Bibliography

CANNABIDIOL, A HELP FOR SEXUALITY?

Caresses, kisses, cuddles and intimacy are essential for a woman's sexual arousal, to facilitate the intercourse, to achieve pleasure and have full sexual fulfillment. But sometimes all of this may not be enough. The decline in desire, especially in couples already run in, pain during intercourse associated with the typical problems of menopause, stress and anxiety are also some of the problems that undermine a couple's sexual well-being.

CBD oil can be a valuable aid to rekindle desire and live a more satisfying sexuality. Women who have used legal cannabis (therefore high in cannabidiol, a substance with no effect psychoactive) before sexual intercourse they declared that they reach orgasm more easily, that they feel pleasure for a longer time and not to feel pain during intercourse.

The oil can be applied locally with a massage in the private parts to stimulate a better flow of blood and prepare the genitals for intercourse or it can be taken in drops to have a more systemic effect business suit.

According to the WHO report, cannabidiol does not cause side effects on our health, it is well tolerated in humans (and animals), and is not associated with any adverse public health effects. The commission of experts also stated that CBD does not induce physical addiction.

The scientific data is still preliminary but according to a recent study published in Sexual medicine women who taking cannabis claimed to have more fulfilling intercourse, increased desire and absence of pain during the act.¹

Why does CBD improve sexuality?

CBD interacts with many receptors both centrally and peripherally with multiple effects and relapses also in the sexual sphere.
In particular, it has been seen that CBD:

• disinhibits, reducing anxiety and improving mood;
• reduces the pain that may occur during sexual intercourse;
• stimulates desire.

Effects on anxiety, stress and mood. The anxiolytic effect of CBD is to be attributed the molecule's ability to stimulate the release of serotonin, a neurotransmitter that plays a key role in mood regulation and anxiety control. 2

Effects on pain. cannabidiol is an effective anti-inflammatory and local use with a balm or oil can help women stimulate natural vaginal lubrication, reducing pain caused by dryness or irritation.

Effects on sexual desire. CBD stimulates sexual desire through a dual mechanism: if administered locally it dilates blood vessels, promoting blood flow and lubrication, if administered systemically it acts at central by stimulating the release of dopamine, the neurotransmitter underlying the mechanism of sexual arousal. The latter would seem to be the main mechanism underlying the relationship between cannabidiol and sexual satisfaction: many of the cannabinoid receptors have been identified precisely in the functional areas of the brain sexual: hypothalamus, prefrontal cortex, amygdala and hippocampus.^3,4

CANNABIS IT IS TRUE THAT ...

Is it true that endocannabinoids play an important role in reproduction? True. Endocannabinoids play an important role in reproduction, particularly in the production of female sex hormones with consequences on the regulation of the female menstrual cycle.
To better understand the mechanism, it is necessary to describe how the release of sex hormones works. The main control of hormone release occurs centrally, in the brain, more precisely in the hypothalamus. The hypothalamus generates hormones, defined release factors (realizing hormone RH), which have the function of stimulating the pituitary gland, a small gland located under the hypothalamus, to produce hormones which in turn will act on the glands peripheral (ovary and testicle), stimulating them to produce estrogen and progesterone in women and testosterone in men. According to what emerges from the studies, endocannabinoids interfere with this mechanism by stimulating the production of release factors (GnRH) by the hypothalamus.

Is it true that cannabidiol can be useful for facilitating intercourse in menopause? True. In menopause, due to hormonal change and in particular the disappearance of estrogen, the mucous membranes are less lubricated. The woman complains of discomfort, itching and irritation of the vagina, sexual intercourse is more difficult and they can become painful. The pain is caused by the abrasions (microscopic, but painful) that may appear on the mucosa at the entrance to the vagina. CBD oil can be a valuable aid both because it reduces pain thanks to its anti-inflammatory effect is because it stimulates blood circulation and promotes lubrication. Also recent studies are highlighting a possible efficacy of cannabidiol in improving the symptoms of menopause, in particular: sleep disturbances, anxiety and mood changes.⁶

Is it true that cannabidiol can improve the symptoms of PMS? True. Many women experience pain, insomnia, irritability, and depression a few days before their period. It seems that cannabis can also help control symptoms typical of the premenstrual period. Is not yet It is clear what the exact underlying mechanism is but it seems to depend on an anti-inflammatory action of cannabinoids.^8,9

