Drug repurposing and emerging adjunctive treatments for schizophrenia.

“Schizophrenia is a frequent disorder, which substantially impairs patients’ quality of life. Moreover, the burden of illness for patients, their families and for the society, in general, is substantial.

Given the current failure of a number of mechanistically new drugs, repurposed compounds may serve as alternative and/or adjunctive agents for schizophrenic patients and for treatment refractory patients in particular. Anti-inflammatory drugs, as well as N-acetylcysteine, a precursor of the major antioxidant glutathione, hormones, glutamatergic and nicotinergic compounds, ‘nutraceuticals’ (e.g., ω-3 fatty acids) and cannabidiol, an endocannabinoid modulator, represent promising agents in this field.”

http://www.ncbi.nlm.nih.gov/pubmed/25866122

A sativex-like combination of phytocannabinoids as a disease-modifying therapy in a viral model of multiple sclerosis.

“Sativex® is an oromucosal spray, containing equivalent amounts of Δ9 -tetrahydrocannabinol (Δ9 -THC) and cannabidiol (CBD)-botanical drug substance (BDS), and which has been approved for the treatment of spasticity and pain associated to multiple sclerosis (MS).

In this study, we investigated whether Sativex® may also serve as a disease-modifying agent in the Theiler’s murine encephalomyelitis virus induced demyelinating disease model of MS…

The data support the therapeutic potential of Sativex® to slow MS progression and its relevance in CNS repair.”

http://www.ncbi.nlm.nih.gov/pubmed/25857324

http://www.thctotalhealthcare.com/category/multiple-sclerosis-ms/

 

Antiepileptic potential of cannabidiol analogs.

“In audiogenic seizure (AGS) susceptible rats, the acute (intraperitoneal and intravenous) dose-response effects of (–)-cannabidiol (CBD) for preventing AGS and for causing rototod neurotoxicity (ROT) were determined.

Also, the anti-AGS and ROT effects of 10 CBD analogs, given in intravenous doses equivalent to the AGS-ED50 (15 mg/kg) and ROT-ID50 (31 mg/kg) of CBD, were ascertained.

Compared to CBD, (–)-CBD diacetate and (–)-4-(2′-olivetyl)-alpha-pinene were equally effective whereas (–)-CBD monomethyl ether, (–)-CBD dimethyl ether, (–)-3′-acetyl-CBD monoacetate, (+)-4-(2′-olivetyl)-alpha-pinene, (–)-and (+)-4-(6′-olivetyl)-alpha-pinene, (+/-)-AF-11, and olivetol were less effective anticonvulsants. Except for (–)- and (+)-4-(2′-olivetyl)-alpha-pinene and olivetol, all analogs showed less ROT than CBD.

Also, CBD and all analogs were not active in tetrahydrocannabinol seizure-susceptible rabbits, the latter a putative model of cannabinoid psychoactivity in humans.

These data suggest anticonvulsant requirements of 2 free phenolic hydroxyl groups, exact positioning of the terpinoid moiety in the resorcinol system and correct stereochemistry.

Moreover, findings of separation of anticonvulsant from neurotoxic and psychoactive activities, notably with CBD diacetate, suggest that additional structural modifications of CBD may yield novel antiepileptic drugs.”

http://www.ncbi.nlm.nih.gov/pubmed/7298873

http://www.thctotalhealthcare.com/category/epilepsy-2/

Differential effect of cannabinol and cannabidiol on THC-induced responses during abstinence in morphine-dependent rats.

“The same dose of cannabinol (CBN) or cannabidiol (CBD) further increased the attenuation of precipitated abstinence signs observed in morphine-dependent rats that also received an acute dose of delta 9-THC. By contrast, rotational behavior (turning), which is observed concomitantly in THC-treated rats during morphine abstinence, was not increased by CBN, but was potentiated by CBD.

These data illustrate differences between psychoinactive cannabinoids in their interaction with delta 9-THC that might be relevant to possible clinical use of Cannabis in narcotic detoxification.”

Cannabidiol, a Major Non-Psychotrophic Cannabis Constituent Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts.

“Cannabinoid ligands regulate bone mass, but skeletal effects of cannabis (marijuana and hashish) have not been reported. Bone fractures are highly prevalent, involving prolonged immobilization and discomfort.

Here we report that the major non-psychoactive cannabis constituent, cannabidiol (CBD), enhances the biomechanical properties of healing rat mid-femoral fractures.

Using Fourier Transform Infrared Spectroscopy we confirmed the increase in collagen crosslink ratio by CBD, which is likely to contribute to the improved biomechanical properties of the fracture callus.

Taken together, these data show that CBD leads to improvement in fracture healing and demonstrate the critical mechanical role of collagen crosslinking enzymes.”

http://www.ncbi.nlm.nih.gov/pubmed/25801536

Δ9-Tetrahydrocannabinol alone and combined with cannabidiol mitigate fear memory through reconsolidation disruption.

“Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the major constituents of the Cannabis sativa plant, which is frequently consumed by subjects exposed to life-threatening situations to relief their symptomatology.

It is still unknown, however, whether THC could also affect the maintenance of an aversive memory formed at that time when taken separately and/or in conjunction with CBD. The present study sought to investigate this matter at a preclinical level.

We report that THC (0.3-10mg/kg, i.p.) was able to disrupt the reconsolidation of a contextual fear memory, resulting in reduced conditioned freezing expression for over 22 days. This effect was dependent on activation of cannabinoid type-1 receptors located in prelimbic subregion of the medial prefrontal cortex and on memory retrieval/reactivation.

Since CBD may counteract the negative psychotropic effects induced by THC and has been shown to be a reconsolidation blocker, we then investigated and demonstrated that associating sub-effective doses of these two compounds was equally effective in attenuating fear memory maintenance in an additive fashion and in a dose ratio of 10 to 1, which contrasts with that commonly found in C. sativa recreational samples.

Of note, neither THC alone nor CBD plus THC interfered with anxiety-related behaviors and locomotor activity, as assessed in the elevated plus-maze test, at a time point coinciding with that used to evaluate their effects on memory reconsolidation.

Altogether, present findings suggest a potential therapeutic value of using THC and/or CBD to mitigate a dysfunctional aversive memory through reconsolidation disruption in post-traumatic stress disorder patients.”

http://www.ncbi.nlm.nih.gov/pubmed/25799920

http://www.thctotalhealthcare.com/category/post-traumatic-stress-disorder-ptsd/

Cannabidiol, a non-psychoactive cannabinoid, leads to EGR2-dependent anergy in activated encephalitogenic T cells.

“Cannabidiol (CBD), the main non-psychoactive cannabinoid, has been previously shown by us to ameliorate clinical symptoms and to decrease inflammation in myelin oligodendrocyte glycoprotein (MOG)35-55-induced mouse experimental autoimmune encephalomyelitis model of multiple sclerosis as well as to decrease MOG35-55-induced T cell proliferation and IL-17 secretion. However, the mechanisms of CBD anti-inflammatory activities are unclear…

Our data suggests that CBD exerts its immunoregulatory effects via induction of CD4(+)CD25(-)CD69(+)LAG3(+) cells in MOG35-55-activated APC/TMOG co-cultures. This is accompanied by EGR2-dependent anergy of stimulated TMOG cells as well as a switch in their intracellular STAT3/STAT5 activation balance leading to the previously observed decrease in Th17 activity.”

http://www.ncbi.nlm.nih.gov/pubmed/25779454

Cannabinoid Replacement Therapy (CRT): Nabiximols (Sativex) as a novel treatment for cannabis withdrawal.

“Cannabis is a common recreational drug that is generally considered to have low addictive potential.

However an increasing number of cannabis users are seeking treatment for dependence on the drug.

There is interest in using agonist (substitution) pharmacotherapies to treat cannabis dependence and here we outline a novel approach involving a buccal spray (Nabiximols) that contains tetrahydrocannabinol (THC) and cannabidiol (CBD).

We review recent research with Nabiximols and highlight findings relevant to clinical practice.”

http://www.ncbi.nlm.nih.gov/pubmed/25777582

Cost-effectiveness of Sativex in multiple sclerosis spasticity: new data and application to Italy.

“This study aims to evaluate the cost-effectiveness of Sativex® (9-delta-tetrahydrocannabinol plus cannabidiol oromucosal spray) when used as add-on therapy for management of resistant MS-related spasticity in the context of the Italian healthcare system…

Sativex can be regarded as a cost-effective treatment option for patients with MS-related spasticity in Italy.”

http://www.ncbi.nlm.nih.gov/pubmed/25771713

http://www.thctotalhealthcare.com/category/multiple-sclerosis-ms/

Safety and Pharmacokinetics of Oral Cannabidiol When Administered Concomitantly With Intravenous Fentanyl in Humans.

“Objectives: Cannabidiol (CBD) is hypothesized as a potential treatment for opioid addiction, with safety studies an important first step for medication development. We determined CBD safety and pharmacokinetics when administered concomitantly with a high-potency opioid in healthy subjects.

Conclusions: Cannabidiol does not exacerbate adverse effects associated with intravenous fentanyl administration. Coadministration of CBD and opioids was safe and well tolerated. These data provide the foundation for future studies examining CBD as a potential treatment for opioid abuse.”

http://journals.lww.com/journaladdictionmedicine/Abstract/publishahead/Safety_and_Pharmacokinetics_of_Oral_Cannabidiol.99700.aspx