THC Weakens Brain Connections Responsible for Pain

“In a fascinating study on humans, THC appears to disconnect areas of the brain responsible for feeling pain. It acts as a cognitive-emotional modulator.  Less pain and less unpleasantness associated with the pain. Very exciting research.”

-   Dr. David Hepburn

THC significantly reduced patients’ pain compared to placebo. THC-induced analgesia was correlated with a reduction in functional connectivity between the anterior cingulate cortex (ACC) and the sensorimotor cortex.

Moreover, the degree of reduction was predictive of the response to THC.

Graph Theory Analysis of local measures demonstrated a reduction in network connectivity in areas involved in pain processing, and specifically in the dorsolateral prefrontal cortex (DLPFC), which were correlated with individual pain reduction.

Read full article here:

https://cdn.doctorsonly.co.il/2018/10/Cannabis-analgesia-in-chronic-neuropathic-pain-Neurology-2018.pdf

Dr. Dave Hepburn website: https://doctordavidhepburn.com

The CB2 receptor plays a significant role in heart function in people with pulmonary hypertension

"The role the endocannabinoid system (ECS) plays in cardiovascular pathology continues to point to a path for possible therapeutic targets. This study shows how the ECS works to prevent death of cardiac cells in pulmonary hypertension, which, if it sounds like a good thing....it is."  -Dr. Dave Hepburn

Article Recommended by Dr. David Hepburn:

CB2-deficiency is associated with a stronger hypertrophy and remodeling of the right ventricle in a murine model of left pulmonary artery occlusion.

Abstract

AIMS:

Pulmonary hypertension (PH) leads to right ventricular (RV) adaptation and remodeling and has deleterious long-term effects on RV function. The endocannabinoid receptor CB2 has been associated with protective effects in adaptation and remodeling of the left ventricle after ischemia. Therefore, we investigated the role of CB2 receptor in RV adaptation after occlusion of the left pulmonary artery (LPA) in a murine model.

MAIN METHODS:

C57/Bl6 (WT)- and CB2 receptor-deficient (Cnr2-/-)-mice underwent paramedian sternotomy and LPA was occluded using a metal clip. Right heart hemodynamic study (Millar®) preceded organ harvesting for immunohistochemistry and mRNA analysis 7 and 21 days (d) post-occlusion.

KEY FINDINGS:

LPA occlusion led to higher RV systolic pressure in Cnr2-/--hearts, while hemodynamics were comparable with WT-hearts after 21d. Cnr2-/--hearts showed higher macrophage infiltration and lower interleukin-10 expression after 7 d, but otherwise a comparable inflammatory mediator expression profile. 

Cardiomyocyte-hypertrophy was stronger in Cnr2-/--mice, presenting with higher tenascin-C expression than WT-hearts. Planimetry revealed higher collagen area in Cnr2-/--hearts and small areas of cardiomyocyte-loss. Surrounding cardiomyocytes were cleaved caspase-3- and TUNEL positive in Cnr2-/--hearts. This was associated by maladaptation of myosin heavy-chain isoforms and lower reactive oxygen scavenger enzymes induction in Cnr2-/--hearts. We found comparable morphological changes in both lungs between the two genotypes.

SIGNIFICANCE:

LPA occlusion led to increased systolic pressure and adaptation of RV in CB2-deficient mice. CB2 receptor seems to modulate RV adaptation through expression of contractile elements, reactive oxygen scavenger enzymes, and inflammatory response in order to prevent cardiomyocyte apoptosis.

To read the full article please visit:

https://www.ncbi.nlm.nih.gov/pubmed/30403990 

Dr. Dave Hepburn website:https://doctordavidhepburn.com

Move Over Epidiolex...Already! - Dr. Dave Hepburn

Article recommend by Dr. Dave Hepburn:

A prospective open-label trial of a CBD/THC cannabis oil in dravet syndrome.

