The pharmacokinetics, efficacy, and safety of a novel selective‐dose cannabis inhaler in patients with chronic pain: A randomized, double‐blinded, placebo‐controlled trial

European Journal of Pain“Precise cannabis treatment dosing remains a major challenge, leading to physicians’ reluctance to prescribe medical cannabis.

Objective

To test the pharmacokinetics, analgesic effect, cognitive performance and safety effects of an innovative medical device that enables the delivery of inhaled therapeutic doses of Δ9‐Tetrahydrocannabinol (THC) in patients with chronic pain.

Methods

In a randomized, three‐arms, double‐blinded, placebo‐controlled, cross‐over trial, 27 patients received a single inhalation of Δ9‐THC: 0.5mg, 1mg, or a placebo.

Δ9‐THC plasma levels were measured at baseline and up to 150‐min post‐inhalation. Pain intensity and safety parameters were recorded on a 10‐cm visual analogue scale (VAS) at pre‐defined time points. The cognitive performance was evaluated using the selective sub‐tests of the Cambridge Neuropsychological Test Automated Battery (CANTAB).

Results

Following inhalation of 0.5 mg or 1mg, Δ9‐THC plasma max ± SD were 14.3 ± 7.7 and 33.8 ± 25.7 ng/ml. max ± SD were 3.7 ± 1.4 and 4.4 ± 2.1 min, and AUC0 → infinity±SD were 300 ± 144 and 769 ± 331 ng*min/ml, respectively. Both doses, but not the placebo, demonstrated a significant reduction in pain intensity compared with baseline and remained stable for 150‐min. The 1‐mg dose showed a significant pain decrease compared to the placebo. Adverse events were mostly mild and resolved spontaneously. There was no evidence of consistent impairments in cognitive performance.

Conclusion

This feasibility trial demonstrated that a metered‐dose cannabis inhaler delivered precise and low THC doses, produced a dose‐dependent and safe analgesic effect in patients with neuropathic pain/ complex‐regional pain syndrome (CRPS). Thus, it enables individualization of medical cannabis regimens that can be evaluated pharmacokinetically and pharmacodynamically by accepted pharmaceutical models.

Significance

Evidence suggests that cannabis‐based medicines are an effective treatment for chronic pain in adults. The pharmacokinetics of THC varies as a function of its route of administration. Pulmonary assimilation of inhaled THC causes rapid onset of analgesia. However, currently used routes of cannabinoids delivery provide unknown doses, making it impossible to implement a pharmaceutical standard treatment plan. A novel selective‐dose cannabis inhaler delivers significantly low and precise doses of THC, thus allowing the administration of inhaled cannabis‐based medicines according to high pharmaceutical standards. These low doses of THC can produce safe and effective analgesia in patients with chronic pain.

To the best of our knowledge, it is the first time that the delivery of selective, significantly low, and precise therapeutic single doses of inhaled THC demonstrates an analgesic effect. It allows patients to reach the optimum balance between symptom relief and controlled side effects, enabling patients to regain their quality of life. In addition, this metered‐dose cannabis inhaler enables the individualization of medical cannabis regimens that can be evaluated pharmacokinetically and pharmacodynamically using accepted pharmaceutical models.”

https://onlinelibrary.wiley.com/doi/10.1002/ejp.1605

Study Finds Microdosing THC Reduces Pain Levels”  https://www.painnewsnetwork.org/stories/2020/7/1/study-finds-microdosing-thc-reduces-pain-levels

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A Cross-Sectional and Prospective Comparison of Medicinal Cannabis Users and Controls on Self-Reported Health

View details for Cannabis and Cannabinoid Research cover image“Despite widespread legalization, the impact of medicinal cannabis use on patient-level health and quality of life (QOL) has not been carefully evaluated.

The objective of this study was to characterize self-reported demographics, health characteristics, QOL, and health care utilization of Cannabis Users compared with Controls.

Results: Cannabis Users self-reported significantly better QOL [t(1054)=−4.19, p<0.001], greater health satisfaction [t(1045)=−4.14, p<0.001], improved sleep [children: t(224)=2.90, p<0.01; adults: [t(758)=3.03, p<0.01], lower average pain severity [t(1150)=2.34, p<0.05], lower anxiety [t(1151)=4.38, p<0.001], and lower depression [t(1210)=5.77, p<0.001] compared with Controls. Cannabis Users reported using fewer prescription medications (rate ratio [RR]=0.86; 95% confidence interval [CI]: 0.77–0.96) and were less likely to have a past-month emergency department visit (RR=0.61; 95% CI: 0.44–0.84) or hospital admission (RR=0.54; 95% CI: 0.34–0.87). Controls who initiated cannabis use after baseline showed significant health improvements at follow-up, and the magnitude of improvement mirrored the between-group differences observed at baseline.

