Social isolation as a promising animal model of PTSD comorbid suicide: neurosteroids and cannabinoids as possible treatment options.

Progress in Neuro-Psychopharmacology and Biological Psychiatry

“Post-traumatic stress disorder (PTSD) is a psychiatric condition characterized by drastic alterations in mood, emotions, social abilities and cognition. Notably, one aspect of PTSD, particularly in veterans, is its comorbidity with suicide.

Elevated aggressiveness predicts high-risk to suicide in humans and despite the difficulty in reproducing a complex human suicidal behavior in rodents, aggressive behavior is a well reproducible behavioral trait of suicide. PTSD animal models are based on a peculiar phenotype, including exaggerated fear memory, anxiety- and depressive-like behaviors associated with neurochemical dysregulations in emotional brain circuitry.

The endocannabinoid and the neurosteroid systems regulate emotions and stress responses, and recent evidence shows these two systems are interrelated and critically compromised in neuropsychiatric disorders. For instance, levels of the neurosteroid, allopregnanolone, as well as those of the endocannabinoids, anandamide and its congener, palmitoylethanolamide are decreased in PTSD.

Similarly, the endocannabinoid system and neurosteroid biosynthesis are altered in suicidal individuals.

Selective serotonin reuptake inhibitors (SSRIs), the only FDA-approved treatments for PTSD and depression, fail to help half of the treatment-seeking patients. This highlights the need for developing biomarker-based efficient therapies. One promising hypothesis points to stimulation of allopregnanolone biosynthesis as a valid end-point to predict treatment response in PTSD patients.

This review highlights running findings on the role of the endocannabinoid and neurosteroid systems in PTSD and suicidal behavior both in a preclinical and clinical perspective. A specific focus is given to predictive PTSD/suicide animal models. Ultimately, we discuss the idea that disruption of neurosteroid and endocannabinoid biosynthesis may offer novel promising biomarker candidates to develop new treatments for PTSD and, perhaps, suicidal behavior.”

https://www.ncbi.nlm.nih.gov/pubmed/30586627

https://www.sciencedirect.com/science/article/pii/S0278584618305839?via%3Dihub

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The association between cannabis use and suicidal behavior in patients with psychiatric disorders: an analysis of sex differences.

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“Cannabis is the most commonly used illicit drug. In the general population, its use has been linked to a heightened propensity for suicidal behavior (SB).

We hypothesize that this association varies in patients with psychiatric disorders. SB is known to vary by sex and therefore an investigation of cannabis‘ association with SB must consider sex differences.

The purpose of this study is to investigate the association between cannabis use and suicide attempts in men and women with psychiatric disorders.

We found no significant association between suicide attempts and cannabis use in men or women.

Our findings indicate that there is no association between cannabis use and suicidal behavior in men or women with psychiatric disorders unlike what was reported for the general population, though the heaviness of cannabis use may have an effect in men.

The impact of cannabis use in psychiatric disorders needs ongoing examination in light of its common use, impending legalization with expected increased access and the uncertainty about cannabis‘ effects on prognosis of psychiatric disorders.

In addition, research should continue to investigate modifiable risk factors of SB in this population of which cannabis is not a significant factor based on this study.”

https://www.ncbi.nlm.nih.gov/pubmed/29891008

https://bsd.biomedcentral.com/articles/10.1186/s13293-018-0182-x

“Cannabis Does Not Increase Suicidal Behavior in Psychiatric Patients” https://neurosciencenews.com/psychiatry-cannabis-suicide-9330/
“Researchers Find That Cannabis Does Not Increase Suicidal Behavior in Psychiatric Patients” https://www.laboratoryequipment.com/news/2018/06/researchers-find-cannabis-does-not-increase-suicidal-behavior-psychiatric-patients
“Cannabis does not increase suicidal behavior in psychiatric patients: McMaster” https://eurekalert.org/pub_releases/2018-06/mu-cdn061318.php

“Cannabis does not increase suicidal behavior in psychiatric patients”  https://www.sciencedaily.com/releases/2018/06/180613162658.htm

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Cannabinoid Receptors, Mental Pain and Suicidal Behavior: a Systematic Review.

