Cannabinoids in the Treatment of Neurological Disorders

“The force of the recent explosion of largely unproven and unregulated cannabis-based preparations on medical therapeutics may have its greatest impact in the field of neurology.

Paradoxically, for 10 millennia this plant has been an integral part of human cultivation, where it was used for its fibers long before its pharmacological properties.

With regard to the latter, cannabis was well known to healers from China and India thousands of years ago; Greek and Roman doctors during classic times; Arab doctors during the Middle Ages; Victorian and Continental physicians in the nineteenth century; American doctors during the early twentieth century; and English doctors until 1971 when a variety of nonevidence-based remedies were removed from the British Pharmaceutical Codex.

The clinical data on cannabis therapeutics are meager and the vast majority are formed by surveys or small studies that are underpowered and/or suffer from multiple methodological flaws, often by virtue of limited research funding for nonaddiction-focused studies. Thus, we know relatively little about the clinical efficacy of cannabinoids for the various neurological disorders for which historical nonscientific and medical literature have advocated its use.

The relative scarcity of proven cannabis-based therapies is not due to data that show that cannabinoids are ineffective or unsafe, but rather reflects a poverty of medical interest and a failure by pharmaceutical companies arising from regulatory restrictions compounded by limits for patent rights on plant cannabinoid-containing preparations that have been used medicinally for millennia, as is the case for most natural products.

We are pleased to have gathered many of the world’s experts together on the basic biology of cannabinoids, as well as their potential role in treating neurologic and psychiatric disorders…

We hope that this issue of Neurotherapeutics will serve to mark the bounds of verifiable scientific knowledge of cannabinoids in the treatment of neuropsychiatric and neurological disorders. At the same time, our contributors have also helped identify areas for future research, as well as the strategies needed to move our base of knowledge forward.

We hope that this volume will help to accelerate the pace of the appropriately focused and productive research and double-blind placebo-controlled randomized trials to the point at which the care of patients is informed by valid data and not just anecdote.”

http://link.springer.com/article/10.1007/s13311-015-0388-0/fulltext.html

Pregnenolone can protect the brain from cannabis intoxication.

“Pregnenolone is considered the inactive precursor of all steroid hormones, and its potential functional effects have been largely uninvestigated.

The administration of the main active principle of Cannabis sativa (marijuana), Δ(9)-tetrahydrocannabinol (THC), substantially increases the synthesis of pregnenolone in the brain via activation of the type-1 cannabinoid (CB1) receptor.

Pregnenolone then, acting as a signaling-specific inhibitor of the CB1 receptor, reduces several effects of THC.

This negative feedback mediated by pregnenolone reveals a previously unknown paracrine/autocrine loop protecting the brain from CB1 receptor overactivation that could open an unforeseen approach for the treatment of cannabis intoxication and addiction.

These data indicate that THC increases pregnenolone through activation of the CB1 receptor…

In conclusion, this new understanding of the role of pregnenolone has the potential to generate new therapies for cannabis dependence.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057431/

The use of cannabinoids as anticancer agents.

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“It is well-established that cannabinoids exert palliative effects on some cancer-associated symptoms. In addition evidences obtained during the last fifteen years support that these compounds can reduce tumour growth in animal models of cancer.

Cannabinoids have been shown to activate an ER-stress related pathway that leads to the stimulation of autophagy-mediated cancer cell death.

In addition, cannabinoids inhibit tumour angiogenesis and decrease cancer cell migration.

The mechanisms of resistance to cannabinoid anticancer action as well as the possible strategies to develop cannabinoid-based combinational therapies to fight cancer have also started to be explored.

In this review we will summarize these observations (that have already helped to set the bases for the development of the first clinical studies to investigate the potential clinical benefit of using cannabinoids in anticancer therapies) and will discuss the possible future avenues of research in this area.” http://www.ncbi.nlm.nih.gov/pubmed/26071989

“… cannabinoids have been shown to alleviate nausea and vomit induced by chemotherapy and several cannabinoid-based medicines [Marinol (THC) and Cesamet (nabilone, a synthetic analogue of THC)] are approved for this purpose. Cannabinoids also inhibit pain, and Sativex (a standardized cannabis extract) has been approved in Canada for the treatment of cancer-associated pain. Other potential palliative effects of cannabinoids in oncology include appetite stimulation and attenuation of wasting. In addition to these palliative actions of cannabinoids in cancer patients, THC and other cannabinoids exhibit antitumour effects in animal models of cancer… a large body of scientific evidences strongly support THC and other cannabinoid agonists exert anticancer actions in preclinical models of cancer… In conclusion there exist solid scientific evidences supporting that cannabinoids exhibit a remarkable anticancer activity in preclinical models of cancer. Since these agents also show an acceptable safety profile, clinical studies aimed at testing them as single agents or in combinational therapies are urgently needed.” http://www.sciencedirect.com/science/article/pii/S0278584615001190

Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome.

