Category Archives: Anxiety

Cannabinoid facilitation of fear extinction memory recall in humans.

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“Animal studies have shown that activation of the cannabinoid system during extinction learning enhances fear extinction and its retention. Specifically, CB1 receptor agonists, such as Δ9-tetrahydrocannibinol (THC), can facilitate extinction recall by preventing recovery of extinguished fear…

 We conducted a study using a randomized, double-blind, placebo-controlled, between-subjects design, coupling a standard Pavlovian fear extinction paradigm and simultaneous skin conductance response (SCR) recording with an acute pharmacological challenge with oral dronabinol (synthetic THC) or placebo (PBO) 2 h prior to extinction learning in 29 healthy adult volunteers (THC = 14; PBO = 15) and tested extinction retention 24 h after extinction learning.

Compared to subjects that received PBO, subjects that received THC showed low SCR to a previously extinguished CS when extinction memory recall was tested 24 h after extinction learning, suggesting that THC prevented the recovery of fear.

These results provide the first evidence that pharmacological enhancement of extinction learning is feasible in humans using cannabinoid system modulators, which may thus warrant further development and clinical testing. This article is part of a Special Issue entitled ‘Cognitive Enhancers’.”

http://www.ncbi.nlm.nih.gov/pubmed/22796109

Therapeutic potential of cannabinoid medicines.

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Drug Testing and Analysis

“Cannabis was extensively used as a medicine throughout the developed world in the nineteenth century but went into decline early in the twentieth century ahead of its emergence as the most widely used illicit recreational drug later that century. Recent advances in cannabinoid pharmacology alongside the discovery of the endocannabinoid system (ECS) have re-ignited interest in cannabis-based medicines.

The ECS has emerged as an important physiological system and plausible target for new medicines. Its receptors and endogenous ligands play a vital modulatory role in diverse functions including immune response, food intake, cognition, emotion, perception, behavioural reinforcement, motor co-ordination, body temperature, wake/sleep cycle, bone formation and resorption, and various aspects of hormonal control. In disease it may act as part of the physiological response or as a component of the underlying pathology.

In the forefront of clinical research are the cannabinoids delta-9-tetrahydrocannabinol and cannabidiol, and their contrasting pharmacology will be briefly outlined. The therapeutic potential and possible risks of drugs that inhibit the ECS will also be considered. This paper will then go on to review clinical research exploring the potential of cannabinoid medicines in the following indications: symptomatic relief in multiple sclerosis, chronic neuropathic pain, intractable nausea and vomiting, loss of appetite and weight in the context of cancer or AIDS, psychosis, epilepsy, addiction, and metabolic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/24006213

http://onlinelibrary.wiley.com/doi/10.1002/dta.1529/abstract

Cannabinoids and glucocorticoids modulate emotional memory after stress.

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“Bidirectional and functional relationships between glucocorticoids and the endocannabinoid system have been demonstrated. Here, I review the interaction between the endocannabinoid and glucocorticoid/stress systems. Specifically, stress is known to produce rapid changes in endocannabinoid signaling in stress-responsive brain regions. In turn, the endocannabinoid system plays an important role in the downregulation and habituation of hypothalamic-pituitary-adrenocortical (HPA) axis activity in response to stress. Glucocorticoids also recruit the endocannabinoid system to exert rapid negative feedback control of the HPA axis during stress. It became increasingly clear, however, that cannabinoid CB1 receptors are also abundantly expressed in the basolateral amygdala (BLA) and other limbic regions where they modulate emotional arousal effects on memory.

 Enhancing cannabinoids signaling using exogenous CB1 receptor agonists prevent the effects of acute stress on emotional memory.

 I propose a model suggesting that the ameliorating effects of exogenously administered cannabinoids on emotional learning after acute stress are mediated by the decrease in the activity of the HPA axis via GABAergic mechanisms in the amygdala.”

http://www.ncbi.nlm.nih.gov/pubmed/23954749

A Brief History of Medical Marijuana – TIME

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“Should Professors Cheech and Chong ever receive university tenure teaching the medical history of their favorite subject, the course pack would be surprisingly thick.