Current Psychiatry Reports

“The current serotonin-based biological model of suicidal behavior (SB) may be too simplistic. There is emerging evidence that other biomarkers and biological systems may be involved in SB pathophysiology. The literature on the endocannabinoid (EC) systems and SB is limited. The objective of the present article is to review all available information on the relationship between cannabinoid receptors (CB1 and CB2 receptors), and SB and/or psychological pain.

RECENT FINDINGS:

Our review is limited by the small number and heterogeneity of studies identified: (1) an autopsy study describing elevated levels of CB1 receptor activity in the prefrontal cortex and suicide in both depression and alcoholism and (2) studies supporting the involvement of both CB1 and CB2 receptors in the regulation of neuropathic pain and stress-induced analgesia. We conclude that cannabinoid receptors, particularly CB1 receptors, may become promising targets for the development of novel therapeutic tools for the treatment of SB.”

https://www.ncbi.nlm.nih.gov/pubmed/29546501

https://link.springer.com/article/10.1007%2Fs11920-018-0880-4

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Role of the Endocannabinoid System in the Neurobiology of Suicide

Cover of The Neurobiological Basis of Suicide

“In the past decade, remarkable advances have been made in cannabinoid (CB) research. The brain endocannabinoid (eCB) system modulates several neurobiological processes and its dysfunction is suggested to be involved in the pathophysiology of mood and drug use disorders.

The CB1 receptor–mediated signaling, in particular, has been shown to play a critical role in the neural circuitry that mediates mood, motivation, and emotional behaviors. This chapter presents the data pertaining to the involvement of the eCB system in depression, suicide, and alcohol addiction.

It appears that the eCB system might have a critical role in the regulation of mood and emotional responses that are impaired in patients with depression and suicidal behavior.

The data provided in this chapter support the notion that the eCB system might be an additional target for the development of a drug against alcohol use, depression, and suicidal behavior.

Among therapeutic agents, antidepressants are the most widely used drugs for the treatment of depression-related disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/23035286

https://www.ncbi.nlm.nih.gov/books/NBK107200/

“Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from cannabis sativa L. The antidepressant action of cannabis as well as the interaction between antidepressants and the endocannabinoid system has been reported. Results of this study show that Δ9-THC and other cannabinoids exert anti-depressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866040/

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High on Life? Medical Marijuana Laws and Suicide

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“Our research examines the relationship between medical marijuana laws (hereafter MMLs) and suicides.

Our results suggest that the passage of a MML is associated with an almost 5 percent reduction in the total suicide rate.

We conclude that the legalization of medical marijuana leads to fewer suicides among young adult males.”

https://www.cato.org/publications/research-briefs-economic-policy/high-life-medical-marijuana-laws-suicide

Study: Medical Marijuana Legalization leads to decrease in suicide rates”   https://www.dailykos.com/stories/2012/2/26/1068413/-Study-Medical-Marijuana-Legalization-leads-to-decrease-in-suicide-rates

“Legal Weed Appears to Cause a Sharp Reduction in Suicides”  https://www.eastbayexpress.com/LegalizationNation/archives/2012/02/07/legal-weed-appears-to-cause-a-sharp-reduction-in-suicides-discuss

“Marijuana Can Help Prevent Suicide, Study Suggests”  http://www.laweekly.com/news/marijuana-can-help-prevent-suicide-study-suggests-2389148

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ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

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“Cannabis sativa is also popularly known as marijuana. It is being cultivated and used by man for recreational and medicinal purposes from many centuries.

Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries.

The research of drugs acting on endocannabinoid system has seen many ups and down in recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve “protective role” in many medical conditions.

Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Tourette’s syndrome could possibly be treated by drugs modulating endocannabinoid system.

Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008.

Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite of some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists.

One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that acts selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted.

Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids.

In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as “protective” and “disease inducing substance”, time-dependent changes in the expression of cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27086601

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Medical Marijuana Laws and Suicides by Gender and Age.

:American Journal of Public Health Logo

 

“We estimated the association between legalizing medical marijuana and suicides.

Legalization was associated with a 10.8%  and 9.4% reduction in the suicide rate of men aged 20 through 29 years and 30 through 39 years, respectively.

Suicides among men aged 20 through 39 years fell after medical marijuana legalization compared with those in states that did not legalize.

The negative relationship between legalization and suicides among young men is consistent with the hypothesis that marijuana can be used to cope with stressful life events.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232164/

http://www.ncbi.nlm.nih.gov/pubmed/24432945

http://ajph.aphapublications.org/doi/10.2105/AJPH.2013.301612

“Legalizing Medical Marijuana May Lead To Fewer Suicides”  https://www.huffingtonpost.com/2014/02/04/marijuana-legalization-suicide_n_4726390.html

“Medical Marijuana Cuts Suicide Rates By 10% In Years Following Legalization”  http://www.medicaldaily.com/medical-marijuana-cuts-suicide-rates-10-years-following-legalization-268472

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The endocannabinoid system and its therapeutic exploitation.

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“The term ‘endocannabinoid’ – originally coined in the mid-1990s after the discovery of membrane receptors for the psychoactive principle in Cannabis, Delta9-tetrahydrocannabinol and their endogenous ligands – now indicates a whole signalling system that comprises cannabinoid receptors, endogenous ligands and enzymes for ligand biosynthesis and inactivation. This system seems to be involved in an ever-increasing number of pathological conditions. With novel products already being aimed at the pharmaceutical market little more than a decade since the discovery of cannabinoid receptors, the endocannabinoid system seems to hold even more promise for the future development of therapeutic drugs. We explore the conditions under which the potential of targeting the endocannabinoid system might be realized in the years to come.”  http://www.ncbi.nlm.nih.gov/pubmed/15340387

http://www.nature.com/nrd/journal/v3/n9/full/nrd1495.html

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Marijuana Can Help Prevent Suicide, Study Suggests

“Marijuana does many magical things, not the least of which is make dubstep listenable. In Los Angeles, we use it pretty much legally for back pain, nausea and hot tubbing.

But a new study from Germany says that, in U.S. states like California where marijuana has become medically legit, rates of suicide have gone down.

The researchers note that suicide is often triggered by “stressful life events.” And you know what can take away the pain?

No. Not Enrique Iglesias. Stress! Or rather, chronic. Depending.

The academics note that “California includes anxiety as a qualifying condition” to obtain medical pot, “while Delaware and New Mexico both allow the use of medical marijuana for post traumatic stress disorder … ”

The Institute for the Study of Labor (IZA) in Bonn, with the help of American researchers such as Daniel I. Rees of the University of Colorado’s Department of Economics, recently published their findings in a paper called High on Life? Medical Marijuana Laws and Suicide (PDF):

Our results suggest that the passage of a medical marijuana law is associated with an almost 5 percent reduction in the total suicide rate, an 11 percent reduction in the suicide rate of 20- through 29-year-old males, and a 9 percent reduction in the suicide rate of 30- through 39-year-old males.

The study takes some wild guesses, and one of them is that maybe medical marijuana users are cutting out the alcohol, which can be depressive:

The strong association between alcohol consumption and suicide related outcomes found by previous researchers (Markowitz et al. 2003; Carpenter 2004; Sullivan et al. 2004; Rodriguez Andres 2005; Carpenter and Dobkin 2009) raises the possibility that medical marijuana laws reduce the risk of suicide by decreasing alcohol consumption.

The academics cite research on animals where there was “a potent anti-depressant effect” when they were injected with low doses of synthetic cannabinoid.