Conclusions: Cannabis use was associated with improved health and QOL. Longitudinal testing suggests that group differences may be due to the medicinal use of cannabis. Although bias related to preexisting beliefs regarding the health benefits of cannabis in this sample should be considered, these findings indicate that clinical trials evaluating the efficacy of defined cannabinoid products for specific health conditions are warranted.

The key finding of this study is that medicinal cannabis use was associated with more positive ratings of health and QOL, assessed across multiple domains. Prospective analyses found that Controls showed improvement in health and QOL if they initiated medicinal cannabis use, and that Cannabis Users showed diminished health and QOL if they stopped cannabis use.”

https://www.liebertpub.com/doi/full/10.1089/can.2019.0096

“The Health Benefits of Medical Marijuana As Reported by Users. Using cannabis for medical reasons has been linked in a study to outcomes including better sleep, less anxiety, and taking fewer prescription medications.” https://www.newsweek.com/health-benefits-medical-marijuana-users-1511647

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The Therapeutic Effectiveness of Full Spectrum Hemp Oil Using a Chronic Neuropathic Pain Model

life-logo“Few models exist that can control for placebo and expectancy effects commonly observed in clinical trials measuring ‘Cannabis’ pharmacodynamics. We used the Foramen Rotundum Inflammatory Constriction Trigeminal Infraorbital Nerve injury (FRICT-ION) model to measure the effect of “full-spectrum” whole plant extracted hemp oil on chronic neuropathic pain sensitivity in mice.

Results: Mechanical allodynia was alleviated within 1 h (d = 2.50, p < 0.001) with a peak reversal effect at 4 h (d = 7.21, p < 0.001) and remained significant throughout the 6 h observation window. There was no threshold change on contralateral whisker pad after hemp oil administration, demonstrating the localization of anesthetic response to affected areas.

Conclusion: Future research should focus on how whole plant extracted hemp oil affects multi-sensory and cognitive-attentional systems that process pain.

The present study shows for the first time that common, commercially available, and easily reproducible full-spectrum hemp oil induces significant anti-allodynic effects with a bell-shaped pain sensitivity effect peeking between 2 and 4 h and lasting over 6 h. The study provides evidence that phytochemical extracts of the Cannabis plant, even with relatively low levels of THC, can significantly improve mechanical pressure pain in animals with established chronic neuropathic hypersensitivity.”

https://www.mdpi.com/2075-1729/10/5/69/htm

“Legal Cannabis hemp oil effectively treats chronic neuropathic pain: study”   https://medicalxpress.com/news/2020-05-legal-cannabis-hemp-oil-effectively.html

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Association of State Marijuana Legalization Policies for Medical and Recreational Use With Vaping-Associated Lung Disease

Author Insights: Bariatric Surgery May Lead to Increases in ...“From June 2019 to January 2020, over 2500 cases of electronic cigarette (e-cigarette)– or vaping–associated lung injury (EVALI) were reported to the Centers for Disease Control and Prevention (CDC).

Some states have legalized marijuana and THC-containing products for recreational use. Many other states allow purchases for qualifying medical purposes. In remaining states, all forms of consumption and distribution are illegal, and individuals who use THC likely obtain it from the black market. If black-market THC products are responsible for EVALI, then case rates may be lower in recreational marijuana states.

The goal of this cross-sectional study was to measure whether states where marijuana is legal have lower rates of EVALI compared with states where it is illegal.

Recreational marijuana states had among the lowest EVALI rates of all states.

The data suggest that EVALI cases were concentrated in states where consumers do not have legal access to recreational marijuana dispensaries. This association was not driven by state-level differences in e-cigarette use, and EVALI case rates were not associated with state-level prevalence of e-cigarette use.

One possible inference from our results is that the presence of legal markets for marijuana has helped mitigate or may be protective against EVALI.”

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2763966

“Legal Marijuana Tied to Lower Rates of Vaping Illness”  https://www.medpagetoday.com/pulmonology/smoking/85807

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Cannabis use disorder among people using cannabis daily/almost daily in the United States, 2002–2016

Drug and Alcohol Dependence“Cannabis use disorder (CUD) prevalence among people reporting past-year cannabis use declined from 2002–2016.

We examined whether similar reductions in CUD were observed among people reporting daily/almost daily cannabis use.

We expected that CUD prevalence among people reporting daily/almost daily use would not decrease.

Results

From 2002–2016, the prevalence of CUD among people reporting daily/almost daily cannabis use decreased by 26.8% in adolescents, by 29.7% in ages 18–25, and by 37.5% in ages 26 + . Prevalence of DSM-IV cannabis dependence decreased significantly among adolescents (-43.9%) and young adults (-26.8%) but remained stable in adults 26 + . Reductions in most dependence items were observed in young adults, with less consistent patterns in adolescents and adults 26 + . Prevalence of DSM-IV cannabis abuse decreased overall and for each abuse item across all age groups.