Abstract

INTRODUCTION: 

Both Tetrahydrocannabidiol (THC) and cannabidiol (CBD) components of cannabis, have been shown to have anticonvulsant effects. Cannabis oils are used to treat seizures in drug-resistant epilepsy (DRE). Recent trials provide data on dosing, side effects, and efficacy of CBD, yet there is a paucity of information on THC in epilepsy. Primary objective was to establish dosing and tolerability of TIL-TC150 - a cannabis plant extract produced by Tilray®, containing 100 mg/mL CBD and 2 mg/mL THC- in children with Dravet syndrome. Secondary objectives were to assess impact of therapy on seizures, electroencephalogram (EEG) and quality of life. 

METHODS: 

Twenty children received add-on therapy with TIL-TC150. The dose ranged from 2 to 16 mg/kg/day of CBD and 0.04 to 0.32 mg/kg/day of THC. Patients were monitored for tolerability and adverse events, and secondary objectives. 

RESULTS: 

Nineteen participants completed the 20-week intervention. Mean dose achieved was 13.3 mg/kg/day of CBD (range 7-16 mg/kg/day) and 0.27 mg/kg/day of THC (range 0.14-0.32 mg/kg/day). Adverse events, common during titration included somnolence, anorexia, and diarrhea. Abnormalities of liver transaminases and platelets were observed with concomitant valproic acid therapy. There was a statistically significant improvement in quality of life, reduction in EEG spike activity, and median motor seizure reduction of 70.6%, with 50% responder rate of 63%. 

CONCLUSIONS: 

TIL-TC150 was safe and well tolerated in our subjects. TIL-TC150 treatment resulted in a reduction in seizure counts, spike index on EEG, and improved quality of life measures. This study provides safety and dosing information for THC-containing cannabinoid preparations.

“A new and improved treatment that includes a touch of THC (which children handle much better than adults). The uptight FDA/DEA/US government would rather not allow any THC due to adherence to tired, old, uneducated biases. It’s a shame for American children that their government remains so willfully ignorant.”

Dr. Dave Hepburn

To read the full article please visit:
https://www.ncbi.nlm.nih.gov/pubmed/30250864

Dr. David Hepburn website:
doctordavidhepburn.com

Impressive New Ways that CBD Works - Dr. Dave Hepburn

Article recommend by Dr. David Hepburn:

Cannabidiol enhances morphine antinociception, diminishes NMDA-mediated seizures and reduces stroke damage via the sigma 1 receptor.

Abstract

Cannabidiol (CBD), the major non-psychotomimetic compound present in the Cannabis sativa plant, exhibits therapeutic potential for various human diseases, including chronic neurodegenerative diseases, such as Alzheimer's and Parkinson's, ischemic stroke, epilepsy and other convulsive syndromes, neuropsychiatric disorders, neuropathic allodynia and certain types of cancer. CBD does not bind directly to endocannabinoid receptors 1 and 2, and despite research efforts, its specific targets remain to be fully identified. Notably, sigma 1 receptor (σ1R) antagonists inhibit glutamate N-methyl-D-aspartate acid receptor (NMDAR) activity and display positive effects on most of the aforesaid diseases. Thus, we investigated the effects of CBD on three animal models in which NMDAR overactivity plays a critical role: opioid analgesia attenuation, NMDA-induced convulsive syndrome and ischemic stroke. In an in vitro assay, CBD disrupted the regulatory association of σ1R with the NR1 subunit of NMDAR, an effect shared by σ1R antagonists, such as BD1063 and progesterone, and prevented by σ1R agonists, such as 4-IBP, PPCC and PRE084. The in vivo administration of CBD or BD1063 enhanced morphine-evoked supraspinal antinociception, alleviated NMDA-induced convulsive syndrome, and reduced the infarct size caused by permanent unilateral middle cerebral artery occlusion. These positive effects of CBD were reduced by the σ1R agonists PRE084 and PPCC, and absent in σ1R-/- mice. Thus, CBD displays antagonist-like activity toward σ1R to reduce the negative effects of NMDAR overactivity in the abovementioned experimental situations.

