Moving on. Now the endocannabinoid system is a network of receptors, endogenous compounds and enzymes crucial for processes like stress responses, mood, sleep, appetite, pain, inflammation and even neuroplasticity. It consists of three main components: Endocannabinoids. These are naturally produced compounds in the body that resemble the cannabinoids found in cannabis. The two primary endocannabinoids are: -Anandamide: Often called the “bliss molecule” (derived from the Sanskrit word ananda, meaning bliss), anandamide binds to cannabinoid receptors and has effects similar to tetrahydrocannabinol (THC), the psychoactive compound in cannabis. -2-Arachidonoylglycerol (2-AG): This endocannabinoid also binds to cannabinoid receptors and has effects akin to cannabidiol (CBD), a non-psychoactive compound in cannabis. Cannabinoid receptors. These are the “locks” that endocannabinoids and plant-derived cannabinoids (phytocannabinoids) bind to, triggering various physiological responses. The two primary receptors are: -CB1 Receptors: Predominantly found in the brain and central nervous system, CB1 receptors influence neurotransmitters like GABA, glutamate, dopamine, and serotonin, affecting mood, memory, appetite, and pain perception. -CB2 Receptors: Mostly located in the immune system, peripheral tissues, and some areas of the brain, CB2 receptors are primarily involved in regulating inflammation and immune responses. Enzymes. These break down endocannabinoids after they’ve fulfilled their function. The key enzymes are: -Fatty Acid Amide Hydrolase (FAAH): Breaks down anandamide. -Monoacylglycerol Lipase (MAGL): Breaks down 2-AG. Now anandamide (AEA) and 2-arachidonoylglycerol (2-AG) exert a predominantly inhibitory influence on penile erection, similar to GABA and opioids. Tonic eCB activity provides a “brake” on pro-erectile pathways. So in case you smoke marijuana, consider supporting the endocannabinoid system with other means that won’t have these effects on libido. Sunlight exposure for example particularly in the morning, increases anandamide levels and enhances CB1 receptor activity. Agmatine sulfate enhances cannabinoid signaling through CB1 receptors and curcumin also binds to CB1 receptors. Cardio upregulates CB1 receptors, increases anandamide levels and enhances cannabinoid signaling. For CB2 you can try magnolia since the magnolol and honokiol it contains activate it. Now prolactin (PRL), a peptide hormone primarily secreted by lactotroph cells in the anterior pituitary, is best known for lactation but plays a significant inhibitory role in male sexual function when elevated (hyperprolactinemia, HPRL). Physiological levels are necessary (low PRL linked to premature ejaculation or reduced ejaculate volume for example), but excess PRL is a well-established cause of reduced libido, erectile dysfunction (ED), delayed/absent orgasm, and even infertility. Surprisingly, though, once i went through all the studies, high prolactin affects 1/10 people with ED at best (if we exclude people who are on antipsychotics, SSRIs or have hypothyroidism, this drops to even 1/50) so it shouldn’t be your first concern unless a test confirms high levels. Normal vs. pathological levels Normal range (men): 2–18 ng/mL (86–390 pmol/L). Mild HPRL: 20–50 ng/mL → often subtle low libido/ED. Moderate–severe: >50–200+ ng/mL → pronounced sexual dysfunction + gynecomastia, galactorrhea (rare in men). Now HPRL impairs erection via multiple overlapping pathways: Central (Hypothalamic/Pituitary): Suppresses GnRH → low LH/FSH → hypogonadism (reduced testosterone) → decreased libido/arousal/NO production. Direct DA antagonism: PRL inhibits central DA turnover → reduced motivation/reward (mesolimbic) and pro-erectile signals (PVN oxytocin/NO). Peripheral: Direct suppression of endothelial NO synthase (eNOS) via PI3K-Akt pathway disruption → impaired smooth muscle relaxation/veno-occlusion (independent of testosterone in a rat model). So, if you have high prolactin, working on dopamine, thyroid, DHT and eNOS are the first steps. And finally we have endothelin-1 (ET-1). This is a 21-amino-acid peptide produced primarily by endothelial cells (via prepro-ET-1 → big ET-1 → mature ET-1 by endothelin-converting enzyme/ECE). It acts as one of the most potent endogenous vasoconstrictors, playing a key role in maintaining vascular tone. In penile physiology, ET-1 contributes to flaccid state maintenance and detumescence by promoting contraction of cavernosal smooth muscle. Production and sources in penile tissue: Primary Source: Vascular endothelium in corpora cavernosa (also smooth muscle cells in some studies). Regulation: Upregulated by hyperglycemia, oxidative stress, inflammation (cytokines), hypoxia, angiotensin II, and low shear stress. Receptors: Mainly ET_A (on smooth muscle; vasoconstriction) and ET_B (on endothelium; NO release/clearance, mixed effects). ET-1 shifts the balance toward contraction (anti-erectile), opposing relaxants like NO. Direct smooth muscle contraction: Binds ET_A receptors (dominant in human cavernosum) → Gq → PLC → IP₃ → Ca²⁺ release/influx → myosin light chain phosphorylation → contraction. Activates RhoA/ROCK pathway → Ca²⁺ sensitization (sustained tone even at low Ca²⁺) . Slow-onset, long-lasting (hours), stronger/more sustained than noradrenaline. Endothelial dysfunction & NO opposition: High ET-1 reduces NO bioavailability (downregulates eNOS, increases oxidative stress). Impairs shear-stress induced relaxation → poor arterial inflow/veno-occlusion. Structural changes (chronic): Promotes smooth muscle proliferation/fibrosis (via nuclear Ca²⁺ signaling, TGF-β). Contributes to corporal veno-occlusive dysfunction (CVOD). Now since elevated or dysregulated ET-1 is implicated in vasculogenic/organic ED, particularly in conditions with endothelial dysfunction such as diabetes and hypertension, addressing these is the best step.