A Phase 1, Randomised, Placebo-Controlled, Dose Escalation Study to Investigate the Safety, Tolerability and Pharmacokinetics of Cannabidiol in Fed Healthy Volunteers.

SpringerLink“There is increasing interest in the use of purified cannabidiol (CBD) as a treatment for a wide range of conditions due to its reported anti-inflammatory, anxiolytic, antiemetic and anticonvulsant properties.

OBJECTIVE:

The objective of this study was to assess the safety, tolerability and pharmacokinetics of a single ascending dose of a new lipid-based oral formulation of CBD in healthy volunteers after a high-fat meal.

RESULTS:

CBD was well tolerated in the healthy volunteers (mean age: 24.0 years) treated with a single oral dose of CBD. There were no safety concerns with increasing the dose and the safety profiles of the CBD-treated and placebo-treated subjects were similar. The most frequently reported treatment emergent adverse events (TEAEs) were headache (17%) and diarrhoea (8%). There were no reported serious adverse events (SAEs) and no clinical laboratory findings, vital signs, ECGs or physical examination findings that were reported as TEAEs or were of clinical significance during the study. After a high-fat meal, CBD was detected in plasma samples at 15 min postdose; the median time to maximum plasma concentration (Tmax) was 4 h across all three CBD dose cohorts. The CBD plasma exposure [maximum observed plasma concentration (Cmax) and the area under the concentration-time curve (AUC)] increased in a dose-proportional manner and declined to levels approaching the lower level of quantification by day 8. The terminal elimination half-life was approximately 70 h, suggesting that 2-3 weeks are needed to fully eliminate CBD.

CONCLUSIONS:

This new CBD formulation demonstrated a favourable safety and tolerability profile in healthy volunteers that was consistent with the profiles reported for other purified CBD products. No severe or serious AEs were observed in this study and there were no safety concerns.”

https://www.ncbi.nlm.nih.gov/pubmed/32409982

“Cannabidiol (CBD) is a major nonpsychoactive cannabinoid derived from the Cannabis plant that has attracted significant interest due to its anti-inflammatory, anxiolytic, antiemetic and anticonvulsant properties. The findings of this study contribute to the evolving knowledge of cannabidiol pharmacokinetics and indicate that this new oral lipid-based formulation of cannabidiol is generally safe and well tolerated at all doses studied. No severe or serious AEs were observed and there were no safety concerns.”

https://link.springer.com/article/10.1007%2Fs13318-020-00624-6

Two-weeks treatment with cannabidiol improves biophysical and behavioral deficits associated with experimental type-1 diabetes.

Neuroscience Letters“The prevalence rates of depression and anxiety are at least two times higher in diabetic patients, increasing morbidity and mortality.

Cannabidiol (CBD) has been identified as a therapeutic agent viable to treat diverse psychiatric disorders. Thus, this study aimed to investigate the effect of CBD treatment (once a day for 14 days starting two weeks after diabetes induction; at doses of 0, 3, 10 or 30 mg/kg, i.p.) on depression- and anxiety-like behaviors associated with experimental diabetes induced by streptozotocin (60 mg/kg; i.p.) in rats.

Levels of plasma insulin, blood glucose, and weight gain were evaluated in all experimental groups, including a positive control group treated with imipramine. The rats were tested in the modified forced swimming test (mFST) and elevated plus maze (EPM) test. Besides, the levels of serotonin (5-HT), noradrenaline (NA) and dopamine (DA) in two emotion-related brain regions, the prefrontal cortex (PFC) and hippocampus (HIP) were evaluated using high-pressure liquid chromatography.

Our results showed that CBD treatment (only at the higher dose of 30 mg/kg) reduced the exaggerated depressive- and anxiogenic-like behaviors of diabetic (DBT) rats, which may be associated with altered 5-HT, NA and/or DA levels observed in the PFC and HIP. Treatment with CBD (higher dose) also induced a significant increase in weight gain and the insulin levels (and consequently reduced glycemia) in DBT rats. The long-term CBD effects gave rise to novel therapeutic strategies to limit the physiological and neurobehavioral deficits in DBT rats.

This approach provided evidence that CBD can be useful for treating psychiatry comorbidities in diabetic patients.”

https://www.ncbi.nlm.nih.gov/pubmed/32360935

“Treatment of diabetic rats with cannabidiol induced antidepressant- and anxiolytic-like behaviors.”

https://www.sciencedirect.com/science/article/abs/pii/S0304394020302901?via%3Dihub

Dosage, Efficacy and Safety of Cannabidiol Administration in Adults: A Systematic Review of Human Trials.

“Considering data from in vitro and in vivo studies, cannabidiol (CBD) seems to be a promising candidate for the treatment of both somatic and psychiatric disorders.