"As the mystery of how CBD actually works is unveiled, many receptors OTHER than cannabinoid receptors are involved. This mechanism/receptors help explain why CBD works for seizures and make morphine more effective (thus requiring a smaller dose)"

Dr. Dave Hepburn

To read the full article please visit:

https://www.ncbi.nlm.nih.gov/pubmed/30223868

Dr. David Hepburn website:
doctordavidhepburn.com

Yet Another Cannabinoid Shows Remarkable Promise - Dr. David Hepburn

Article recommend by Dr. David Hepburn:

Effect of cannabidiolic acid and -tetrahydrocannabinol on carrageenan-induced hyperalgesia and edema in a rodent model of inflammatory pain.

Abstract

RATIONALE:

Cannabidiol (CBD), a non-intoxicating component of cannabis, or the psychoactive Δ9-tetrahydrocannabiol (THC), shows anti-hyperalgesia and anti-inflammatory properties.

OBJECTIVES:

The present study evaluates the anti-inflammatory and anti-hyperalgesia effects of CBD's potent acidic precursor, cannabidiolic acid (CBDA), in a rodent model of carrageenan-induced acute inflammation in the rat hind paw, when administered systemically (intraperitoneal, i.p.) or orally before and/or after carrageenan. In addition, we assess the effects of oral administration of THC or CBDA, their mechanism of action, and the efficacy of combined ineffective doses of THC and CBDA in this model. Finally, we compare the efficacy of CBD and CBDA.

RESULTS:

CBDA given i.p. 60 min prior to carrageenan (but not 60 min after carrageenan) produced dose-dependent anti-hyperalgesia and anti-inflammatory effects. In addition, THC or CBDA given by oral gavage 60 min prior to carrageenan produced anti-hyperalgesia effects, and THC reduced inflammation. The anti-hyperalgesia effects of THC were blocked by SR141716 (a cannabinoid 1 receptor antagonist), while CBDA's effects were blocked by AMG9810 (a transient receptor potential cation channel subfamily V member 1 antagonist). In comparison to CBDA, an equivalent low dose of CBD did not reduce hyperalgesia, suggesting that CBDA is more potent than CBD for this indication. Interestingly, when ineffective doses of CBDA or THC alone were combined, this combination produced an anti-hyperalgesia effect and reduced inflammation.

CONCLUSION:

CBDA or THC alone, as well as very low doses of combined CBDA and THC, has anti-inflammatory and anti-hyperalgesia effects in this animal model of acute inflammation.

“CBDA is the precursor of CBD and is the raw form of cannabis. Already considered 100x more powerful than CBD as an anti-nauseant (anti emetic) and may have a role in the reduction of breast cancer metastasis PLUS anxiety. Stay tuned to see how interesting a molecule this non psychoactive little gem might be.”

Dr. David Hepburn

To read the full article please visit: 

https://www.ncbi.nlm.nih.gov/pubmed/30225659

Dr. David Hepburn website: 

doctordavidhepburn.com

New Study of Cannabinoids in Prostate Cancer - Dr. David Hepburn

Article recommend by Dr. David Hepburn:

Cannabinoid WIN 55,212-2 induces cell cycle arrest and apoptosis, and inhibits proliferation, migration, invasion, and tumor growth in prostate cancer in a cannabinoid-receptor 2 dependent manner.

Abstract

BACKGROUND: 

Cannabinoids have demonstrated anticarcinogenic properties in a variety of malignancies, including in prostate cancer. In the present study, we explored the anti-cancer effects of the synthetic cannabinoid WIN 55,212-2 (WIN) in prostate cancer. 

METHODS: 

Established prostate cancer cells (PC3, DU145, LNCaP) were treated with varying concentrations of WIN. Cell proliferation was determined by the MTS assay. The anti-migration and anti-invasive potential of WIN was examined by the wound healing assay and the matrigel invasion assay. Cell cycle analysis was performed by flow cytometry, and mechanistic studies were performed by Western blot. Athymic mice (n = 10) were inoculated with human PC3 cells. Once tumors reached 100 mm3 , animals were randomized into two groups: saline control and WIN (5 mg/kg), delivered by intraperitoneal injection three times per week for 3 weeks. 