1. Lynn BK, Lopez JD, et al. The relationship between marijuana use prior to sex and sexual function in women. Sex Med 2019; 7: 192-7.
2. Sales AL, Fogaca MV, et al. Cannabidiol induces rapid and sustained antidepressant-like effects through increased bdnf signaling and synaptogenesis in the prefrontal cortex. Mol Neurobiol 2019; 56: 1070-81.
3. Lynn B, Gee A, et al. Effects of cannabinoids on female sexual function. Sex Med Rev 2019.
4. Lazenka MF, Tomarchio AJ, et al. Role of dopamine type 1 receptors and dopamine- and camp-regulated phosphoprotein mr 32 kda in δ9-tetrahydrocannabinol – mediated induction of δfosb in the mouse forebrain. J Pharmacol Exp Ther 2015; 354: 316-27.
5. Walker OLS, Holloway AC, et al. The role of the endocannabinoid system in female reproductive tissues. J Ovarian Res 2019; 12: 3.
6. Hill, M. and Gorzalka, B. (2009). The endocannabinoid system and the treatment of mood and anxiety disorders. CNS Neurological Disorders Drug Targets 2009; 8: 451-8.
7. Kogan, Natalya M., et al. Cannabidiol, a major non psychotropic cannabis constituent enhances fracture healing and stimulates lysyl hydroxylase activity in osteoblasts. J Bone Miner Res 2015; 30: 1905-13.
8. Slavin MN, Farmer S, et al. Cannabis and symptoms of PMS and PMDD. Addiction Research and Theory 2017
9. Russian EB. Cannabis treatments in obstetrics and gynecology: a historical review. Journal of Cannabis Therapeutics 2002; 2: 5-35

Endometriosis, what does it consist of and what is the use of cannabidiol? Endometriosis is a condition characterized by the presence of cells in the endometrium, the mucous membrane that lines the uterus, outside the uterus itself.4 This causes a state of inflammation with consequent pain during the period premenstrual, menstrual and ovulation. It is also not uncommon for women to complain of chronic pain even during sexual intercourse. For the management of this condition, the reference therapy is hormonal in combination with anti-inflammatory drugs; however drug therapy is not always sufficient for the management and control of ache.^4,5
Recent studies, still preliminary, have highlighted the involvement of the endocannabinoid system in the pathogenesis of the disease, showing a reduction in pain in women using cannabis. Who suffers from endometriosis it seems to have a lower expression of CB1 receptors in the uterus and it is hypothesized that this feature may contribute painful sensation.5 According to what emerges from studies, the administration of cannabinoids externally allows a better modulation of the endocannabinoid system with positive effects on pain management.⁶

• Dmitrieva N, Nagabukuro H, et al. Endocannabinoid involvement in endometriosis. Pain. 2010; 151: 703-10.
• Bouaziz J, Bar On A, et al. The clinical significance of endocannabinoids in endometriosis pain management. Cannabis Cannabinoid Res 2017; 2: 72-80.
• Armor M, Sinclair J, et al. Self-management strategies among Australian women with endometriosis: a national online survey. BMC Complement Altern Med 2019; 19:

VISNADINA

The growing interest in improving women's sexual function provided by topical application vulvar of Visnadina, a natural extractive substance with vasodilatory properties, has been evaluated in numerous recent clinical research.

Visnadine is an active ingredient in the fruit of Ammi visnaga, a plant belonging to the family of Umbelliferae,

Visnadine works by inhibiting the contractile responses mediated by the opening of the Ca2þ input channels.

A blind vs placebo clinical research, by Sparavigna A, et al. (2019), evaluated the vasokinetic activity of a Visnadine gel on the mucosal genitals of 15 postmenopausal women in good health investigating the the effectiveness of the treatment according to the subjective judgment of women by measuring the heat, degree of lubrication, and the sensations at the vulvar level. Research has shown that a single application of Visnadine has determined a significant increase in vulvar hyperemia, accompanied by a significant increase in local turgor than to placebo. Women reported a pleasant feeling of well-being.

