Cannabidiol in Medical Marijuana: Research Vistas and Potential Opportunities.

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“The high and increasing prevalence of medical marijuana consumption in the general population invites the need for quality evidence regarding its safety and efficacy. Herein, we synthesize extant literature pertaining to the phytocannabinoid cannabidiol (CBD) and its brain effects.

The principle phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) and CBD are the major pharmacologically active cannabinoids. The effect of CBD on brain systems as well as on phenomenological measures (e.g. cognitive function) are distinct and in many cases opposite to that of Δ9-THC.

Cannabidiol is without euphoriant properties, and exerts antipsychotic, anxiolytic, anti-seizure, as well as anti-inflammatory properties.

It is essential to parcellate phytocannabinoids into their constituent moieties as the most abundant cannabinoid have differential effects on physiologic systems in psychopathology measures. Disparate findings and reports related to effects of cannabis consumption reflect differential relative concentration of Δ9-THC and CBD.

Existing literature, notwithstanding its deficiencies, provides empirical support for the hypothesis that CBD may exert beneficial effects on brain effector systems/substrates subserving domain-based phenomenology. Interventional studies with purified CBD are warranted with a call to target-engagement proof-of-principle studies using the research domain criteria (RDoC) framework.” https://www.ncbi.nlm.nih.gov/pubmed/28501518

http://www.sciencedirect.com/science/article/pii/S1043661817303559

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A chronic low dose of Δ9-tetrahydrocannabinol (THC) restores cognitive function in old mice

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“The balance between detrimental, pro-aging, often stochastic processes and counteracting homeostatic mechanisms largely determines the progression of aging. There is substantial evidence suggesting that the endocannabinoid system (ECS) is part of the latter system because it modulates the physiological processes underlying aging.

The activity of the ECS declines during aging, as CB1 receptor expression and coupling to G proteins are reduced in the brain tissues of older animals and the levels of the major endocannabinoid 2-arachidonoylglycerol (2-AG) are lower. However, a direct link between endocannabinoid tone and aging symptoms has not been demonstrated.

Here we show that a low dose of Δ9-tetrahydrocannabinol (THC) reversed the age-related decline in cognitive performance of mice aged 12 and 18 months. This behavioral effect was accompanied by enhanced expression of synaptic marker proteins and increased hippocampal spine density.

THC treatment restored hippocampal gene transcription patterns such that the expression profiles of THC-treated mice aged 12 months closely resembled those of THC-free animals aged 2 months. The transcriptional effects of THC were critically dependent on glutamatergic CB1 receptors and histone acetylation, as their inhibition blocked the beneficial effects of THC.

Thus, restoration of CB1 signaling in old individuals could be an effective strategy to treat age-related cognitive impairments.”

https://www.nature.com/nm/journal/vaop/ncurrent/full/nm.4311.html

“CAN MARIJUANA RESTORE MEMORY? NEW STUDY SHOWS CANNABIS CAN REVERSE COGNITIVE DECLINE IN MICE” http://www.newsweek.com/cannabis-marijuana-restores-memory-learning-cognitive-decline-596160

“A little cannabis every day might keep brain ageing at bay” https://www.newscientist.com/article/2130257-a-little-cannabis-every-day-might-keep-brain-ageing-at-bay/

“Low-dose cannabinoid THC restores memory and learning in old mice”  http://www.medicalnewstoday.com/articles/317342.php

“Daily Dose Of Cannabis May Protect And Heal The Brain From Effects Of Aging”  https://www.forbes.com/sites/janetwburns/2017/05/08/daily-dose-of-cannabis-may-protect-and-heal-the-brain-from-effects-of-aging/#70ef658f2e44

“Cannabis reverses aging processes in the brain”  https://medicalxpress.com/news/2017-05-cannabis-reverses-aging-brain.html

“Future dementia cure – Chemical in cannabis could REVERSE the ageing process” http://www.express.co.uk/life-style/health/801827/dementia-cure-cannabis-THC-chemical-memory

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Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial.

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“A double-blind study was performed comparing 5 mg delta-9-tetrahydrocannabinol (THC) p.o., 50 mg codeine p.o., and placebo in a patient with spasticity and pain due to spinal cord injury. The three conditions were applied 18 times each in a randomized and balanced order. Delta-9-THC and codeine both had an analgesic effect in comparison with placebo. Only delta-9-THC showed a significant beneficial effect on spasticity. In the dosage of THC used no altered consciousness occurred.”

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Δ9-Tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptors

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“It has been suggested that the endocannabinoid system elicits neuroprotection against excitotoxic brain damage.

In the present study the therapeutic potential of AM 404 on ischaemia-induced neuronal injury was investigated in vivo and compared with that of the classical cannabinoid receptor type 1 (CB1) agonist, Δ9-tetraydrocannabinol (THC), using a model of transient global cerebral ischaemia in the gerbil.

