Author Archives: David Worrell

Acute Stress Suppresses Synaptic Inhibition and Increases Anxiety via Endocannabinoid Release in the Basolateral Amygdala.

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“Stress and glucocorticoids stimulate the rapid mobilization of endocannabinoids in the basolateral amygdala (BLA).

Cannabinoid receptors in the BLA contribute to anxiogenesis and fear-memory formation. We tested for rapid glucocorticoid-induced endocannabinoid regulation of synaptic inhibition in the rat BLA.

Together, these findings suggest that acute stress causes a long-lasting suppression of synaptic inhibition in BLA neurons via a membrane glucocorticoid receptor-induced release of 2-AG at GABA synapses, which contributes to stress-induced anxiogenesis.

We show that acute stress increases anxiety-like behavior via an endocannabinoid-dependent mechanism centered in the BLA.

The stress-induced endocannabinoid modulation of synaptic transmission in the BLA contributes, therefore, to the stress regulation of anxiety, and may play a role in anxiety disorders of the amygdala.”

http://www.ncbi.nlm.nih.gov/pubmed/27511017

Medical Marijuana-Opportunities and Challenges

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“Over the recent years, public and political opinions have demonstrated increasing support for the legalization of medical marijuana.

To date, 24 states as well as the District of Columbia have legalized cannabis for medical use, 4 states have legalized the recreational use of Marijuana.

Marijuana is derived from the hemp plant Cannabis sativa. Δ-9-tetrahydrocannabinol (THC) is the major psychoactive constituent of cannabis, while cannabidiol (CBD) is the major non-psychoactive constituent. THC is a partial agonist at CB1 and CB2 receptors, while CBD at high levels is an antagonist CB1 and CB2.

CB1 is abundantly expressed in the brain, and CB2 is expressed on immune cells (expression of CB2 on neurons remains controversial). The brain also produces endogenous cannabis-like substances (endocannabinoids) that bind and activate the CB1/CB2 receptors.

There is tremendous interest in harnessing the therapeutic potential of plant-derived and synthetic cannabinoids.

This Editorial provides an overview of diseases that may be treated by cannabinoids.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948749/

Marijuana users do not have increased healthcare utilization: A National Health and Nutrition Examination Survey (NHANES) study

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“There is paucity of data on healthcare utilization due to marijuana use on a national scale.

Our study found no significant association exists between marijuana use and healthcare utilization.

The frequency of marijuana use also does not have significant impact on healthcare utilization.”

http://www.ejinme.com/article/S0953-6205(16)30231-X/fulltext

Effective treatment of spasticity using dronabinol in pediatric palliative care.

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“Cannabis extracts have a wide therapeutic potential but in many countries they have not been approved for treatment in children so far.

We conducted an open, uncontrolled, retrospective study on the administration of dronabinol to determine the value, efficacy, and safety of cannabis-based medicines in the treatment of refractory spasticity in pediatric palliative care.

Sixteen children, adolescents and young adults having complex neurological conditions with spasticity (aged 1.3-26.6 years, median 12.7 years) were treated with dronabinol by our specialized pediatric palliative care team between 01.12.2010 and 30.04.2015 in a home-care setting. Therapeutic efficacy and side effects were closely monitored.

RESULTS:

Drops of the 2.5% oily tetrahydrocannabinol solution (dronabinol) were administered. A promising therapeutic effect was seen, mostly due to abolishment or marked improvement of severe, treatment resistant spasticity (n = 12). In two cases the effect could not be determined, two patients did not benefit. The median duration of treatment was 181 days (range 23-1429 days). Dosages to obtain a therapeutic effect varied from 0.08 to 1.0 mg/kg/d with a median of 0.33 mg/kg/d in patients with a documented therapeutic effect. When administered as an escalating dosage scheme, side effects were rare and only consisted in vomiting and restlessness (one patient each).

No serious and enduring side effects occurred even in young children and/or over a longer period of time.

CONCLUSIONS:

In the majority of pediatric palliative patients the treatment with dronabinol showed promising effects in treatment resistant spasticity.”

http://www.ncbi.nlm.nih.gov/pubmed/27506815

Cannabinoids As Potential Treatment for Chemotherapy-Induced Nausea and Vomiting.

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“Despite the advent of classic anti-emetics, chemotherapy-induced nausea is still problematic, with vomiting being somewhat better managed in the clinic.

If post-treatment nausea and vomiting are not properly controlled, anticipatory nausea-a conditioned response to the contextual cues associated with illness-inducing chemotherapy-can develop. Once it develops, anticipatory nausea is refractive to current anti-emetics, highlighting the need for alternative treatment options.

One of the first documented medicinal uses of Δ(9)-tetrahydrocannabinol (Δ(9)-THC) was for the treatment of chemotherapy-induced nausea and vomiting (CINV), and recent evidence is accumulating to suggest a role for the endocannabinoid system in modulating CINV.