Other RCTs had previously been conducted:

Caputo A and coll (2018) studied the effect of one visnadine oil on 60 using a questionnaire self-assessment with 19 questions in six areas including desire, arousal, lubrication, orgasm, satisfaction and pain. Those with a final FSFI score ≥26 - regarded as a physiological sex life - represented the control group. on the contrary, they were assigned to the experimental group if their FSFi score was <26, thus indicating a poorly satisfying sex life.

Satisfaction with sexual activity - as assessed by women at baseline (T0) and after 8 weeks (T1) by FSFI - were the primary measures of effectiveness. 29 women were included in each group. The differences are positioned from 19% for orgasm to + 36% for satisfaction. The change in the FSFi total score was + 24%, and all observed differences were statistically significant (T0 vs. T1, P <0.05).

Overall, all delta values were far higher in the experimental group than in controls (P. <0.05 for all comparisons). For the vast majority of women belonging to the experimental group (27/29, 93%), a "physiological" score of 26 was achieved.

Laganà AS, et al (2018) in a single-arm pilot study instead studied the effect of visnadine associated with colostrum on vaginal atrophy in 47 postmenopausal women. The sexual function index as assessed by a questionnaire was evaluated at time and after 15 days of treatment, showing a significant improvement of all parameters and the total score (p <0.0001). A double-blind, randomized, pilot study placebo-controlled, was conducted (2017).

The AA evaluated the efficacy and tolerability of a Visnadine formulation on 60 volunteer women for 30 days. The main outcome measure was the improvement in the Female Sexual Function Index score (FSFI) (cut-o ≤ 26.55 for female sexual dysfunction [FSD]). The secondary outcomes were sexual satisfaction and tolerability with the product. Treated group 30 women vs placebo group 29 women. In the women treated there is there was an improvement in the FSFI index from 25.0 ± 3.8 to 27.9 ± 2.4 (p <0.001), while no changes in the PL group (from 25.4 ± 5.0 to 25.6 ± 4.7).

Statistically significant differences at T1 have been reported in women diagnosed with positive FSD (p <0.001) or negative (p <0.01) using active treatment.

Women with FSD reported significantly greater improvement in satisfaction with their function sexual when treated with visnadine spray compared to PL (p <0.001), as well as more arousal (p <0.001), pleasure (p <0.001) and less time to orgasm (p <0.003).

Caruso S et al. 2018 had conducted a similar clinical study, involving 38 women between the ages of 25 and 40 affected by FSAD, however enrolled in a randomized crossover study, according to two possible sequences: daily and on request. The female sexual function index (FSFI) and the female sexual stress scale (FSDS) were used to assess sexual function and sexual distress, respectively. The small number of women and the lack of a placebo group do not allow definitive conclusions.

Also of interest is the Eco Color Doppler study included in the research, used to measure blood flow clitoral. Finally, clitoral blood flow is significantly improved during daily use of both sequences (p <.001). Each woman had requested consultation for lack of sensation clitoral, lack of vaginal lubrication or being slow to respond after sufficient stimulation sexual, with a recurrent inability to achieve or maintain sufficient sexual arousal. Drawing of the two-period crossover study allowed us to obtain results from every woman during treatment with vulvar visnadine spray on request or daily.

The main findings of the study were that women with FSAD, not related to drugs, can draw benefit from treatment with Visnadine spray, which has been shown to be more effective when administered daily rather than on request. In fact, the women in sequence A had a gradual improvement of sexual activity and quality of sexual life, from request to administration daily. The objective evaluation of the effectiveness of Visnadine vulvar spray, measured by the color Doppler of the Clitoral arterial blood flow showed a similar trend to subjective ratings. In fact, vascular engorgement was better during the daily versus the on demand phases of both sequences administration.