“There is a great need for safe and effective therapies for treatment of infantile spasms (IS) and Lennox-Gastaut syndrome (LGS). Based on anecdotal reports and limited experience in an open-label trial, cannabidiol (CBD) has received tremendous attention as a potential treatment for pediatric epilepsy, especially Dravet syndrome.

We sought to document the experiences of children with IS and/or LGS who have been treated with CBD-enriched cannabis preparations.

Perceived efficacy and tolerability were similar across etiologic subgroups.

Eighty-five percent of all parents reported a reduction in seizure frequency, and 14% reported complete seizure freedom.

Reported side effects were far less common during CBD exposure, with the exception of increased appetite (30%).

A high proportion of respondents reported improvement in sleep (53%), alertness (71%), and mood (63%) during CBD therapy… this study suggests a potential role for CBD in the treatment of refractory childhood epilepsy including IS and LGS…”

http://www.ncbi.nlm.nih.gov/pubmed/25935511

“Safety and side effects of cannabidiol, a Cannabis sativa constituent.”  http://www.ncbi.nlm.nih.gov/pubmed/22129319

“Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa…” http://www.ncbi.nlm.nih.gov/pubmed/19690824

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

Cannabinoids Inhibit T-cells via Cannabinoid Receptor 2 in an in vitro Assay for Graft Rejection, the Mixed Lymphocyte Reaction

Logo of nihpa

 

“Cannabinoids are known to have anti-inflammatory and immunomodulatory properties.

Cannabinoid receptor 2 (CB2) is expressed mainly on leukocytes and is the receptor implicated in mediating many of the effects of cannabinoids on immune processes.

This study tested the capacity of Δ9-tetrahydrocannabinol (Δ9-THC) and of two CB2-selective agonists to inhibit the murine Mixed Lymphocyte Reaction (MLR), an in vitro correlate of graft rejection following skin and organ transplantation. Both CB2-selective agonists and Δ9-THC significantly suppressed the MLR in a dose dependent fashion…

Together, these data support the potential of this class of compounds as useful therapies to prolong graft survival in transplant patients.

Cannabinoids were reported to have effects on immune responses as early as the 1970s, but the basis for this activity was not understood until the cannabinoid receptors were cloned

Ideally, the anatomically disparate expression of CB1 and CB2 would allow for the use of compounds selective for CB2, and thus eliminate the unwanted psychoactive effects from CB1 activation, while maintaining the anti-inflammatory and immunosuppressive properties.

CB2-selective cannabinoids have been proposed as possible candidates to block graft rejection.

The results presented in this paper show that Δ9-THC, a mixed CB1/CB2 agonist, and two CB2-selective agonists can inhibit the Mixed Lymphocyte Reaction (MLR), an in vitro correlate of organ and skin graft rejection.”

 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864984/

Promising cannabinoid-based therapies for Parkinson’s disease: motor symptoms to neuroprotection.

“Parkinson’s disease (PD) is a slow insidious neurological disorder characterized by a loss of dopaminergic neurons in the midbrain. Although several recent preclinical advances have proposed to treat PD, there is hardly any clinically proved new therapeutic for its cure.

Increasing evidence suggests a prominent modulatory function of the cannabinoid signaling system in the basal ganglia. Hence, use of cannabinoids as a new therapeutic target has been recommended as a promising therapy for PD.

The elements of the endocannabinoid system are highly expressed in the neural circuit of basal ganglia wherein they bidirectionally interact with dopaminergic, glutamatergic, and GABAergic signaling systems.

As the cannabinoid signaling system undergoes a biphasic pattern of change during progression of PD, it explains the motor inhibition typically observed in patients with PD.

Cannabinoid agonists such as WIN-55,212-2 have been demonstrated experimentally as neuroprotective agents in PD, with respect to their ability to suppress excitotoxicity, glial activation, and oxidative injury that causes degeneration of dopaminergic neurons.

Additional benefits provided by cannabinoid related compounds including CE-178253, oleoylethanolamide, nabilone and HU-210 have been reported to possess efficacy against bradykinesia and levodopa-induced dyskinesia in PD.