The aim of this review was to collect dose(s), dosage schemes, efficacy and safety reports of CBD use in adults from clinical studies.

From the controlled trials, we identified anxiolytic effects with acute CBD administration, and therapeutic effects for social anxiety disorder, psychotic disorder and substance use disorders.

There was evidence to support single dose positive effect on social anxiety disorder, short medium-term effects on symptomatic improvement in schizophrenia and lack of effect in the short medium-term on cognitive functioning in psychotic disorders.

Overall, the administration was well tolerated with mild side effects.”

https://www.ncbi.nlm.nih.gov/pubmed/32231748

https://www.jocmr.org/index.php/JOCMR/article/view/4090

Cannabidiol in sport : ergogenic or else?

Pharmacological Research“In the sports domain, cannabis is prohibited by the World Anti-Doping Agency (WADA) across all sports in competition since 2004. The few studies on physical exercise and cannabis focused on the main compound i.e. Δ9-tetrahydrocannabinol. Cannabidiol (CBD) is another well-known phytocannabinoid present in dried or heated preparations of cannabis. Unlike Δ9-tetrahydrocannabinol, CBD is non-intoxicating but exhibits pharmacological properties that are interesting for medical use.

The worldwide regulatory status of CBD is complex and this compound is still a controlled substance in many countries. Interestingly, however, the World Anti-Doping Agency removed CBD from the list of prohibited substances – in or out of competition – since 2018. This recent decision by the WADA leaves the door open for CBD use by athletes.

In the present opinion article we wish to expose the different CBD properties discovered in preclinical studies that could be further tested in the sport domain to ascertain its utility. Preclinical studies suggest that CBD could be useful to athletes due to its anti-inflammatory, analgesic, anxiolytic, neuroprotective properties and its influence on the sleep-wake cycle. Unfortunately, almost no clinical data are available on CBD in the context of exercise, which makes its use in this context still premature.”

https://www.ncbi.nlm.nih.gov/pubmed/32205233

“Athletes could benefit from CBD to manage pain, inflammation and the swelling processes associated with injury. CBD could be useful to manage anxiety, fear memory process, sleep and sleepiness in athletes. CBD could be interesting for the management of mild traumatic brain injury and chronic traumatic encephalopathy.”

https://www.sciencedirect.com/science/article/abs/pii/S1043661819326143?via%3Dihub

Cannabinoid modulation of corticolimbic activation to threat in trauma-exposed adults: a preliminary study.

 SpringerLink“Excessive fear and anxiety, coupled with corticolimbic dysfunction, are core features of stress- and trauma-related psychopathology, such as posttraumatic stress disorder (PTSD).

Interestingly, low doses of ∆9-tetrahydrocannabinol (THC) can produce anxiolytic effects, reduce threat-related amygdala activation, and enhance functional coupling between the amygdala and medial prefrontal cortex and adjacent rostral cingulate cortex (mPFC/rACC) during threat processing in healthy adults.

Together, these findings suggest the cannabinoid system as a potential pharmacological target in the treatment of excess fear and anxiety. However, the effects of THC on corticolimbic functioning in response to threat have not be investigated in adults with trauma-related psychopathology.

OBJECTIVE:

To address this gap, the present study tests the effects of an acute low dose of THC on corticolimbic responses to threat in three groups of adults: (1) non-trauma-exposed healthy controls (HC; n = 25), (2) trauma-exposed adults without PTSD (TEC; n = 27), and (3) trauma-exposed adults with PTSD (n = 19).

METHODS:

Using a randomized, double-blind, placebo-controlled, between-subjects design, 71 participants were randomly assigned to receive either THC or placebo (PBO) and subsequently completed a well-established threat processing paradigm during functional magnetic resonance imaging.

RESULTS:

In adults with PTSD, THC lowered threat-related amygdala reactivity, increased mPFC activation during threat, and increased mPFC-amygdala functional coupling.

CONCLUSIONS:

These preliminary data suggest that THC modulates threat-related processing in trauma-exposed individuals with PTSD, which may prove advantageous as a pharmacological approach to treating stress- and trauma-related psychopathology.”

https://www.ncbi.nlm.nih.gov/pubmed/32162103

https://link.springer.com/article/10.1007%2Fs00213-020-05499-8

Cannabis and the exocannabinoid and endocannabinoid systems. Their use and controversies.