• Bernorio R, et al. Effectiveness and tolerability of a spray formulation containing Visnadine in women self-reporting sexual symptoms: a randomized double-blind placebo-controlled pilot study. J Endocrinol Invest. 2018 Jun; 41 (6): 729-737. doi: 10.1007 / s40618-017-0801-0.
• Caputo A, Natoli A, Radice R, Zanardi G, Giacomelli L. Effectiveness of an intimate oil solution containing visnadine in women self-reporting sexual symptoms. Minerva Ginecol. 2018 Aug; 70 (4): 492-493. doi: 10.23736 / S0026-4784.18.04209-0.
• Caruso S et al. Randomized crossover study investigating daily versus on-demand vulvar Visnadine spray in women affected by female sexual arousal disorder. Gynecol Endocrinol. 2018 Feb; 34 (2): 110-114. doi: 10.1080 / 09513590.2017.1354366.
• Laganà AS, et al Preliminary results of a single-arm pilot study to assess the safety and efficacy of visnadine, prenylflavonoids and bovine colostrum in postmenopausal sexually active women affected by vulvovaginal atrophy. Maturitas. 2018 Mar; 109: 78-80. doi: 10.1016 / j.maturitas.2017.12.015.
• Sparavigna A, et al. A randomized single-blind placebo-controlled study of a Visnadine Emulgel formulation on healthy postmenopausal women. Minerva Ginecol. 2019 Oct; 71 (5): 353-358. doi: 10.23736 / S0026-4784.19.04398-3.

LA FORSKOINA - COLEUS BARBATUS -

Forskolin is extracted from Coleus forskohlii, a plant typical of traditional Indian medicine, a derivative terpene characterized from a biological point of view by interesting vasodilating properties.

Vascular activities

Forskolin was initially studied by Mulhall et al. (1997) as an intracavernous vasoactive agent in management of vasculogenic impotence, and subsequently by other AAs to consider it a potential alternative natural to Viagra (Drewes SE, 2003).

In in vitro tests, forskolin and PGE1 alone caused concentration-dependent relaxation. There combination of the two agents produced a synergistic response. The clinical survey in 31 patients did not show adverse effects. Overall, 61% of these reported an improvement in penile stiffness and / or duration of erection using a combination of forskolin, papaverine, phentolamine and PGE1.

Nitric oxide (NO) is considered the most important factor for the relaxation of the vessels of the corpora cavernosa, as well such as PGE1 which acts in part by increasing intracellular concentrations of cyclic adenosine monophosphate (cAMP). Recent results obtained with the adenylate cyclase stimulator forskolin suggest that the smooth muscle relaxation of the corpora cavernosa of the penis leading to penile erection can be achieved through the path of cAMP (Andersson Ke et al, 1997).

Endothelium-derived relaxation factors (EDRF) including nitric oxide (NO), prostacyclin (PGI2) are now recognized to induce relaxation of vascular smooth muscle, in part through activation of K + channels. And the activity of these channels in vascular myocytes is increased by forskolin and protein kinase A (PKA) (Waldron, 1999).

Indirect hormonal activities

In addition to a vasodilating function, forskolin has also shown biological effects of a hormonal nature on the synthesis and activity of testosterone. Forskolin binds as a first effect and increases the cAMP production. But this in turn activates the enzyme protein kinase A, which positively affects the binding of the androgen receptor.

Not to mention that cAMP is also a signal for the production of testosterone (steroidogenesis) in Leydig cells of the testes. This is actually more important than it might seem. In fact it determines also an increase in the levels of StAR, a protein necessary for the stimulation of the enzymes involved in the synthesis of testosterone from cholesterol. In essence, a high cAMP leads to a cascade of events from the rise of high levels of luteinizing hormone (LH) which binds to testosterone production.

In an article published in the Journal of Obesity Research in 2005, the researchers gave the participants the forskolin over the course of 12 weeks and observed an average increase in free testosterone of 33%, with reduction of fat mass and increase of that (Godard, 2005). A 2001 study by Badmaev noted similar results.

Di Giovanni et al. (1992) evaluated the effects of steroid hormones (i.e. testosterone and hydrocortisone) on beta 2-adrenergic receptors and their signal transduction in the myocyte of the genital tract. Why the stimulation of the beta-adrenergic receptor causes smooth muscle relaxation through the activation of adenyl cyclase and the subsequent production of cyclic AMP (cAMP). Link studies with i radioligands demonstrated that these two steroid hormones produced a 70-80% increase in the density of beta-2 adrenergic receptors in these myocytes. Stimulation of beta-2 adrenergic receptors with isoproterenol resulted in a significant increase in cAMP in control myocytes; cells treated with testosterone for 24 hours demonstrated a comparable response to isoproterenol, while hydrocortisone for 24 hours produced a cAMP response greater than 50%. And direct stimulation with forskolin resulted in increased production of CAMP in myocytes treated with testosterone compared to controls (Di Giovanni L et al, 1992).

