. Intravesical instillation of synthetic cannabinoids also had an effect on bladder response pointing towards the involvement of CB-1 receptors when compared to the CB-2, with CB-1 appearing to be the primary mediator of voiding effects [24]. In a separate murine model of acrolein-induced cystitis, cannabinoids were found to significantly counteract the irritative effects of the chemical, suggesting a potential role for bladder pain management in humans [25, 26]. Overall, THC and synthetic cannabinoid agonists of the CB-1 and to a lesser extent CB-2 receptor appear to have generally beneficial short-term effects on voiding in animal models. Long-term effects and chronic adaptation are still mostly unknown.

Effects of Marijuana on Human Voiding

Human voiding response to cannabinoids has not been much studied, although an identifiable effect appears to exist. Cannabis usage induced intriguing responses in bladder and urine proteomics: increases in immune response pathways, and carbohydrate-related mechanisms, among others [27]. Two cross-sectional population studies have found a statistically significant association between marijuana usage and the presence of LUTS. First, 3037 men aged 20–59 and completing the National Health and Nutrition Examination Survey from 2005 to 2008 found that self-reported marijuana users experienced less LUTS [28•]. More recently, it was observed that in a sample of 173,469 men (aged 45 or over), those who were identified as using cannabis were significantly more likely to receive treatment for LUTS/BPH than men who were not [29]. This “substance use-symptom” relationship between marijuana and LUTS/BPH was not present in the same group when assessed for the effects of alcohol consumption.

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These two findings address separate end points: self-reported voiding dysfunction is different than the receipt of treatment for LUTS/BPH. Additionally, the age groups were somewhat different in these two groups, and it was not possible to control the NHANES data for age-related correlation of usage. This is important because the use of marijuana decreases substantially with age: 30% of adults in the 18–25 age group reported marijuana usage in the past year, but this rate drops to 3.4% of those who are 50–64 years old and 0.6% in adults over 65 [30]. It seems likely that adult marijuana users represent a somewhat distinct population subset, behaviorally, socially, or biologically. Perhaps, men who use marijuana, especially those that use into adult life and past the age of 45, find it therapeutic in the same fashion that leads general and younger users to report lower baseline urinary symptoms. Alternatively, continued consumption in later life may be a marker for long-term exposure and a high cumulative dose of cannabinoid, which in turn may represent a damaging effect. It is not possible to draw conclusions regarding effects of chronic exposure to marijuana from these data. Other substances of abuse and toxins can result in severe and direct urinary morbidity, such as ketamine [31], although this pharmacological agent is unrelated to THC and marijuana.

In multiple sclerosis (MS) patients, cannabinoids showed some beneficial effects on muscular spasticity and on urinary function in men and women, although results have varied between the studies and formulation of cannabinoid administration [32]. A survey of MS patients using marijuana found that over half of patients reported subjective improvement in urinary symptoms, and others confirmed improvement in urge and incontinence, thereby, supporting self-selection for a perceived benefit of cannabinoids [14–17]. A controlled trial of cannabinoids and placebo in 24 patients with a variety of neurological symptoms, primarily from MS, showed a notable improvement in pain and other symptoms, including LUTS improvement in cannabinoid users.

Depression and LUTS

Depressive disorder is a common medical problem among older adult males. It has significant health-related quality of life implications including decreased functional status and increased mortality, and is a risk factor for the development of other chronic diseases [33]. Depression as a diagnosis is characterized by depressed mood and loss of interest in enjoyable facets of life and/or pleasure. The condition can manifest itself in a variety of ways both mentally and physically [34]. The prevalence of depression in adults is 7.7% in those age 20–39, 8.4% in those age 40–59, and 8.0% in those age 60 and over, according to the National Health and Nutrition Examination Survey (2013–2016). Clinical studies revealed a correlation between depression and the diagnosis of LUTS. A review of 547 men identified that the 22% who scored poorly on a geriatric depression scale were three times more likely to also have severe LUTS, as was defined by an IPSS score of > 20. 9 Similar observations have been made in patients from Australia and Korea [35–37], and a systematic review of nocturia also found strong correlation with depression [38]. Our group was able to identify the same association in an American sample of 173,649 men, with the diagnosis of depression carrying an odds ratio of 2.05 (95% CI 1.95, 2.16) for requiring LUTS/BPH therapy after multivariable controls [29]. The range of depression prevalence in patients with LUTS lies within 11.5–12.3% [39, 40]. The severity of LUTS directly correlates with increasing severity of depressive symptoms, as well as with higher odds of suicidal ideation in cross-sectional studies [41, 42]. Whether this is a centrally mediated effect or whether the depressive state is a consequence of other symptoms and organ dysfunction is still unknown.