“Cannabis (marijuana) is one of the most consumed psychoactive substances in the world. The term marijuana is of Mexican origin. The primary cannabinoids that have been studied to date include cannabidiol and delta-9-tetrahydrocannabinol, which is responsible for most cannabis physical and psychotropic effects. Recently, the endocannabinoid system was discovered, which is made up of receptors, ligands and enzymes that are widely expressed in the brain and its periphery, where they act to maintain balance in several homeostatic processes. Exogenous cannabinoids or naturally-occurring phytocannabinoids interact with the endocannabinoid system. Marijuana must be processed in a laboratory to extract tetrahydrocannabinol and leave cannabidiol, which is the product that can be marketed. Some studies suggest cannabidiol has great potential for therapeutic use as an agent with antiepileptic, analgesic, anxiolytic, antipsychotic, anti-inflammatory and neuroprotective properties; however, the findings on cannabinoids efficacy and cannabis-based medications tolerability-safety for some conditions are inconsistent. More scientific evidence is required in order to generate recommendations on the use of medicinal cannabis.”

https://www.ncbi.nlm.nih.gov/pubmed/32091020

http://gacetamedicademexico.com/frame_eng.php?id=348

Effects of short-term cannabidiol treatment on response to social stress in subjects at clinical high risk of developing psychosis.

 “Stress is a risk factor for psychosis and treatments which mitigate its harmful effects are needed.

Cannabidiol (CBD) has antipsychotic and anxiolytic effects.

OBJECTIVES:

We investigated whether CBD would normalise the neuroendocrine and anxiety responses to stress in clinical high risk for psychosis (CHR) patients.

RESULTS:

One-way analysis of variance (ANOVA) revealed a significant effect of group (HC, CHR-P, CHR-CBD (p = .005) on cortisol reactivity as well as a significant (p = .003) linear decrease. The change in cortisol associated with experimental stress exposure was greatest in HC controls and least in CHR-P patients, with CHR-CBD patients exhibiting an intermediate response. Planned contrasts revealed that the cortisol reactivity was significantly different in HC compared with CHR-P (p = .003), and in HC compared with CHR-CBD (p = .014), but was not different between CHR-P and CHR-CBD (p = .70). Across the participant groups (CHR-P, CHR-CBD and HC), changes in anxiety and experience of public speaking stress (all p’s < .02) were greatest in the CHR-P and least in the HC, with CHR-CBD participants demonstrating an intermediate level of change.

CONCLUSIONS:

Our findings show that it is worthwhile to design further well powered studies which investigate whether CBD may be used to affect cortisol response in clinical high risk for psychosis patients and any effect this may have on symptoms.”

https://www.ncbi.nlm.nih.gov/pubmed/31915861

“Antipsychotic effects of CBD have been linked to its effects on levels of the endogenous cannabinoid anandamide (AEA) potentially by inhibiting its catalytic enzyme fatty acid amide hydrolase (FAAH). Recent preclinical work has also suggested that CBD may block the anxiogenic effects of chronic stress that was associated with a concomitant decrease in the expression of FAAH following CBD treatment. To the best of our knowledge, this is the first study to have investigated the effects of short-term treatment with CBD on experimentally induced stress in the context of psychosis risk. Notwithstanding its limitations, the present study provides a strong rationale for future studies to investigate whether CBD may have potential to mitigate the harmful effects of stress in the course of daily life by attenuating the altered neuroendocrine and psychological responses to acute stress in CHR participants.”

https://link.springer.com/article/10.1007%2Fs00213-019-05442-6

Cannabinoids and the endocannabinoid system in anxiety, depression, and dysregulation of emotion in humans.

Image result for ovid journal“This review is to summarize most recent evidence published in the last 18 months on medical and recreational use of cannabis and cannabinoids in relation to anxiety, depression (unipolar and bipolar), and dysregulation of emotions as part of posttraumatic stress disorders (PTSD) and emotionally instable personality disorders.

It also covers the investigation of endocannabinoids as potential biomarkers in these conditions. This is important with increasing medicinal use of cannabinoids and growing social tolerance towards recreational cannabis use.

RECENT FINDINGS:

There is some recent evidence suggesting cannabinoids, cannabidiol or cannabidiol-enriched cannabis preparations have anxiolytic properties. In addition, depression may be worsened by cannabis use, however, randomized controlled trials (RCT) are lacking.

New evidence also suggests that cannabidiol or cannabidiol-enriched cannabis use for PTSD and emotion regulation can induce hyporesponse to fear and stress. Further, several lines of evidence point to the endocannabinoid system as a key player in some of the reviewed disorders, in particular anxiety and PTSD.

SUMMARY:

The most recent evidence for a therapeutic use of cannabinoids in the reviewed conditions is weak and lacking well designed RCTs. However, there is some indication of the role of the endocannabinoid system in these conditions that warrant further studies.”

https://www.ncbi.nlm.nih.gov/pubmed/31714262

https://insights.ovid.com/crossref?an=00001504-900000000-99165

Effects of cannabidiol (CBD) in neuropsychiatric disorders: A review of pre-clinical and clinical findings.