The effects of an LHRH agonist on the production of cyclic AMP and testosterone stimulated by LH and forskolin are also been studied in vitro on Leydig cells of rats purified, as evidenced by the work of Sullivan et al (1984). Forskolin-stimulated cyclic AMP production was not inhibited by the LHRH agonist. There forskolin increased testosterone production to the same levels achieved by LH and pre-incubation with the LHRH agonist increased testosterone production stimulated by both forskolin and LH.

• Andersson KE, Stief CG. Neurotransmission and the contraction and relaxation of penile erectile tissues. World J Urol. 1997; 15 (1): 14-20. doi: 10.1007 / bf01275151.
• Baba K. Smooth muscle regulation of PGE1 and forskolin in rabbit cavernosal tissue by cyclic GMP-and cyclic AMP-dependent mechanisms. St. Marianna Med. J. Vol. 32, pp. 527 533, 2004
• Badmaev, V., et al. "Diterpene Forskolin: A possible new compound for reduction of body weight by increasing lean body max. " Townsend Letter for Doctors and Patients 115 (2001).
• DiGiovanni L, Austin R, Phillippe M. Steroid hormone modulation of cAMP production in response to beta adrenergic receptor stimulation in genital tract myocytes.
• Drewes SE, George J, Khan F. Recent findings on natural products with erectile-dysfunction activity. Phytochemistry. 2003 Apr; 62 (7): 1019-25. doi: 10.1016 / s0031-9422 (02) 00621-0.
• Godard, Michael P., Brad A. Johnson, and Scott R. Richmond. "Body composition and hormonal adaptations associated with forskolin consumption in overweight and obese men. " Obesity Research8 (2005): 1335-1343.
• Hedin L, Rosberg S Forskolin effects on the cAMP system and steroidogenesis in the immature rat ovary. Mol Cell Endocrinol. 1983 Nov; 33 (1): 69-80. doi: 10.1016 / 0303-7207 (83) 90057-6.
• In Vitro Cell Dev Biol. 1992 Jul-Aug; 28A (7-8): 509-14. doi: 10.1007 / bf02634134.
• Meidan R, Lim P, McAllister JM, Hsueh AJ. Hormonal regulation of androgen biosynthesis by primary cultures of testis cells from neonatal rats. Endocrinology. 1985 Jun; 116 (6): 2473-82. doi: 10.1210 / endo-116-6-2473.
• Mulhall, J.P., Daller, M., Traish, A.M., Gupta, S., Park, K., Sal-impour, P., Payton, T.R., Krane, R.J., Goldstein, THE., 1997. Intra-carvenosal forskolin: role in management of vasculogenic impotence resistant to standard 3-agent pharmacotherapy. J Urol. 158, 1752-1759.
• Sullivan MH, Cooke BA. LHRH agonist decreases LH- but not forskolin-stimulated cyclic AMP levels in rat Leydig cells in vitro. Mol Cell Endocrinol. 1984 Jun; 36 (1-2): 115-22. doi: 10.1016 / 0303-7207 (84) 90090-x.
• Waldron GJ, Cole WC.Activation of vascular smooth muscle K + channels by endothelium-derived relaxing factors. Clin Exp Pharmacol Physiol. 1999 Feb; 26 (2): 180-4. doi: 10.1046 / j.1440-1681.1999.03006.x.

CBD and TERPENES

The Cannabis plant and its compounds and derivatives are made up of an important variety of substances: of the 483 elements identified to date, some such as the 66 cannabinoids are found only in cannabis, while others such as i terpenes, the most abundant with over 140 members, are spread across the entire plant kingdom.

Of all cannabinoids, CBD is the most promising from a pharmacological point of view, thanks to lack of psycho-activity, together with the proven anti-inflammatory, antioxidant, anxiolytic e neuro-protective.¹

In November 2017, the WHO (The World Health Organization) classified CBD as a substance that cannot be determined abuse or dependence in humans, no evidence emerges about public health problems related to its consumption. In January 2018, the World Anti-Doping Agency also eliminates CBD from substances prohibited for use by athletes ².