Conclusions

Contrary to expectations, CUD prevalence decreased significantly across all ages reporting daily/almost daily cannabis use between 2002–2016. Cannabis dependence prevalence decreased for adolescents and young adults and was stable only among adults ages 26+ reporting daily/almost daily cannabis use. Potential drivers of this decrease should be further explored.

The prevalence of cannabis use disorder decreased in frequent cannabis users. Endorsement of cannabis abuse items decreased in adolescents and young adults. Endorsement of cannabis dependence items decreased mainly in young adults. Changes in social attitudes and frequent users’ features may explain findings.”

https://www.sciencedirect.com/science/article/abs/pii/S0376871619303989

“Cannabis use disorder is declining among young adolescents and young adults. The prevalence of cannabis use disorder decreased in 2002 to 2016 among frequent users. Changes in social attitudes and the traits of frequent users may explain the decline, according to researchers. This is one of the first studies to examine the general health profile of people using cannabis daily or almost daily and the trends in the prevalence of cannabis use disorder in this population.”

https://www.sciencedaily.com/releases/2019/10/191031100512.htm

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Does cannabis use modify the effect of post-traumatic stress disorder on severe depression and suicidal ideation? Evidence from a population-based cross-sectional study of Canadians

Image result for journal of psychopharmacology“Post-traumatic stress disorder sharply increases the risk of depression and suicide. Individuals living with post-traumatic stress disorder frequently use cannabis to treat associated symptoms.

We sought to investigate whether cannabis use modifies the association between post-traumatic stress disorder and experiencing a major depressive episode or suicidal ideation.

This study provides preliminary epidemiological evidence that cannabis use may contribute to reducing the association between post-traumatic stress disorder and severe depressive and suicidal states. There is an emerging need for high-quality experimental investigation of the efficacy of cannabis/cannabinoids for the treatment of post-traumatic stress disorder.”

https://www.ncbi.nlm.nih.gov/pubmed/31684805

https://journals.sagepub.com/doi/10.1177/0269881119882806

“Cannabis could help alleviate depression and suicidality among people with PTSD” https://medicalxpress.com/news/2019-11-cannabis-alleviate-depression-suicidality-people.html

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Using cannabis for pain management after spinal cord injury: a qualitative study.

Image result for spinal cord series and cases

“OBJECTIVES:

To explore why individuals with spinal cord injury (SCI) choose to use cannabis to manage their pain and their experiences in doing so.

RESULTS:

Eight individuals participated in this study. We interpreted six themes that captured the participants’ perspectives regarding their choice to, and perceptions of, using cannabis to manage SCI pain. Participants were motivated to use cannabis when other pain management strategies had been ineffective and were well-informed, knowledgeable cannabis consumers. Participants reported cannabis reduced their pain quickly and enabled them to engage in activities of daily living and participate in life roles without the drowsiness of traditional prescribed pain medication. Despite the positive aspects, participants were concerned about the irregularity of supply and inconsistent dosage.

CONCLUSIONS:

Findings show that cannabis is used to reduce pain after SCI and enable increased community participation. Findings suggest that future studies examining the efficacy of cannabinoids in managing pain include function and participation outcome measures rather than solely focusing on measuring pain intensity. Focusing on meaningful outcomes may contribute to a greater understanding of the experiences of people with SCI.”

https://www.ncbi.nlm.nih.gov/pubmed/31632740

https://www.nature.com/articles/s41394-019-0227-3

“Cannabis helps those with spinal cord injuries escape pain”  https://medicalxpress.com/news/2019-10-cannabis-spinal-cord-injuries-pain.html

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Cannabidiol Counteracts the Psychotropic Side-Effects of Δ-9-Tetrahydrocannabinol in the Ventral Hippocampus Through Bi-Directional Control of ERK1-2 Phosphorylation

Journal of Neuroscience“Evidence suggests that the phytocannabinoids Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) differentially regulate salience attribution and psychiatric risk. The ventral hippocampus (vHipp) relays emotional salience via control of dopamine (DA) neuronal activity states, which are dysregulated in psychosis and schizophrenia. Using in-vivo electrophysiology in male Sprague Dawley rats, we demonstrate that intra-vHipp THC strongly increases ventral tegmental area (VTA) DA neuronal frequency and bursting rates, decreases GABA frequency, and amplifies VTA beta, gamma and epsilon oscillatory magnitudes via modulation of local extracellular signal-regulated kinase phosphorylation (pERK1-2). Remarkably, whereas intra-vHipp THC also potentiates salience attribution in morphine place-preference and fear conditioning assays, CBD co-administration reverses these changes by down-regulating pERK1-2 signaling, as pharmacological re-activation of pERK1-2 blocked the inhibitory properties of CBD. These results identify vHipp pERK1-2 signaling as a critical neural nexus point mediating THC-induced affective disturbances and suggest a potential mechanism by which CBD may counteract the psychotomimetic and psychotropic side-effects of THC.