Our findings demonstrate that AM 404 and THC reduce neuronal damage caused by bilateral carotid occlusion in gerbils and that this protection is mediated through an interaction with CB1 and opioid receptors.

Endocannabinoids might form the basis for the development of new neuroprotective drugs useful for the treatment of stroke and other neurodegenerative pathologies.

There is some evidence from experiments with mice that increasing anandamide or 2-arachidonoyl glycerol content may lead to neuroprotection.

Collectively, our data demonstrate that AM 404 and THC protect against neuronal ischaemia-induced injury through a mechanism involving cannabinoid and opioid receptors but not vanilloid receptors.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2189998/

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Combined cannabinoid therapy via an oromucosal spray.

“Extensive basic science research has identified the potential therapeutic benefits of active compounds extracted from the Cannabis sativa L. plant (the cannabinoids). It is recognized that a significant proportion of patients suffering with the debilitating symptoms of pain and spasticity in multiple sclerosis or other conditions smoke cannabis despite the legal implications and stigma associated with this controlled substance. GW Pharmaceuticals have developed Sativex (GW- 1000-02), a combined cannabinoid medicine that delivers and maintains therapeutic levels of two principal cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), via an oromucosal pump spray, that aims to minimize psychotropic side effects.”  https://www.ncbi.nlm.nih.gov/pubmed/16969427

“Sativex has proved to be well tolerated and successfully self-administered and self-titrated in both healthy volunteers and patient cohorts. Clinical assessment of this combined cannabinoid medicine has demonstrated efficacy in patients with intractable pain (chronic neuropathic pain, pain due to brachial plexus nerve injury, allodynic peripheral neuropathic pain and advanced cancer pain), rheumatoid arthritis and multiple sclerosis (bladder problems, spasticity and central pain), with no significant intoxication-like symptoms, tolerance or withdrawal syndrome.”  https://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summaryn_pr?p_JournalId=4&p_RefId=1021517

“Sativex(®) (nabiximols, USAN name) oromucosal spray contains the two main active constituents of Cannabis sativa, tetrahydrocannabinol and cannabidiol in a 1:1 molecular ratio, and acts as an endocannabinoid system modulator.”  https://www.ncbi.nlm.nih.gov/pubmed/21449855

“Abuse potential and psychoactive effects of δ-9-tetrahydrocannabinol and cannabidiol oromucosal spray (Sativex), a new cannabinoid medicine. Evidence to date suggests that abuse or dependence on Sativex is likely to occur in only a very small proportion of recipients.” https://www.ncbi.nlm.nih.gov/pubmed/21542664

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The Role of Cannabinoids in the Treatment of Cancer in Pediatric Patients.

“Cannabis has been used in folk medicine to alleviate pain, depression, amenorrhea, inflammation and numerous other medical conditions. In cancer patients specifically, cannabinoids are well known to exert palliative effects; their best-established use is the inhibition of chemotherapy-induced nausea and vomiting, but they are applied also to alleviate pain, stimulate appetite, and attenuate wasting. More recently, cannabinoids have gained special attention for their role in cancer cell proliferation and death.

Anti-cancer efficacy of cannabinoids:

The ability of cannabinoids to reduce tumor growth was reported for the first time by Munson et al. in 1975. They showed by in vitro and in vivo experiments that several phytocannabinoids, including THC, decreased Lewis lung adenocarcinoma proliferation in a dose-dependent manner. Nevertheless, it was not until the 2000s that the interest in these compounds as anti-cancer agents was renewed, predominantly due to the work of Guzman in gliomas, and the demonstration of cannabinoids’ anti-cancer effects on various types of tumors. The anti-tumorigenic effect of the endo- and phytocannabinoids was demonstrated in several in vitro and in vivo models of a wide variety of adult tumors including glioma, prostate, breast, leukemia, lymphoma, pancreas, melanoma, thyroid, colorectal and hepatocellular carcinoma tumors.

Given our positive results, we suggest that non-THC cannabinoids such as CBD might provide a basis for the development of novel therapeutic strategies without the typical psychotropic effects of THC that limit its use in pediatric patients.

Overall, the cannabinoids, and specifically the non-psychoactive CBD, may show future promise in the treatment of cancer”

https://www.ima.org.il/FilesUpload/IMAJ/0/228/114216.pdf

https://www.ima.org.il/imaj/ViewArticle.aspx?aId=4044

https://www.ncbi.nlm.nih.gov/pubmed/28457057

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Cannabis Use, Medication Management and Adherence Among Persons Living with HIV.