The anti-inflammatory action of CBD is mediated both by the interaction with the vanilloid receptors and by the inhibition of lipoxygenase and cyclooxygenase ^10,11 in fact, in animal studies it has been seen how it achieves efficacy analgesic hundreds of times higher than aspirin ^12,13

In a 2016 study ¹⁴ Hammell and coll. underline the anti-inflammatory efficacy of CBD when administered transdermally in a mouse model of arthritic pain. After evoking the painful stimulus by injection of CFA (Complete Freud's adjuvant, saline solution: peanut oil 1: 1) are given gel preparations based of CBD at different concentrations (0.6, 3.1, 6.2 or 62.3 mg / day) and analyzed the circumference of the joint and degree of invasion of inflammatory cells into the tissue. The results showed that the gels have the highest CBD doses (6.2 and 62.3mg) reduced tissue thickness by almost 50%, compared to the lowest preparations concentration that did not significantly alter tissue edema.

The numerous effects of CBD on serotonergic transmission, particularly mediated by the 5-HT1A receptor, an important rationale for the use of this and other phyto-cannabinoids in the treatment of anxiety. In a recent trial randomized clinical (Crippa et al, 2010)¹⁵ emerges as patients diagnosed with social anxiety disorder treated with CBD-based preparations had marked improvements in terms of reduced cognitive and anxiety symptoms compared to placebo ^15,16,17.

Only in recent years has the role of the family of terpenes and flavonoids been investigated, which themselves have intrinsic biological properties, terpenes represent the largest group of volatile substances, part integral with the essential oil, better extractable with steam distillation. Unlike the cannabinoids are these that determine the characteristic aroma of the plant.

Terpenes are pharmacologically very versatile compounds: they are lipophilic, they interact with membrane ion channels a level of muscle and neuronal cells, neuro-receptor systems, protein-coupled receptors ^19,20,21,22.

Like any other active substance, they each have their own biological activity, but it reveals itself more and more interesting their possible synergistic role with cannabinoids, in amplifying some of their properties, such as activity anti-inflammatory, analgesic, anxiolytic, antidepressant, antibacterial.

The most significant terpenes from a quantitative and physiological point of view as regards the possible role pharmacological, are β-Caryophyllene and β-Myrcene.

Beta-caryophyllene (β-Caryophyllene) is the more common of the two forms of caryophyllene, also found in cinnamon, cloves, black pepper, oregano, basil, rosemary and in hops. It represents the essential oil of Cannabis about 18-20% of the essential oil.

It has shown efficacy as an analgesic24, antioxidant and its anti-inflammatory activity via PGE-1 similar to that exerted by indomethacin, it is comparable in potency to the toxic substance phenylbutazone, but different from these agents, caryophyllene showed a cytoprotective effect on the gastric mucosa ²⁵.

The Myrcene, present in essential oil in a percentage of 22-23%, is the most common among the monoterpenoids present in cannabis, and how caryophyllene has an important anti-inflammatory, analgesic and anxiolytic ^26,27 and is widely exploited in the cosmetics industry.

Myrcene reduces inflammation through the prostaglandin pathway (PGE-2) 26, moreover, again in studies of laboratory performed on rodents, it was found that myrcene acts as a muscle relaxant.
The greatest revelation regarding caryophyllene was perhaps the demonstration of the selective competitive activity against the CB2 receptor, suggesting further evidence to support the possible synergy between cannabinoids and terpenoids. ^14,19,20,23

In a 2013 study it is shown that orally administered Beta-Caryophyllene has an effect analgesic24 in inflammatory and neuropathic pain of CB2 immediate rodents. This was however absent a was induced selective blockade of CB2r by its specific antagonist SR144528. In this sense, theories on the synergistic effect that can arise from preparations composed of cannabinoids and non-cannabinoid molecules. A study fits into this context ³⁵ preliminary of 2019 which investigates the interaction between the terpenoid Myrcene and the activity of TRVP1 (Nociceptive Transient Receptor Potential channel). The results show that myrcene induces a significantly greater flow of Ca2 + TRVP-mediated ions than other terpenes contained in the extract used, and how this is inhibited by the specific receptor antagonist TVRP1, capsazepine.
These data therefore show that TVRP1 is a target, in addition to THC and CBD, also by terpenoids such as Myrcene, suggesting its potential therapeutic analgesic effect ³³.

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