Despite promising preclinical studies for PD, use of cannabinoids has not been studied extensively at the clinical level. In this review, we reassess the existing evidence suggesting involvement of the endocannabinoid system in the cause, symptomatology, and treatment of PD. We will try to identify future threads of research that will help in the understanding of the potential therapeutic benefits of the cannabinoid system for treating PD.”

http://www.ncbi.nlm.nih.gov/pubmed/25888232

“To conclude, development of safe, effective cannabis-based medicines targeting different mechanisms may have a significant impact in PD therapy.”

Full-text: http://www.molecularneurodegeneration.com/content/10/1/17

http://www.thctotalhealthcare.com/category/parkinsons-disease/

Endocannabinoid System

Wiley

“The endocannabinoid system (ECS) is defined as the signalling system composed of: (1) the two G‐protein‐coupled receptors known as cannabinoid receptors of type‐1 and ‐2 (CB1 and CB2); (2) the two most studied endogenous agonists of such receptors, the endocannabinoids anandamide (N‐arachidonoyl‐ethanolamine) and 2‐AG (2‐arachidonoyl‐glycerol); (3) enzymes and other proteins regulating the tissue levels of endocannabinoids; and (4) enzymes and other proteins that, together with endocannabinoids, regulate the activity of cannabinoid receptors.

A key role of the ECS is emerging in the control not only of central and peripheral nervous system functions, but also of most aspects of mammalian physiology, including energy intake, processing and storage, the immune response, reproduction and cell fate.

The ECS is also subject to dysregulation, and this seems to contribute to the symptoms and progress of several diseases. Hence, the possibility of developing new therapies starting from our increasing knowledge of the ECS is discussed.”

http://www.els.net/WileyCDA/ElsArticle/refId-a0023403.html

http://www.thctotalhealthcare.com/category/endocannabinoid-system/

The potential of inhibitors of endocannabinoid metabolism as anxiolytic and antidepressive drugs-A practical view.

“The endocannabinoid system, comprising cannabinoid CB1 and CB2 receptors, their endogenous ligands anandamide and 2-arachidonoylglyerol, and their synthetic and metabolic enzymes, are involved in many biological processes in the body, ranging from appetite to bone turnover.

Compounds inhibiting the breakdown of anandamide and 2-arachidonoylglycerol increase brain levels of these lipids and thus modulate endocannabinoid signalling.

In the present review, the preclinical evidence that these enzymes are good targets for development of novel therapies for anxiety and depression are discussed from a practical, rather than mechanistic, point of view.

It is concluded that the preclinical data are promising, albeit tempered by problems of tolerance as well as effects upon learning and memory for irreversible monoacylglycerol lipase inhibitors, and limited by a focus upon male rodents alone.

Clinical data so far has been restricted to safety studies with inhibitors of anandamide hydrolysis and a hitherto unpublished study on such a compound in elderly patients with major depressive disorders, but under the dose regimes used, they are well tolerated and show no signs of “cannabis-like” behaviours.”

http://www.ncbi.nlm.nih.gov/pubmed/25791296

Molecular Mechanisms of Cannabinoid Protection from Neuronal Excitotoxicity

“Cannabinoids protect neurons from excitotoxic injury…

Endogenous or exogenous cannabinoids have shown neuroprotective effects…

The main finding reported here is that cannabinoids protect neurons from excitotoxic injury by a mechanism that involves the activation of CB1R and inhibition of NOS and PKA….

Cannabinoid receptor agonist drugs protect neurons…

By identifying the signaling pathways responsible for cannabinoid effects in animal models of disease and their human counterparts, it may be possible to design more specific and therefore more efficacious cannabinoid-based therapies.”

http://molpharm.aspetjournals.org/content/69/3/691.long

Delta9-tetrahydrocannabinol protects hippocampal neurons from excitotoxicity. http://www.ncbi.nlm.nih.gov/pubmed/17140550

Interactions of the opioid and cannabinoid systems in reward: Insights from knockout studies.

“The opioid system consists of three receptors, mu, delta, and kappa, which are activated by endogenous opioid peptides (enkephalins, endorphins, and dynorphins).

The endogenous cannabinoid system comprises lipid neuromodulators (endocannabinoids), enzymes for their synthesis and their degradation and two well-characterized receptors, cannabinoid receptors CB1 and CB2.

These systems play a major role in the control of pain as well as in mood regulation, reward processing and the development of addiction.

Both opioid and cannabinoid receptors are coupled to G proteins and are expressed throughout the brain reinforcement circuitry.

A better understanding of opioid-cannabinoid interactions may provide novel strategies for therapies in addicted individuals.”

http://www.ncbi.nlm.nih.gov/pubmed/25698968