As early as 2737 B.C., the mystical Emperor Shen Neng of China was prescribing marijuana tea for the treatment of gout, rheumatism, malaria and, oddly enough, poor memory. The drug’s popularity as a medicine spread throughout Asia, the Middle East and down the eastern coast of Africa, and certain Hindu sects in India used marijuana for religious purposes and stress relief. Ancient physicians prescribed marijuana for everything from pain relief to earache to childbirth…

By the late 18th century, early editions of American medical journals recommend hemp seeds and roots for the treatment of inflamed skin, incontinence and venereal disease. Irish doctor William O’Shaughnessy first popularized marijuana’s medical use in England and America. As a physician with the British East India Company, he found marijuana eased the pain of rheumatism and was helpful against discomfort and nausea in cases of rabies, cholera and tetanus.”

http://content.time.com/time/health/article/0,8599,1931247,00.html

The endocannabinoid system and its therapeutic exploitation.

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Image result for Nat Rev Drug Discov.

“The term ‘endocannabinoid’ – originally coined in the mid-1990s after the discovery of membrane receptors for the psychoactive principle in Cannabis, Delta9-tetrahydrocannabinol and their endogenous ligands – now indicates a whole signalling system that comprises cannabinoid receptors, endogenous ligands and enzymes for ligand biosynthesis and inactivation. This system seems to be involved in an ever-increasing number of pathological conditions. With novel products already being aimed at the pharmaceutical market little more than a decade since the discovery of cannabinoid receptors, the endocannabinoid system seems to hold even more promise for the future development of therapeutic drugs. We explore the conditions under which the potential of targeting the endocannabinoid system might be realized in the years to come.”  http://www.ncbi.nlm.nih.gov/pubmed/15340387

http://www.nature.com/nrd/journal/v3/n9/full/nrd1495.html

Smoking Cannabis Reduces Pain, Helps Sleep And Improves Mood For Those With Chronic Symptoms

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“For patients with chronic (long-term) neuropathic pain, smoking cannabis was found to reduce symptoms of pain, improve mood and help sleep, a report published in CMAJ (Canadian Medical Journal Association) revealed. When damage or dysfunction of the nervous system results in chronic neuropathic pain, patients have few treatment options, such as antidepressants, local anesthetics, anticonvulsants or opioids. However, these medications often have undesirable side effects and do not work for everybody.

The authors inform that oral cannabinoids have been effective in reducing the symptoms of some types of pain. However, they many have different effects and risks compared to smoked cannabis.

Investigators from McGill University Health Centre (MUHC) and McGill University carried out a randomized, controlled trial to determine the analgesic effect of smoked cannabis in 21 patients, aged 18 years or more, all of them with chronic neuropathic pain. THC levels (drug potencies) were divided into 2.5%, 6% and 9.4%. Some participants also received a placebo (0%).

The researchers inform that there was a correlation between increased THC content and better sleep quality. Symptoms of depression and/or anxiety were also reduced at 9.5% THC level.”

More: http://www.medicalnewstoday.com/articles/199376.php

Cannabinoids ameliorate impairments induced by chronic stress to synaptic plasticity and short-term memory.

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“Repeated stress is one of the environmental factors that precipitates and exacerbates mental illnesses like depression and anxiety as well as cognitive impairments. We have previously shown that cannabinoids can prevent the effects of acute stress on learning and memory.