Whether the depressive state is a CNS-mediated effect, a consequence of other symptoms and organ pathology, or broad CNS dysfunction occurs in parallel to LUTS in the aging male is still unknown. Likely, a decline in organ function, for example, of the urinary bladder, might be paralleled or enhanced by a decrease in the function of the central or peripheral nervous system.

Adding to the myriad of interrelated factors is the apparent interaction between depression and cannabis usage. A study of 14,000 twins from Australia as well as other groups has suggested a correlation between heavy marijuana usage and depression [46–49]. The exact relationship between the two entities is not completely established, but studies suggest that regular marijuana use in adolescents results in a decrease in size in certain regions of the brain (hippocampus, amygdala, prefrontal cortex) that are dense in endocannabinoid receptors [50]. Furthermore, early cannabis use was also associated with anhedonia and decreased serotonin levels in adults [51]. The underlying deficiency in the intrinsic endocannabinoid system may be involved in heightened risk of post-traumatic stress development and may be the cause of increased cannabis use [52]. The use of cannabinoids may also play a role in other behavioral diseases where the intrinsic endocannabinoid system appears to mediate neurochemical changes underlying the placebo effect [53]. Could a subset of individuals similarly discover that the addition of exogenous cannabinoid to their own internal milieu corrects other forms of bother? There is a complex interaction between cannabinoid use, depression, and LUTS and further studies will be needed to understand their effects on each other ( Fig. 1 ).

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Update on Cannabis and Prostate Cancer

Research since the March 2018 posting of the blog below supports the anti-tumor effect of non-psychoactive CBD (cannabidiol), one of 100+ identified plant-derived cannabinoid compounds. For example, Kis et al. note that lab studies have shown a chemopreventive effect of cannabidiol in prostate cancer (PCa) as well as stimulating PCa cancer cell death pathways and boosting genomic antitumor activity. [i] Furthermore, CBD is a “potent inhibitor” of the release of exosomes from PCa cells; exosomes are very tiny particles containing molecular messages that can change the behavior of healthy cells that receive them, and are thus a biogenetic pathway for the spread of PCa. A cell study by Kosgodade et al. revealed that CBD’s ability to regulate the release of PCa exosomes is one of its mechanisms for anti-cancer activity, though such dose-dependent activity appears more powerful in some types of cells others. [ii]

Thus, there is clear evidence that CBD has properties that inhibit PCa cell growth and division, encouraging cancer cell death, and block cancer cells from transforming normal cells into PCa. However, all research thus far has been conducted either in lab animals or using lab-cultured PCa cell lines. The only human clinical trials of CBD are with advanced PCa patients for management of pain and chemotherapy side effects. Thus, the potential use of CBD as a PCa prevention or a treatment for localized PCa is promising but remains hypothetical.

Cannabis (marijuana, pot, weed, grass etc.) is a widely used recreational and medicinal drug. In fact, cannabis use dates far back in ancient times, probably for the same two purposes. Today, state laws in the U.S. are rapidly becoming more permissive less than a century after it was made illegal in 1937.

According to Ramos & Bianco (1912), “The plant contains many chemical compounds that have different pharmacological properties, varying in quantity and quality depending on the strain, culture, and storage conditions. In 1964, Mechoulam and colleagues found that delta-9-tetrahydrocannabinol (THC) was the major psychoactive ingredient of cannabis.”[iii] These compounds, including THC, are called cannabinoids, and 66 separate cannabinoids have been identified.

Cannabinoids produce their physical and psychological effects by interacting with specific receptors on cell surfaces that have an affinity for these compounds. There are two types of receptors:

  • Cannabinoid receptor type 1 (CB1) are mostly found in the brain, and also in the male and female reproductive systems. To a lesser extent, they exist in central and peripheral pain pathways (nerves) which may explain why pain relief is a benefit of cannabinoids, particularly THC.
  • Cannabinoid receptor type 2 (CB2) are primarily found in the immune system, and may be associated with anti-inflammatory and other therapeutic effects of cannabis.

Cannabis and prostate cancer

There has been both enthusiasm and caution about cannabis use and cancer. By mid-2015, 23 states had legalized medical marijuana, one of the primary uses being to ease the side effects of chemotherapy and radiation in cancer treatment. As described above, CB1 receptors play a key role in cancer pain relief.

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Now, as scientific research into the two types of cannabinoid receptors has progressed, understanding how cannabinoids interact with prostate cancer cells opens the possibility of using these compounds to restrict the activity, including the growth and spread, of prostate cancer itself.

