June 3rd – June 10th, 2022
Endocannabinoids & Post-Traumatic Stress Disorder (PTSD) Symptoms
Treatment with endocannabinoids was associated with increased anxiety and general distress depression, a new study reports.
According to the American Psychological Association, post-traumatic stress disorder (PTSD) is defined as an anxiety problem that develops after extremely traumatic events, such as combat (e.g., affecting war veterans), crimes, accidents, or natural disasters. [1] This results in frequent flashbacks, nightmares, and increased anxiety, leading to decreased sleep time and quality, with women having a higher lifetime prevalence of PSTD than men. [2],[3],[4] While current therapies such as cognitive behavior therapy (CBT) or pharmacological treatments (e.g., selective serotonin reuptake inhibitors [SSRIs], paroxetine, sertraline) have shown some relief, there is an increasing need to shift the focus towards novel therapeutic avenues, in part due the limited efficacy and adverse side effects of above interventions. [5]
One target that is gaining attention is the endocannabinoid system (ECS), known to play important roles in the regulation of stress, depressive, and anxiety behavior. [6] It is composed of internally produced (or “endogenous”) cannabinoids, enzymes responsible for their synthesis and degradation, and cannabinoid receptors (CB1R and CB2R), distributed throughout the body. Endogenous cannabinoids (e.g., anandamide or N-arachidonoyl ethanolamine (AEA) and 2-Arachidonolyglycerol (2-AG)) are a large group of compounds derived naturally from fatty acids which interact with cannabinoid receptors to activate downstream targets.
Previous studies have indicated that circulating 2-AG plasma levels were reduced in individuals who were exposed to the world trade center attacks. [7] Additionally, reduced AEA levels and upregulation of CB1R within a key neural circuit involved in fear processes were recorded in individuals who were exposed to trauma. [8] However, other studies did not show differences in AEA and 2-AG levels between PTSD patients and controls. [9],[10]
A group of researchers in the Netherlands aimed to investigate whether AEA and 2-AG levels were associated with post-treatment symptom reduction in war veterans with (54 participants) or without PTSD diagnosis (26 participants) and separated the findings depending on cannabis use. [11] Additionally, clinical symptoms were also assessed following treatment with AEA or 2-AG. They found that baseline endocannabinoid levels did not differ between the groups when past cannabis use was not factored in the analysis. However, lower endocannabinoid levels were recorded in participants who reported previous cannabis use, independent of PTSD diagnosis. Additionally, post AEA and 2-AG treatments were correlated with increased anxiety, anxious arousal, and general distress depression symptoms.
The authors concluded:” Since endocannabinoids are mainly generated ‘on demand’ future work will benefit from investigating endocannabinoid circulation under both rest and stressful conditions. This will lead to a better understanding about how the ECS (dys)functions under stressful conditions and during extinction therapy sessions.”
Will Ukraine Legalize Medical Cannabis?
Despite being at war with Russia, the country could be on the verge to offer medical cannabis to restricted patients.
On June 7th, 2022, Ukraine’s Health Minister Viktor Liashko announced that a bill was drafted and approved by the Cabinet of Ministers and was on its way to the Ukraine Parliament, where it will need at least 226 votes to pass. The bill would ensure a strict control of cultivation, production, and sale of medical cannabis for patients under specific medical conditions (e.g., post-traumatic stress disorder (PTSD), HIV, cancer…).
Liashko said: “We understand the negative consequences of the war on the mental health camp…We understand the number of people who will require medical treatment in the last breath.” [12]
Ukraine partially approved the use of certain cannabis-like products (e.g., dronabinol and nabilone) for medical uses in April 2021. [13]
Understanding the Effects of Cannabidiol (CBD), Δ9-Tetrahydrocannabinol (Δ9-THC), and in Combination on Human Brain Connectivity
This study reports that some of the effects of Δ9-THC administration was mitigated by co-administration of CBD.
As more and more US states and countries legalize cannabis for medical and recreational purposes, understanding its therapeutic and potentially harmful effects are necessary.