Here we aimed to find whether chronic cannabinoid treatment would alleviate the long-term effects of exposure to chronic restraint stress on memory and plasticity as well as on behavioral and neuroendocrine measures of anxiety and depression. Late adolescence rats were exposed to chronic restraint stress for two weeks followed each day by systemic treatment with vehicle or with the CB1/2 receptor agonist WIN55,212-2 (1.2 mg/kg). Thirty days after the last exposure to stress, rats demonstrated impaired long-term potentiation (LTP) in the ventral subiculum (vSub)-nucleus accumbens (NAc) pathway, impaired performance in the prefrontal cortex (PFC)-dependent object recognition task and the hippocampal-dependent spatial version of this task, increased anxiety levels, and significantly reduced expression of glucocorticoid receptors (GRs) in the amygdala, hippocampus, PFC and NAc. Chronic WIN55,212-2 administration prevented the stress-induced impairment in LTP levels and in the spatial task, with no effect on stress-induced alterations in unconditioned anxiety levels or GR levels. The CB1 antagonist AM251 (0.3 mg/kg) prevented the ameliorating effects of WIN55,212-2 on LTP and short-term memory. Hence, the beneficial effects of WIN55,212-2 on memory and plasticity are mediated by CB1 receptors and are not mediated by alterations in GR levels in the brain areas tested.

 Our findings suggest that cannabinoid receptor activation could represent a novel approach to the treatment of cognitive deficits that accompany a variety of stress-related neuropsychiatric disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/23426383

Cannabidiol Inhibits Growth and Induces Programmed Cell Death in Kaposi Sarcoma–Associated Herpesvirus-Infected Endothelium

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“Kaposi sarcoma is the most common neoplasm caused by Kaposi sarcoma–associated herpesvirus (KSHV). Current treatments for Kaposi sarcoma can inhibit tumor growth but are not able to eliminate KSHV from the host. When the host’s immune system weakens, KSHV begins to replicate again, and active tumor growth ensues. New therapeutic approaches are needed.

Cannabidiol (CBD), a plant-derived cannabinoid, exhibits promising antitumor effects without inducing psychoactive side effects. CBD is emerging as a novel therapeutic for various disorders, including cancer.

In this study, we investigated the effects of CBD both on the infection of endothelial cells (ECs) by KSHV and on the growth and apoptosis of KSHV-infected ECs, an in vitro model for the transformation of normal endothelium to Kaposi sarcoma….

Cannabidiol (CBD) was first isolated in 1940. It is a major component of the plant Cannabis sativa, which is also the source of Δ9-tetrahydrocannabinol (Δ9-THC). Due to its multiple biological activities, CBD has been identified as a potential clinical agent. Moreover, CBD affects these activities without the psychoactive side effects that typify Δ9-THC. Recent studies have documented the potential antitumorigenic properties of CBD in the treatment of various neoplasms, including breast cancer, lung cancer, bladder cancer, glioblastoma,and leukemia.CBD induces these effects through a variety of mechanisms and signaling pathways

CBD has been evaluated clinically for the treatment of various conditions, including anxiety, psychosis, and pain. In contrast to other members of the cannabinoid family, CBD has a strong safety profile and induces no psychotropic effects.Therefore, it has become an attractive agent in the search for new anticancer therapies.Our current study demonstrated that CBD preferentially enhanced apoptosis and inhibited the proliferation of KSHV-infected endothelial cells. This selective targeting of KSHV-induced neoplasia suggests that CBD may have a desirable therapeutic index when used to treat cancer. Moreover, a recent study demonstrated that CBD can be delivered effectively by nasal and transdermal routes, which may be particularly valuable for the treatment of Kaposi sarcoma oral or skin lesions.”

Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527984/

Cannabidiol Relieves Psychosis in Schizophrenia, Why is it Illegal?

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“A molecule in cannabis (CBD) has shown to relieve anxiety and symptoms of psychosis in people diagnosed with schizophrenia, though many patients are denied or discouraged from this medicine with fewer side effects than pharmaceutical products because the DEA has deemed the cannabis plant to be “illegal”. The U.S. government needs to answer “why?” this medicine warrents time in prison when nobody is being harmed.

 Investigators concluded, “Our results provide evidence that the non-cannabimimetic constituent of marijuana, cannabidiol, exerts clinically relevant antipsychotic effects that are associated with marked tolerability and safety, when compared with current medications. … The results … potentially represent a completely new mechanism in the treatment of schizophrenia.”