Here, we review studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system in human patients and pre-clinical animal models of nausea and vomiting.”

http://www.ncbi.nlm.nih.gov/pubmed/27507945

A new antipsychotic mechanism of action for cannabidiol

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Totally dope! – A new antipsychotic mechanism of action for cannabidiol, by Anand Gururajan

“The pharmacological strategy for the treatment of schizophrenia has not changed in the six decades since chlorpromazine was introduced in 1952. Although several newer agents have recently gained approval, the mechanism of action of antipsychotics is still largely based on normalising dopaminergic neurotransmission which does not adequately address the symptomatology of a very complex disorder. Moreover, they cause side effects such as extrapyramidal motor symptoms and metabolic syndrome which can worsen the patient condition.

In this regard, preclinical and clinical studies since the ’90s have demonstrated the antipsychotic potential of cannabidiol (CBD), a derivative of the cannabis sativa plant which does not have the adverse psychoactive properties of tetrahydrocannabinol.

In particular, CBD has been shown to be effective in attenuating the positive symptoms of schizophrenia with a negligible side-effect profile.

Accumulating evidence implicates dysfunction of the mammalian target of rapamycin (mTOR) signaling cascade in the pathophysiology of schizophrenia. Thus, in a recent paper, Renard et al. (2016) used the amphetamine (AMPH)-sensitisation protocol in rats to investigate whether the antipsychotic effects of CBD were mediated by its effects on the mTOR cascade. Specifically, they focused on the nucleus accumbens shell (NASh) which has been implicated as a therapeutically relevant ‘hot-spot’ for antipsychotic action and is one of the brain regions targeted by CBD.

Thus, together with the fact that CBD alone had no behavioural effects, the behavioural findings reinforce the potential utility of this cannabinoid as an antipsychotic for the treatment of the positive symptoms of schizophrenia.”

http://medicalxpress.com/news/2016-08-antipsychotic-mechanism-action-cannabidiol.html

Cannabigerol is a novel, well-tolerated appetite stimulant in pre-satiated rats.

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“The appetite-stimulating properties of cannabis are well documented and have been predominantly attributed to the hyperphagic activity of the psychoactive phytocannabinoid, ∆9-tetrahydrocannabinol (∆9-THC).

However, we have previously shown that a cannabis extract devoid of ∆9-THC still stimulates appetite, indicating that other phytocannabinoids also elicit hyperphagia. One possible candidate is the non-psychoactive phytocannabinoid cannabigerol (CBG), which has affinity for several molecular targets with known involvement in the regulation of feeding behaviour.

CBG produced no adverse effects on any parameter in the neuromotor tolerability test battery. In the feeding assay, 120-240 mg/kg CBG more than doubled total food intake and increased the number of meals consumed, and at 240 mg/kg reduced latency to feed. However, the sizes or durations of individual meals were not significantly increased.

CONCLUSIONS:

Here, we demonstrate for the first time that CBG elicits hyperphagia, by reducing latency to feed and increasing meal frequency, without producing negative neuromotor side effects. Investigation of the therapeutic potential of CBG for conditions such as cachexia and other disorders of eating and body weight regulation is thus warranted.”

http://www.ncbi.nlm.nih.gov/pubmed/27503475

The Effect of Muscarinic Receptor Modulators on the Antinociception Induced by CB2 Receptor Agonist, JWH133 in Mice.

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“There is no published study regarding the interaction between muscarinic receptor modulators and antinociception induced by cannabinoidreceptor (CB2) agonist. The effect of pilocarpine (a muscarinic agonist) and atropine (a muscarinic antagonist) on JWH-133 (a CB2 agonist) induced analgesia in mice was studied. First the analgesic effect of JWH-133 (0.001-1 mg/Kg) or pilocarpine (2.5-20 mg/kg) or atropine (0.2-5 mg/kg) was evaluated. Subsequently, the effect of co-administration of pilocarpine (2.5 mg/kg) or atropine (5 mg/kg) and JWH-133 (0.001-1 mg/Kg) were studied too. JWH-133 and pilocarpine provoked antinociception in mice but atropine did not. Pilocarpine potentiated the analgesic effect of JWH-133 but atropine antagonized that. It can be concluded that JWH-133 induced antinociception is affected by muscarinic receptor modulators in mice.”

http://www.ncbi.nlm.nih.gov/pubmed/27504865

The impact of drugs for multiple sclerosis on sleep.

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“Although there is a growing literature on the presence of sleep disorders in multiple sclerosis (MS), few studies have specifically addressed the impact of drugs on sleep of these patients. Moreover, even when sleep is considered, quantitative assessment by standardized questionnaires or polysomnography is lacking.

The studies that have been done highlight that interferon-beta and some symptomatic medications may affect sleep, thus contributing to fatigue, depression, and poor quality of life; conversely, natalizumab and cannabinoids may improve sleep.

Common limitations of the literature reviewed here are small sample size, selection bias, and often a lack of objective outcome measures. Clinicians need to remember to ask about sleep in all MS patients and intervene when appropriate. A systematic approach that takes sleep into account is recommended to enhance recognition and appropriate management of sleep disruption, including disorders related to medication. Consideration of the impact on sleep should also be part of the design of trials of new therapies.”

http://www.ncbi.nlm.nih.gov/pubmed/27503906