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“Cannabis is used to relieve nausea, trigger weight gain, and reduce pain among adults living with HIV; however, the relationship between its use and medication adherence and management is unclear. Participants (N = 107) were from an ongoing cohort study of community-dwelling HIV+ adults, stratified by cannabis (CB) use: HIV+/CB+ (n = 41) and HIV+/CB- (n = 66). CB+ participants either tested positive in a urine toxicology screen for THC or had a self-reported history of regular and recent use. HIV-status was provided by physician results and/or biomarker assessment. Adherence was measured via the Morisky scale and medication management was assessed via the Medication Management Test-Revised. After adjusting for gender, we found no association between cannabis use group and adherence nor medication management. The amount of cannabis used was also not associated with measures of adherence and management. Preliminary findings suggest that cannabis use may not adversely influence medication adherence/management among adults living with HIV.”

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Significant Tic Reduction in An Otherwise Treatment-Resistant Patient with Gilles de la Tourette Syndrome Following Treatment with Nabiximols.

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“Early anecdotal reports and preliminary studies suggested that cannabinoid-based medicines such as delta-9-tetrahydrocannabinol (THC) are effective in the treatment of Gilles de la Tourette syndrome (TS).

We report a single case study of a patient with otherwise treatment-resistant TS successfully treated with nabiximols.

Our results provide further evidence that treatment with nabiximols may be effective in the treatment of patients with TS.

Given the positive response exhibited by the patient highlighted in this report, further investigation of the effects of nabiximols is proposed on a larger group of patients in a clinical trial setting.”

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Anti-inflammatory effects of the cannabidiol derivative dimethylheptyl-cannabidiol – studies in BV-2 microglia and encephalitogenic T cells

“Preparations derived from Cannabis sativa (marijuana and hashish) have become widespread since ancient times, both as therapeutic agents and in recreational smoking.

Among the more than 60 phytocannabinoids identified in Cannabis extracts, the two most abundant are Δ9-tetrahydrocannabinol (THC), the major psychotropic constituent, and cannabidiol (CBD), the major non-psychoactive component.

Cannabinoids were shown to exert a wide range of therapeutic effects, and many of the cannabinoids, especially CBD, were shown to possess potent anti-inflammatory and immunomodulatory activities. In addition, it was shown that several cannabinoids have pro-apoptotic, neuroprotective, and antitumor properties

Dimethylheptyl-cannabidiol (DMH-CBD), a non-psychoactive, synthetic derivative of the phytocannabinoid cannabidiol (CBD), has been reported to be anti-inflammatory in RAW macrophages. Here, we evaluated the effects of DMH-CBD at the transcriptional level in BV-2 microglial cells as well as on the proliferation of encephalitogenic T cells.

The results show that DMH-CBD has similar anti-inflammatory properties to those of CBD. DMH-CBD downregulates the expression of inflammatory cytokines and protects the microglial cells by inducing an adaptive cellular response against inflammatory stimuli and oxidative injury. In addition, DMH-CBD decreases the proliferation of pathogenic activated TMOG cells.

Several CBD derivatives were also shown to have anti-inflammatory and anti-proliferative properties.

The results show that DMH-CBD induces similar anti-inflammatory, anti-proliferative, and stress response effects to those previously observed for CBD.”

https://www.degruyter.com/view/j/jbcpp.2016.27.issue-3/jbcpp-2015-0071/jbcpp-2015-0071.xml

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Cannabis ‘mimics love hormone in the brain’, study finds – marking new research possibilities for autism

Cannabis behaves like the human 'love hormone'

“Cannabis has a reputation for inducing feelings of peace and love – and now scientists claim they have found the reason why.

A new study reveals the illegal drug acts much in the same way as chemicals produced by the natural ‘love hormone’ oxytocin, which is known to boost emotional feelings and bonding towards romantic partners, between mothers and babies and friends.

The research, conducted on mice, found that higher levels of oxytocin led to the release of anandamide – which behaves very similarly in the brain to the psychoactive ingredient in cannabis, THC.

Both chemicals attach to the same brain cell receptors, producing a similar ‘high’.

As part of the study, the researchers found that blocking anandamide reduced the pro-social effects of oxytocin – while a drug which preserved anandamide in the mice’s brains seemed to make them happier around other mice than other, untreated, animals.

Scientists say the results could highlight new paths for research in the treatment of autism, for which symptoms often include difficulty socialising.

It is very difficult to directly deliver oxytocin to the brain, however.

Dr Daniele Piomelli, of the Italian Institute of Technology in Genoa, Italy, said another strategy could be to intervene further down the oxytocin-anandamide pathway.

Our findings open the exciting possibility that drugs that block the degradation of anandamide, which are currently being tested for various anxiety disorders, could give a boost to the brain’s own oxytocin and help people with autism socialise more.

– DR DANIELE PIOMELLI, RESEARCHER

The findings were published in the journal Proceedings of the National Academy of Sciences.”

http://www.itv.com/news/2015-10-27/cannabis-mimics-love-hormone-in-the-brain-study-finds/

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