RESULTS: 

WIN significantly reduced prostate cancer cell proliferation, migration, invasion, induced apoptosis, and arrested cells in Go/G1 phase in a dose-dependent manner. Mechanistic studies revealed these effects were mediated through a pathway involving cell cycle regulators p27, Cdk4, and pRb. Pre-treatment with a CB2 antagonist, AM630, followed by treatment with WIN resulted in a reversal of the anti-proliferation and cell cycle arrest previously seen with WIN alone. In vivo, administration of WIN resulted in a reduction in the tumor growth rate compared to control (P < 0.05). 

CONCLUSIONS: 

The following study provides evidence supporting the use of WIN as a novel therapeutic for prostate cancer.

“Important news for men with prostates and the women who love them (the men...not the prostates). Potential novel therapeutics for this very common cancer that is the second leading cause of cancer death in American men, behind lung cancer.”

Dr. David Hepburn

To read the full article please visit: 

https://www.ncbi.nlm.nih.gov/pubmed/30242861

Dr. David Hepburn website: 

doctordavidhepburn.com

Schizophrenia More Likely to Lead to Cannabis Use…. Not the Reverse - Dr Dave Hepburn

Article recommend by Dr. Dave Hepburn:

GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia.

Abstract 

Cannabis use is a heritable trait that has been associated with adverse mental health outcomes. In the largest genome-wide association study (GWAS) for lifetime cannabis use to date (N = 184,765), we identified eight genome-wide significant independent single nucleotide polymorphisms in six regions. All measured genetic variants combined explained 11% of the variance. Gene-based tests revealed 35 significant genes in 16 regions, and S-PrediXcan analyses showed that 21 genes had different expression levels for cannabis users versus nonusers. The strongest finding across the different analyses was CADM2, which has been associated with substance use and risk-taking. Significant genetic correlations were found with 14 of 25 tested substance use and mental health-related traits, including smoking, alcohol use, schizophrenia and risk-taking. Mendelian randomization analysis showed evidence for a causal positive influence of schizophrenia risk on cannabis use. Overall, our study provides new insights into the etiology of cannabis use and its relation with mental health.

“It is well known that cannabis use is higher in those with schizophrenia. However, cannabis has never been shown to cause schizophrenia; in fact, the opposite appears to be true as more research is lining up showing that those with schizophrenia are more likely to turn to cannabis, possibly to help deal with the social isolation and/or a genetic predisposition as this study infers. Once again, any who claim that cannabis causes schizophrenia, are simply incorrect.” 

Dr. Dave Hepburn

To read the full article please visit:
https://www.ncbi.nlm.nih.gov/pubmed/30150663

Dr. David Hepburn website:
doctordavidhepburn.com

   

Cannabinoid Receptor Protects Against Hearing Loss Caused by Chemotherapy - Dr. David Hepburn

Article recommend by Dr. David Hepburn:

The Endocannabinoid/Cannabinoid Receptor 2 System Protects Against Cisplatin-Induced Hearing Loss