The cannabis plant is home to more than 500 phytocannabinoids, with cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC), being the most investigated compounds in the scientific community. Δ9-THC exerts its effects via partial activation of cannabinoid receptor 1 and 2 (CB1R, CB2R) while CBD has little binding affinity for either receptor but can reduce the effects of Δ9-THC when co-administered. [14],[15] While CB1R are also found in the peripheral nervous system (PNS), they are mostly abundant in the central nervous system (CNS), specifically in brain regions known to regulate cognition, memory, and reward referred to as the striatum. [16]
Inconsistency among studies reporting on the effects of CBD, Δ9-THC, or when both are combined, led to a group of researchers in London to investigate their effects on functional connectivity of the striatum in two placebo-controlled, double-blind studies. [17]
The first study included patients who inhaled Δ9-THC, Δ9-THC + CBD or placebo while the second included patients who were orally administered CBD or placebo and all patients were subjected to functional magnetic resonance imaging (fMRI), used to measure brain activity by detecting changes associated with blood flow. On one hand, they found that Δ9-THC and in combination with CBD led to changes in connectivity in the sensorimotor network while Δ9-THC alone specifically affected the limbic striatum network. On the other hand, CBD led to increased connectivity in the associative network with mild limbic and sensorimotor networks disruptions.
The authors concluded: “This is the first report in human subjects of data from THC, THC + CBD and CBD acute challenges, achieved using a unified set of analysis methods, and with all comparisons performed in a placebo-controlled, double-blind design… A key question for future research is understanding how these acute effects translate into longer-term effects in chronic users, what role these striato-cortical connections may have in the pathophysiology of cannabis use disorder and cannabis-related psychosis, and what therapeutic options might usefully target them.”
Cannabinoid Receptors Are Expressed in Endometriotic Lesions in Women with Endometriosis
Findings suggest that these lesions could respond to cannabinoids-based medications.
Endometriosis is a common, long-term, and inflammation disorder of the female reproductive system where there is surgical detection of endometrial tissue outside the uterus. [18] According to the World Health Organization, it affects about 10% (190 million) of reproductive age women and girls globally. [19] Symptoms include painful periods, chronic pelvic pain, fatigue, or depression and anxiety, leading to social and psychological consequences. Pain medications such as nonsteroidal anti-inflammatory medications (NSAID) and opioids are the most common medications prescribed, but while the former can lead to side effects, the latter are often associated with withdrawal and addiction-like feelings. [20],[21]
With anti-inflammatory origins and potential pain-relieving properties, the endocannabinoid system (ECS) represents an alternative therapeutic avenue to treat endometriosis. However, studies demonstrating whether endometriotic lesions express cannabinoid receptor 1 and 2 (CB1R, CB2R) are lacking.
Rush University Medical Center published a study using archived normal ovarian tissues, ovaries with endometriotic lesions, normal endometrial, and normal myometrial tissues collected from women who underwent surgery for ovarian endometriosis. [22] Using a wide array of biochemical techniques, they showed that CB1R and CB2R were expressed in endometriotic lesions in the ovary, suggesting that targeted pain medications may be helpful to relieve pain and inflammation in these patients.
They concluded: “This study further showed that compared with stromal tissues surrounding the lesion, the intensities of CB1 and CB2 expression were significantly higher in endometriotic lesions in the ovary… The results of this study will be a foundation for a clinical study with a larger cohort to determine the feasibility of cannabinoids as effective painkillers and/or immune modulators for these patients.”
References
[1] https://www.apa.org/topics/ptsd, assessed on June 10th, 2022
[2] Olff M. Sex and gender differences in post-traumatic stress disorder: an update. Eur J Psychotraumatol 2017 8(sup4): 1351204.
[3] Giarratano P, Ford JD, Nochajski TH. Gender Differences in Complex Posttraumatic Stress Symptoms, and Their Relationship to Mental Health and Substance Abuse Outcomes in Incarcerated Adults. J Interpers Violence 2020;35:1133-57.
[4] https://www.psychologytoday.com/us/blog/the-mindful-self-express/201809/why-women-have-higher-rates-ptsd-men, assessed on June 10th, 2022
[5] Cipriani A, Williams T, Nikolakopoulou A, et al. Comparative efficacy and acceptability of pharmacological treatments for post-traumatic stress disorder in adults: a network meta-analysis. Psychol Med 2018;48:1975-84.