 “Studies have suggested a wide range of possible therapeutic effects of cannabidiol on several conditions, including Parkinson’s disease, Alzheimer’s disease, cerebral ischemia, diabetes, rheumatoid arthritis, other inflammatory diseases, nausea and cancer,” Zuardi writes. Let’s look at a few of these in detail, shall we?

1. Antiepileptic action
“In 1973, a Brazilian group reported that CBD was active in … blocking convulsions produced in experimental animals.”

2. Sedative action
“In humans with insomnia, high doses of CBD increased sleep duration compared to placebo.”

3. Anxiolytic action
“CBD induce[s] a clear anxiolytic effect and a pattern of cerebral activity compatible with an anxiolytic activity.”

4. Antipsychcotic action
“[C]linical studies suggest that CBD is an effective, safe and well-tolerated alternative treatment for schizophrenic patients.”

5. Antidystonic action
“CBD … had antidystonic effects in humans when administered along with standard medication to five patients with dystonia, in an open study.”

6. Antioxidative action
“[I]t was demonstrated that CBD can reduce hydroperoxide-induced oxidative damage as well as or better than other antioxidants. CBD was more protective against glutamate neurotoxicity than either ascorbate or a-tocopherol, indicating that this drug is a potent antioxidant.”

7. Neuroprotective action
“A marked reduction in the cell survival was observed following exposure of cultured rat pheochromocytoma PC12 cells to beta-A peptide. Treatment of the cells with CBD prior to beta-A exposure significantly elevated the cell survival.”

8. Antiinflammatory action
“CBD, administered i.p. or orally, has blocked the progression of arthritis.”

9. Cardioprotective action
“CBD induces a substantial cardioprotective effect.”

10. Action on diabetes
“CBD treatment of NOD (non-obese diabetic) mice before the development of the disease reduced its incidence from 86% in the non-treated control mice to 30% in CBD-treated mice. … It was also observed that administration of CBD to 11-14 week old female NOD mice, which were either in a latent diabetes stage or had initial symptoms of diabetes, ameliorated the manifestations of the disease.”

11. Antiemetic action
“The expression of this conditioned retching reaction was completely suppressed by CBD and delta9-THC, but not by ondansetron, [an] antagonist that interferes with acute vomiting.”

12. Anticancer action
“A study of the effect of different cannabinoids on eight tumor cell lines, in vitro, has clearly indicated that, of the five natural compounds tested, CBD was the most potent inhibitor of cancer cell growth.”

In sum, the past 45 years of scientific study on CBD has revealed the compound to be non-toxic, non-psychoactive, and to possess a multitude of therapeutic properties. Yet, to this day it remains illegal to possess or use (and nearly impossible to study in US clinical trials) simply because it is associated with marijuana.

What possible advancements in medical treatment may have been achieved over the past decades had US government officials chosen to advance — rather than inhibit — clinical research into CBD (which, under federal law, remains a Schedule I drug defined as having “no currently accepted medical use”)? Perhaps it’s time someone asks John Walters or the DEA?” 

Read more: http://rinf.com/alt-news/latest-news/cannabidiol-relieves-psychosis-in-schizophrenia-why-is-it-illegal/17827/

The endocannabinoid system and the treatment of mood and anxiety disorders.

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“The central endocannabinoid system is a neuroactive lipid signalling system in the brain which acts to control neurotransmitter release. The expression patterns of this system throughout limbic regions of the brain ideally situate it to exert regulatory control over emotional behaviour, mood and stress responsivity. A growing body of evidence unequivocally demonstrates that deficits in endocannabinoid signalling may result in depressive and anxiogenic behavioral responses, while pharmacological augmentation of endocannabinoid signalling can produce both antidepressive and anxiolytic behavioral responses. The aim of this review is to summarize current knowledge of the role of the endocannabinoid system in the etiology and treatment of mood and anxiety disorders, such as depression, anxiety and post-traumatic stress disorder.

Collectively, both clinical and preclinical data argue that cannabinoid receptor signalling may be a realistic target in the development of a novel class of agent for the pharmacotherapy of mood and anxiety disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/19839936