Abstract

Previous studies have demonstrated the presence of cannabinoid 2 receptor (CB2R) in the rat cochlea which was induced by cisplatin. In an organ of Corti-derived cell culture model, it was also shown that an agonist of the CB2R protected these cells against cisplatin-induced apoptosis. In the current study, we determined the distribution of CB2R in the mouse and rat cochleae and examined whether these receptors provide protection against cisplatin-induced hearing loss. In a knock-in mouse model expressing the CB2R tagged with green fluorescent protein, we show distribution of CB2R in the organ of Corti, stria vascularis, spiral ligament and spiral ganglion cells. A similar distribution of CB2R was observed in the rat cochlea using a polyclonal antibody against CB2R. Trans-tympanic administration of (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone (JWH015), a selective agonist of the CB2R, protected against cisplatin-induced hearing loss which was reversed by blockade of this receptor with 6-iodo-2-methyl-1-[2-(4-morpholinyl)ethyl]-1H-indol-3-yl](4-methoxyphenyl)methanone (AM630), an antagonist of CB2R. JWH015 also reduced the loss of outer hair cells (OHCs) in the organ of Corti, loss of inner hair cell (IHC) ribbon synapses and loss of Na+/K+-ATPase immunoreactivity in the stria vascularis. Administration of AM630 alone produced significant hearing loss (measured by auditory brainstem responses) which was not associated with loss of OHCs, but led to reductions in the levels of IHC ribbon synapses and strial Na+/K+-ATPase immunoreactivity. Furthermore, knock-down of CB2R by trans-tympanic administration of siRNA sensitized the cochlea to cisplatin-induced hearing loss at the low and middle frequencies. Hearing loss induced by cisplatin and AM630 in the rat was associated with increased expression of genes for oxidative stress and inflammatory proteins in the rat cochlea. In vitro studies indicate that JWH015 did not alter cisplatin-induced killing of cancer cells suggesting this agent could be safely used during cisplatin chemotherapy. These data unmask a protective role of the cochlear endocannabinoid/CB2R system which appears tonically active under normal conditions to preserve normal hearing. However, an exogenous agonist is needed to boost the activity of endocannabinoid/CB2R system for protection against a more traumatic cochlear insult, as observed with cisplatin administration.

“One of the several possible nasty side effects of a common anticancer medication, is hearing loss. Activation of CB2R appears to prevent this, indicating an important role of the ECS (endocannabinoid system) in neuroprotection."

Dr. David Hepburn

To read the full article please visit:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6110918/

Dr. David Hepburn website:
doctordavidhepburn.com

Majority of Pain Specialists Prescribe Cannabis - Dr. David Hepburn

Article recommend by Dr. David Hepburn:

Personal experience and attitudes of pain medicine specialists in Israel regarding the medical use of cannabis for chronic pain.

Abstract:

INTRODUCTION:

The scientific study of the role of cannabis in pain medicine still lags far behind the growing use driven by public approval. Accumulated clinical experience is therefore an important source of knowledge. However, no study to date has targeted physicians who actually use cannabis in their daily practice. 

METHODS: 

Registered, active, board-certified pain specialists in Israel (n=79) were asked to complete a Web-based survey. The survey was developed using the Qualtrics Online Survey Software. Questions were formulated as multiple-choice questions, and these addressed three areas of interest: 1) doctors' personal experience; 2) the role of cannabis in pain medicine; and 3) cannabis medicalization and legalization. 

RESULTS: 

Sixty-four percent of all practicing pain specialists in Israel responded. Almost all prescribe cannabis. Among them, 63% find cannabis moderately to highly effective, 56% have encountered mild or no side effects, and only 5% perceive it as significantly harmful. Common indications are neuropathic pain (65%), oncological pain (50%), arthralgias (25%), and any intractable pain (29%). Leading contraindications are schizophrenia (76%), pregnancy/breastfeeding (65%), and age <18 years (59%). Only 12% rated cannabis as more hazardous than opiates. On a personal note, 45% prefer cannabis for themselves or a family member. Lastly, 54% would like to see cannabis legalized in Israel. 

CONCLUSION:

In this survey, pain clinicians experienced in prescribing cannabis over prolonged periods view it as an effective and relatively safe treatment for chronic pain, based on their own experience. Their responses suggest a possible change of paradigm from using cannabis as the last resort.

“For virtually all types of pain, specialists in Israel, a country with a long experience with medical cannabis, use it not only for patients but 45% actually prefer cannabis for themselves or a family member.”

Dr. David Hepburn

To read the full article please visit:
https://www.ncbi.nlm.nih.gov/pubmed/30104896

Dr. David Hepburn website:
doctordavidhepburn.com

Cannabis lozenges reduce pain efficiently - Dr. David Hepburn

Article recommended by Dr. Dave Hepburn

Self-Reported Effectiveness and Safety of Trokie® Lozenges: A Standardized Formulation for the Buccal Delivery of Cannabis Extracts.

Abstract:

Therapeutic use of cannabinoids, the main active ingredients of Cannabissativa L., is often hindered by their limited bioavailability and undesirable psychoactivity. 