Of course this flies in the face of tons of research — not to mention what Dr. Drew Pinsky has said several times — that cannabis and depression go together like milk and cookies.

And, it seems clear to us, the only solid argument to be made here is there might be a correlation between medical marijuana states and lower rates of suicides.

Hmm. National suicide rates have been decreasing across the board.

Researchers say they focused mostly on young men because most medical marijuana patients in states like Arizona, Colorado and Montana are males, and roughly half are under 40. Data on women, apparently, was weak. (Women are four times less likely to commit successful suicide in general).

The German study’s rosy conclusion:

… The legalization of medical marijuana leads to an improvement in the psychological well being of young adult males, an improvement that is reflected in fewer suicides.

Believe that. Or not.”

By Dennis Romero

http://blogs.laweekly.com/informer/2012/02/marijuana_suicide_medical_states_california.php

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Marijuana Prevents Suicides

“In 2010, 38 thousand people committed suicide. About seven thousand were veterans.”

PTSD: U.S. soldier on patrol in Kabul
“U.S. soldier on patrol in Kabul – by Tim King Salem-News.com

(PORTLAND, OR) – The Oregonian and and The New York Times both had headlines, May 3, 2013, ‘Suicides Surge in United States and Oregon’.

I believe military PTSD victims have the highest rate but there are far more civilians in that same age group. For veterans, it is about 20 suicides per day, what that amounts to per thousand patients is the different kind of statistic that I am familiar with. The newspaper articles give their statistics as so many per thousand. They indicate that currently, the suicide rate for the middle aged, (35-64) is 18 per thousand each year, that age group is the highest rate. The overall rate for the U.S. is 14 per thousand per year.

I know more about the military veterans because I had more than 1,000 in my total population of 5,000 patients. Considering that the military veterans represent only about 1% of the population, with my 20% being veterans, this makes a good study group.

For military veterans, PTSD, from mild to severe, is about 20% of the group. This means 600 thousand PTSD victims. The actual figure is probably higher. Most are not being treated by the VA and they are using a number of different therapies. Many who live in states where it is legal, have reverted to marijuana. But many states, including Oregon, will not accept PTSD for a permit. New Mexico does allow Marijuana for PTSD Veterans. In New Mexico, 50% of the permit holders are veterans.

I started seeing military PTSD veterans about as soon as Oregon’s medical marijuana law became effective. But PTSD is not acceptable in Oregon. Most veterans had physical wounds, making them eligible for a permit.

I wrote my first article on this subject, February 13, 2009, ‘Marijuana Vs Antidepressants for PTSD’. The VA uses these drugs by the ton and while deadly, they are no more effective than sugar pills, but usually worse and often are used for suicide. That article has had 868 Facebook recommends, indicating strong interest.

My second article, ‘Medical Marijuana Prevents PTSD Suicides!’, was published Sept 22 2012., has 581 FB recommends.

My latest article on this subject, from March 25 2013, ‘PTSD/Depression and Anguish: Marijuana Vs. Many Fake Dangerous Drugs’ had 340 recommends.

This gets us to the current newspaper articles, in which military suicides are not even mentioned!

When you are 50, looking for a job, it can be fruitless. And it must be getting as bad for those even in their 40’s because the bright young smart alecks are striving to get into the workplace before it is too late.

The unemployed are now in desperate situations with no good way out and no resources. Anguish overtakes them and depression may be one of the symptoms for PTSD, etc.

There are about 19 states with legal marijuana, which represents more than 50% of the U.S. population. And speaking of those 19 states, those people can use this valuable medicine, marijuana. Another option is alcoholism and death.”

 

“MEDICAL MARIJUANA IS THE BEST ANTI-SUICIDE DRUG!”

-Dr. Phillip Leveque Doctor of Pharmacology Salem-News.com

http://salem-news.com/articles/may032013/ptsd-suicides-pl.php

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