SIGNIFICANCE STATEMENT

Strains of marijuana with high levels of delta-9-tetrahydrocannabinol (THC) and low levels of cannabidiol (CBD) have been shown to underlie neuropsychiatric risks associated with high potency cannabis use. However, the mechanisms by which CBD mitigates the side effects of THC have not been identified. We demonstrate that THC induces cognitive and affective abnormalities resembling neuropsychiatric symptoms directly in the hippocampus, while dysregulating dopamine activity states and amplifying oscillatory frequencies in the ventral tegmental area via modulation of the extracellular signal-regulated kinase (ERK) signaling pathway. In contrast, CBD co-administration blocked THC-induced ERK phosphorylation, and prevented THC-induced behavioural and neural abnormalities. These findings identify a novel molecular mechanism that may account for how CBD functionally mitigates the neuropsychiatric side-effects of THC.”

https://www.ncbi.nlm.nih.gov/pubmed/31570536

https://www.jneurosci.org/content/early/2019/09/27/JNEUROSCI.0708-19.2019

“Western University researchers show how CBD blocks side-effects of THC in cannabis. Research out of Western University is showing for the first time how cannabidiol (CBD) helps to lessen negative psychiatric side effects of tetrahydrocannabinol (THC) in cannabis.”  https://globalnews.ca/news/5970908/western-university-research-cbd-thc-cannabis/

“Cannabis study reveals how CBD offsets the psychiatric side-effects of THC”  https://neurosciencenews.com/cbd-thc-psychosis-15002/

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Cannabidiol attenuates seizures and EEG abnormalities in Angelman syndrome model mice.

 Image result for J Clin Invest.“Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, lack of speech, ataxia, EEG abnormalities, and epilepsy. Seizures in AS individuals are common, debilitating, and often drug-resistant. Therefore, there is an unmet need for better treatment options.

Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, has antiseizure activity and behavioral benefits in preclinical and clinical studies for some disorders associated with epilepsy, suggesting that the same could be true for AS.

Here we show that acute CBD (100 mg/kg) attenuated hyperthermia- and acoustically-induced seizures in a mouse model of AS. However, neither acute CBD nor a two-weeklong course of CBD administered immediately after a kindling protocol could halt the pro-epileptogenic plasticity observed in AS model mice.

CBD had a dose-dependent sedative effect, but did not have an impact on motor performance. CBD abrogated the enhanced intracortical local field potential power, including delta and theta rhythms observed in AS model mice, indicating that CBD administration could also help normalize the EEG deficits observed in individuals with AS.

Our results provide critical preclinical evidence supporting CBD treatment of seizures and alleviation of EEG abnormalities in AS, and will thus help guide the rational development of CBD as an AS treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/31503547

https://www.jci.org/articles/view/130419

“CBD Could Help Treat Angelman Syndrome, Says Study”   https://www.analyticalcannabis.com/articles/cbd-could-help-treat-angelman-syndrome-says-study-311798

“Medical marijuana saved the life of 8 year old boy with Angelman Syndrome”   http://www.chicagonow.com/soapbox-momma/2016/05/medical-marijuana-saved-the-life-of-8-year-old-boy-with-angelman-syndrome/

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Role of the endocannabinoidome in human and mouse atherosclerosis.

“The Endocannabinoid (eCB) system and its role in many physiological and pathological conditions is well described and accepted, and includes cardiovascular disorders. However, the eCB system has been expanded to an “-ome”; the endocannabinoidome (eCBome) that includes endocannabinoid-related mediators, their protein targets and metabolic enzymes, many of which significantly impact upon cardiometabolic health. These recent discoveries are here summarized with a special focus on their potential involvement in atherosclerosis. We described the role of classical components of the eCB system (eCBs, CB1 and CB2 receptors) and eCB-related lipids, their regulatory enzymes and molecular targets in atherosclerosis. Furthermore, since increasing evidence points to significant cross-talk between the eCBome and the gut microbiome and the gut microbiome and atherosclerosis, we explore the possibility that a gut microbiome – eCBome axis has potential implications in atherosclerosis.”

https://www.ncbi.nlm.nih.gov/pubmed/31448709

http://www.eurekaselect.com/174465/article

“Oral cannabinoid therapy reduces progression of atherosclerosis”  https://www.medscape.com/viewarticle/787468

“The active ingredient in marijuana that produces changes in brain messages appears to fight atherosclerosis — a hardening of the arteries.” https://www.webmd.com/heart-disease/news/20050406/marijuana-chemical-fights-hardened-arteries

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