How cannabis affects prostate cancer cells

Research shows that prostate cancer cells have higher levels of expression of both CB1 and CB2 receptors than normal cells. To put it another way, the cancer cells have a greater affinity for cannabinoids than normal cells. Laboratory studies[iv] have demonstrated that when the cells are treated with a specific cannabinoids, three consequences occur:

  1. In general, the cells became less viable and more prone to apoptosis (programmed cell death), and
  2. Androgen receptor activity on the cancer cell surfaces decreased (prostate cancer appears to be “fueled” by androgens, or male hormones)
  3. Two cannabinoids, THC and CBD, discourage the formation of tumor blood vessels (angiogenesis) needed by prostate cancer tumors to nourish themselves.[v]

A very extensive study was conducted by De Petrocellis et al. (2012)[vi] using both prostate cancer cells in lab containers and prostate cancer tumor cells implanted in mice. Non-THC cannabinoids were thus tested for their biochemical effects on individual cells as well as actual tumor behavior in live animals. The overall results were encouraging, with the authors suggesting that “non-THC cannabinoids, and CBD in particular, retard proliferation and cause apoptosis of PCC [prostate cancer cells] via a combination of cannabinoid receptor-independent, cellular and molecular mechanisms.”

The current state of cannabinoids and prostate cancer

With such promising research evidence that cannabinoids are destructive to prostate cancer cells, what is happening with actual prostate cancer patients? Not much, according to a prostate.net blog:

There are many stories of people who have used cannabis oil to shrink prostate cancer tumors, and many of the people had success combining the oil with traditional therapies to fight their cancer. The problem with getting hard data and studies is that United States laws make it challenging for clinical studies on the marijuana plant to take place. Plus, there seems to be a lack of funding for the research. The studies that have taken place tend to focus on symptoms (such as pain relief and nausea) rather than the efficacy of the cannabis oil to shrink cancer tumors.

Yet the research teams who have published their results with laboratory experiments, both in lab containers and animal studies, are clearly calling for clinical trials with patients. They point out that non-THC cannabinoids demonstrate properties that keep the cells from proliferating, spreading, building their own blood supply, and taking up androgens (male hormones). In addition, the De Petrocellis study found that under certain conditions, cannabinoids had a synergistic effect with chemotherapy (docetaxel) or hormone therapy (bicalutamide). Such features conjure visions of creative directions in prostate cancer treatment.

Ramos & Bianco explicitly describe a constructive scenario for prostate cancer patients with painful metastasis to the bone. As they state, cannabinoids “harbor analgesic properties that aid bone cancer pain, reduce opioid consumption, side effects, and dependence, as well as exhibiting anti-androgenic effects on experimental prostate cancer cells.”

Perhaps today’s trend of relaxing cannabis restrictions will open the path to human clinical trials, and the real value of cannabinoids in the treatment of prostate cancer will be revealed.

[i] Kis B, Ifrim FC, Buda V, Avram S et al. Cannabidiol-from Plant to Human Body: A Promising Bioactive Molecule with Multi-Target Effects in Cancer. 2019 Nov 25;20(23):5905

[ii] Kosgodage US, Mould R, Henley AB, AV et al. Cannabidiol (CBD) Is a Novel Inhibitor for Exosome and Microvesicle (EMV) Release in Cancer. Front Pharmacol. 2018 Aug 13;9:889.

[iii] Ramos J, Bianco F. The role of cannabinoids in prostate cancer: basic science perspective and potential clinical applications. Indian J Urol. 2012 Jan-Mar;28(1):9-14.

[iv] Sarfaraz S, Afaq F, Adhami VM, Malik A, Mukhtar H. Cannabinoid receptor agonist-induced apoptosis of human prostate cancer cells LNCaP proceeds through sustained activation of ERK1/2 leading to G1 cell cycle arrest.J Biol Chem. 2006 Dec 22;281(51):39480-91.

[vi] De Petrocellis L, Ligresti A, Schiano Moriello A, Iapelli M et al. Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms.Br J Pharmacol. 2013 Jan;168(1):79-102.

About Dr. Dan Sperling

Dan Sperling, MD, DABR, is a board certified radiologist who is globally recognized as a leader in multiparametric MRI for the detection and diagnosis of a range of disease conditions. As Medical Director of the Sperling Prostate Center, Sperling Medical Group and Sperling Neurosurgery Associates, he and his team are on the leading edge of significant change in medical practice. He is the co-author of the new patient book Redefining Prostate Cancer, and is a contributing author on over 25 published studies. For more information, contact the Sperling Prostate Center.