We conducted an observational study in December 2016 and another one in February 2018 to investigate respectively: (i) the effectiveness of Trokie® lozenges, a standardized formulation containing cannabis extracts, to deliver cannabinoids via buccal absorption and (ii) its long-term safety. 

Participants were members of the Palliative Care Corporation health clinic, registered California cannabis patients, and had a diagnosis of chronic non-cancer pain. For the effectiveness study, 49 participants were asked to self-report pain perception before and after 1-12 weeks of taking Trokie® lozenges, using an 11-point pain intensity numeric rating scale (PI-NRS). A mean reduction in PI-NRS score of 4.9 ± 2.0 points was observed. Onset of analgesia typically varied between 5 and 40 min, which seems consistent with, at least partial, buccal absorption. 

In the safety study, 35 participants were asked to complete a questionnaire about adverse events (AEs) associated with Trokie® lozenges. AEs were reported by 16 subjects (46%), the most common being dizziness/unsteadiness (N = 7), bad taste (N = 5), and throat irritation/dry mouth (N = 4). None of the self-reported AEs resulted in a serious medical situation and most of them had limited impact on daily functions. 

Despite the AEs, 90% of participants reported being "satisfied" or "very satisfied" with the product. These observations suggest that buccal administration of standardized extracts via Trokie® lozenges may represent an efficacious and safe approach to cannabis administration.

“Yet another study pointing the promising analgesic properties of cannabis, this using a quicker different delivery mechanism than ingestion.”

Dr. Dave Hepburn 

To read the full article please visit:

https://www.ncbi.nlm.nih.gov/pubmed/30154694

David Hepburn website:

doctordavidhepburn.com

CBD Induces Rapid and Sustained Antidepressant Like Effects

Article recommended by Dr. David Hepburn:

Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex.

Abstract:

Currently available antidepressants have a substantial time lag to induce therapeutic response and a relatively low efficacy. The development of drugs that addresses these limitations is critical to improving public health. Cannabidiol (CBD), a non-psychotomimetic component of Cannabis sativa, is a promising compound since it shows large-spectrum therapeutic potential in preclinical models and humans. 

However, its antidepressant properties have not been completely investigated. Therefore, the aims of this study were to investigate in male rodents (i) whether CBD could induce rapid and sustained antidepressant-like effects after a single administration and (ii) whether such effects could be related to changes in synaptic proteins/function. Results showed that a single dose of CBD dose-dependently induced antidepressant-like effect (7-30 mg/kg) in Swiss mice submitted to the forced swim test (FST), 30 min (acute) or 7 days (sustained) following treatment. 

Similar effects were observed in the Flinders Sensitive and Flinders Resistant Line (FSL/FRL) rats and the learned helplessness (LH) paradigm using Wistar rats. The acute antidepressant effects (30 min) were associated with increased expression of synaptophysin and PSD95 in the medial prefrontal cortex (mPFC) and elevated BDNF levels in both mPFC and hippocampus (HPC). CBD also increased spine density in the mPFC after 30 min, but not 7 days later. 

Intracerebroventricular injection of the TrkB antagonist, K252a (0.05 nmol/μL), or the mTOR inhibitor, rapamycin (1 nmol/μL), abolished the behavioral effects of CBD. These results indicate that CBD induces fast and sustained antidepressant-like effect in distinct animal models relevant for depression. These effects may be related to rapid changes in synaptic plasticity in the mPFC through activation of the BDNF-TrkB signaling pathway. The data support a promising therapeutic profile for CBD as a new fast-acting antidepressant drug.

“This is not insignificant. Clearly, CBD is psychoactive but in ways that harness the brain’s natural neuroplasticity to create synapses in areas that create and control emotions. The fact that CBD induces fast and sustained antidepressant-like effects is very encouraging. Clinical studies should follow, as a fast acting antidepressant is a much sought after commodity."

Dr. David Hepburn 

To read the full article please visit:

https://www.ncbi.nlm.nih.gov/pubmed/29869197

Dr. David Hepburn website:

doctordavidhepburn.com