[6] Hill MN, Patel S. Translational evidence for the involvement of the endocannabinoid system in stress-related psychiatric illnesses. Biol Mood Anxiety Disord 2013;3(1):19. DOI: 10.1186/2045-5380-3-19
[7] Hill MN, Bierer LM, Makotkine I, et al. Reductions in circulating endocannabinoid levels in individuals with post-traumatic stress disorder following exposure to the World Trade Center attacks. Psychoneuroendocrinology 2013;38(12):2952-61. DOI: 10.1016/j.psyneuen.2013.08.004.
[8] Neumeister A, Normandin MD, Pietrzak RH, et al. Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study. Mol Psychiatry 2013;18(9):1034-40. DOI: 10.1038/mp.2013.61
[9] Crombie KM, Leitzelar BN, Brellenthin AG, Hillard CJ, Koltyn KF. Loss of exercise- and stress-induced increases in circulating 2-arachidonoylglycerol concentrations in adults with chronic PTSD. Biol Psychol 2019;145:1-7. DOI: 10.1016/j.biopsycho.2019.04.002
[10] Hauer D, Schelling G, Gola H, et al. Plasma concentrations of endocannabinoids and related primary fatty acid amides in patients with post-traumatic stress disorder. PLoS One 2013;8(5):e62741. DOI: 10.1371/journal.pone.0062741
[11] Leen NA, de Weijer AD, van Rooij SJH, Kennis M, Baas JMP, Geuze E. The Role of the Endocannabinoids 2-AG and Anandamide in Clinical Symptoms and Treatment Outcome in Veterans with PTSD. Chronic Stress (Thousand Oaks). 2022 Jun 9;6:24705470221107290. doi: 10.1177/24705470221107290.
[12] https://www.facebook.com/photo/?fbid=2654143418051099&set=a.124023501063116, assessed on June 10th, 2022
[13] https://www.kyivpost.com/ukraine-politics/ukraine-legalizes-certain-types-of-medical-cannabis-products.html, assessed on June 10th, 2022
[14] Pertwee RG (2008) The diverse CB 1 and CB 2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. British Journal of Pharmacology 153(2): 199–215
[15] Chesney E, McGuire P, Freeman TP, Strang J, Englund A. Lack of evidence for the effectiveness or safety of over-the-counter cannabidiol products. Ther Adv Psychopharmacol 2020;10:2045125320954992. DOI: 10.1177/2045125320954992
[16] Vuckovic S, Srebro D, Vujovic KS, Vucetic C, Prostran M. Cannabinoids and Pain: New Insights From Old Molecules. Front Pharmacol 2018;9:1259. DOI: 10.3389/fphar.2018.01259
[17] Wall MB, Freeman TP, Hindocha C, et al. Individual and combined effects of cannabidiol and Delta(9)-tetrahydrocannabinol on striato-cortical connectivity in the human brain. J Psychopharmacol 2022;36(6):732-744. DOI: 10.1177/02698811221092506.
[18] Sampson JA. Metastatic or Embolic Endometriosis, due to the Menstrual Dissemination of Endometrial Tissue into the Venous Circulation. Am J Pathol 1927;3(2):93-110 43.
[19] https://www.who.int/news-room/fact-sheets/detail/endometriosis, assessed on June 10th, 2022
[20] Bouaziz J, Bar On A, Seidman DS, Soriano D. The Clinical Significance of Endocannabinoids in Endometriosis Pain Management. Cannabis Cannabinoid Res 2017;2(1):72-80. DOI: 10.1089/can.2016.0035
[21] Manjiani D, Paul DB, Kunnumpurath S, Kaye AD, Vadivelu N. Availability and utilization of opioids for pain management: global issues. Ochsner J 2014;14(2):208-15
[22] Allam S, Paris E, Lazcano I, et al. Detection of Cannabinoid Receptor Expression by Endometriotic Lesions in Women with Endometriosis as an Alternative to Opioid-Based Pain Medication. J Immunol Res 2022;2022:4323259. DOI: 10.1155/2022/4323259