Progress in Molecular Biology and Translational Science“Cannabis sativa (cannabis) is one of the oldest plants cultivated by men. Cannabidiol (CBD) is the major non-psychomimetic compound derived from cannabis. It has been proposed to have a therapeutic potential over a wide range of neuropsychiatric disorders.

In this narrative review, we have summarized a selected number of pre-clinical and clinical studies, examining the effects of CBD in neuropsychiatric disorders. In some pre-clinical studies, CBD was demonstrated to potentially exhibit anti-epileptic, anti-oxidant, anti-inflammatory anti-psychotic, anxiolytic and anti-depressant properties. Moreover, CBD was shown to reduce addictive effects of some drugs of abuse.

In clinical studies, CBD was shown to be safe, well-tolerated and efficacious in mitigating the symptoms associated with several types of seizure disorders and childhood epilepsies.

Given that treatment with CBD alone was insufficient at managing choreic movements in patients with Huntington’s disease, other cannabis-derived treatments are currently being investigated. Patients with Parkinson’s disease (PD) have reported improvements in sleep and better quality of life with CBD; however, to fully elucidate the therapeutic potential of CBD on the symptoms of PD-associated movement disorders, larger scale, randomized, placebo-controlled studies still need to be conducted in the future.

Currently, there are no human studies that investigated the effects of CBD in either Alzheimer’s disease or unipolar depression, warranting further investigation in this area, considering that CBD was shown to have effects in pre-clinical studies.

Although, anxiolytic properties of CBD were reported in the Social Anxiety Disorder, antipsychotic effects in schizophrenia and anti-addictive qualities in alcohol and drug addictions, here too, larger, randomized, placebo-controlled trials are needed to evaluate the therapeutic potential of CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/31601406

https://www.sciencedirect.com/science/article/pii/S187711731930095X?via%3Dihub

Emerging role of cannabinoids and synthetic cannabinoid receptor 1/cannabinoid receptor 2 receptor agonists in cancer treatment and chemotherapy-associated cancer management

Journal of Cancer Research and Therapeutics“Cannabis was extensively utilized for its medicinal properties till the 19th century. A steep decline in its medicinal usage was observed later due to its emergence as an illegal recreational drug.

Advances in technology and scientific findings led to the discovery of delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis, that further led to the discovery of endogenous cannabinoids system consisting of G-protein-coupled receptors – cannabinoid receptor 1 and cannabinoid receptor 2 along with their ligands, mainly anandamide and 2-arachidonoylglycerol.  Endocannabinoid (EC) is shown to be a modulator not only for physiological functions but also for the immune system, endocrine network, and central nervous system.

Medicinal research and meta-data analysis over the last few decades have shown a significant potential for both THC and cannabidiol (CBD) to exert palliative effects. People suffering from many forms of advanced stages of cancers undergo chemotherapy-induced nausea and vomiting followed by severe and chronic neuropathic pain and weight loss.

THC and CBD exhibit effective analgesic, anxiolytic, and appetite-stimulating effect on patients suffering from cancer. Drugs currently available in the market to treat such chemotherapy-induced cancer-related ailments are Sativex (GW Pharmaceutical), Dronabinol (Unimed Pharmaceuticals), and Nabilone (Valeant Pharmaceuticals).

Apart from exerting palliative effects, THC also shows promising role in the treatment of cancer growth, neurodegenerative diseases (multiple sclerosis and Alzheimer’s disease), and alcohol addiction and hence should be exploited for potential benefits.

The current review discusses the nature and role of CB receptors, specific applications of cannabinoids, and major studies that have assessed the role of cannabinoids in cancer management.

Specific targeting of cannabinoid receptors can be used to manage severe side effects during chemotherapy, palliative care, and overall cancer management. Furthermore, research evidences on cannabinoids have suggested tumor inhibiting and suppressing properties which warrant reconsidering legality of the substance.

Studies on CB1 and CB2 receptors, in case of cancers, have demonstrated the psychoactive constituents of cannabinoids to be potent against tumor growth.

Interestingly, studies have also shown that activation of CB1 and CB2 cannabinoid receptors by their respective synthetic agonists tends to limit human cancer cell growth, suggesting the role of the endocannabinoid system as a novel target for treatment of cancers.

Further explorations are required to exploit cannabinoids for an effective cancer management.”

http://www.cancerjournal.net/preprintarticle.asp?id=263538

“Could Cannabis Kill Cancer Cells? A New Study Looks Promising”  https://www.portlandmercury.com/blogtown/2019/08/15/26977361/could-cannabis-kill-cancer-cells-a-new-study-looks-promising

“Study Reviews How Marijuana Compounds Inhibit Tumor Growth And Kill Cancer Cells” https://www.marijuanamoment.net/study-reviews-how-marijuana-compounds-inhibit-tumor-growth-and-kill-cancer-cells/