“The term cannabinoids encompasses compounds produced by the plant Cannabis sativa, such as delta9-tetrahydrocannabinol, and synthetic counterparts. Their actions occur mainly through activation of cannabinoid type 1 (CB1) receptors. Arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG) serve as major endogenous ligands (endocannabinoids) of CB1 receptors. Hence, the cannabinoid receptors, the endocannabinoids, and their metabolizing enzymes comprise the endocannabinoid system. Cannabinoids induce diverse responses on anxiety- and fear-related behaviors. Generally, low doses tend to induce anxiolytic-like effects, whereas high doses often cause the opposite. Inhibition of endocannabinoid degradation seems to circumvent these biphasic effects by enhancing CB1 receptor signaling in a temporarily and spatially restricted manner, thus reducing anxiety-like behaviors. Pharmacological blockade or genetic deletion of CB1 receptors, in turn, primarily exerts anxiogenic-like effects and impairments in extinction of aversive memories. Interestingly, pharmacological blockade of Transient Receptor Potential Vanilloid Type-1 (TRPV1) channel, which can be activated by anandamide as well, has diametrically opposite consequences. This book chapter summarizes and conceptualizes our current knowledge about the role of (endo)cannabinoids in fear and anxiety and outlines implications for an exploitation of the endocannabinoid system as a target for new anxiolytic drugs.”
Tag Archives: cannabis
Pharmacological exploitation of the endocannabinoid system: new perspectives for the treatment of depression and anxiety disorders?
“Animal experiments suggest that drugs promoting endocannabinoid action may represent a novel strategy for the treatment of depression and anxiety disorders.
Because of its analgesic, antiemetic and tranquilizing effects, the herb Cannabis sativa has been used for medical purposes for centuries. In addition, preparations of cannabis, such as marijuana, hashish or skunk, have a long history as drugs of abuse.1 Typical effects of cannabis abuse are amnesia, sedation and a feeling of well-being described as “bliss”.2 In the middle of the last century, Raphael Mechoulam and colleagues identified Δ9-tetrahydrocannabinol (Δ9-THC) as the main psychoactive ingredient of this herb. Today, it is known that Cannabis sativa contains more than 60 substances, such as cannabidiol, cannabinol and cannabicromene, which are referred to as phytocannabinoids.3 Their lipid nature posed a significant obstacle to chemical experiments, which might explain why the discovery of phytocannabinoids occurred late compared to other natural compounds (e.g. morphine was isolated from opium in the XIX century). The molecular structure rendered it likely that Δ9-THC exerts its effects primarily by changing physico-chemical characteristics of cell membranes. Therefore it came as a surprise that specific binding sites could be identified within the mammalian brain,4 followed by isolation and characterization of endogenous binding substances, named endocannabinoids.5 The development of novel pharmacological compounds targeting receptors or ligand synthesis and degradation revealed a number of complex brain functions, which are tightly controlled by the endocannabinoid system. The aim of the present review is to briefly introduce this system and its pharmacology, to discuss its involvement in psychopathology and to illustrate its therapeutic potential.
Conclusion
Malfunctions in the endocannabinoid system may promote the development and maintenance of psychiatric disorders such as depression, phobias and panic disorder. Thus, CB1 agonists or inhibitors of anandamide hydrolysis are expected to exert antidepressant and anxiolytic effects. Future studies should consider 1) the development of CB1 antagonists that cannot readily cross the blood-brain barrier, 2) shifts in the balance of CB1 vs. TRPV1 signalling, 3) the allosteric site of CB1 receptor and 4) the potential involvement of CB2 receptor in mood regulation. Striking similarities in (endo)cannabinoid action in animals and men render it likely that the new pharmacological principle outlined in the present article may find their way into clinical practice.”
Pharmacological Evaluation of Cannabinoid Receptor Ligands in a Mouse Model of Anxiety: Further Evidence for an Anxiolytic Role for Endogenous Cannabinoid Signaling
“Extracts of Cannabis sativa have been used for their calming and sedative effects for centuries. Recent developments in drug discovery have suggested that modulation of neuronal endogenous cannabinoid signaling systems could represent a novel approach to the treatment of anxiety-related disorders while minimizing the adverse effects of direct acting cannabinoid receptor agonists. In this study, we evaluated the effects of direct cannabinoid receptor agonists and antagonists and endocannabinoid-modulating drugs on anxiety-like behavior in mice using the elevated-plus maze.
These data indicate that activation of CB1 cannabinoid receptors reduces anxiety-like behaviors in mice and further support an anxiolytic role for endogenous cannabinoid signaling. These results suggest that pharmacological modulation of this system could represent a new approach to the treatment of anxiety-related psychiatric disorders.
Marijuana is widely used throughout the world for recreational and therapeutic purposes. A common reason given for continued marijuana use in certain populations is reduction in anxiety and relaxation; however, adverse reactions, including heightened anxiety and panic, are common and widely cited reasons for discontinuation of marijuana use. The adverse effects of marijuana are more pronounced during novel or stressful environmental conditions, after consumption of large doses of cannabis, and in naive users…”
Worth Repeating: Marijuana Treats Anxiety and Depression
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| Lumír Ondřej Hanuš (left), discoverer of endogenous ligand, anandamide, from brain (1992) and Raphael Mechoulam (right), discoverer of psychoactive compound, (-)-trans-delta-9-tetrahydrocannabinol, from Cannabis sativa L. (1964). Both compounds bind to the CB1 and 2 cannabinoid receptors in the brain. |
“This post is dedicated to these two great medical researchers. The fathers of homeostatic cannabinoid based medicine:
Lumír Ondřej Hanuš, discoverer of the endogenous ligand, anandamide, from the brain (1992) and Raphael Mechoulam, discoverer of the psychoactive compound, THC, from Cannabis sativa (1964). Both compounds bind to the CB1 and 2 cannabinoid receptors in the brain.
These two men need to be nominated and awarded the 2012 Nobel Prize in medicine for discovering the healing potential of cannabis. Their discoveries will save the human race a great deal of suffering. Thank you for your gift to humanity, gentlemen.”
Pot Compound Reduces Anxiety
“According to clinical trial data published online in The Journal of Psychopharmacology, the administration of the non-psychoactive component of marijuana [cannabinoid cannabidiol (CBD)] reduces anxiety in subjects with social anxiety disorder (SAD).
The anti-anxiety activity of oral doses of CBD in ten subjects was assessed by investigators at the University of Sao Paulo in Brazil in a double blind, placebo-controlled trial.
Researchers concluded, “CBD reduces anxiety in SAD and that this is related to its effects on activity in limbic and paralimbic brain areas.”
This study is the first clinical trial to investigate the effects of cannabinoid cannabidiol on human pathological anxiety and its underlying brain mechanisms.
Previous studies in the context of CBD have suggested that the compound possesses anti-inflammatory activity, anti-cancer activity, and neuroprotective effects – among other therapeutic properties.
The study “Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report,” appeared online in The Journal of Psychopharmacology.”
Anxiolytic effect of cannabidiol derivatives in the elevated plus-maze.
“1.In order to assess the presence of anxiolytic properties in cannabidiol (CBD) derivatives HU-219, HU-252 and HU-261, these drugs were tested in rats submitted to the elevated plus-maze model of anxiety.
2. Additional groups received diazepam or CBD. HU-219 (0.03-1 mg/kg) and CBD (5 mg/kg) significantly increased the percentage of open arm entries without changing the total number of entries, an anxiolytic-like effect.
3. Both HU-252 and HU-261 increased the percentage of time spent in open arms and the total number of entries, but only at the dose of 1 mg/kg.
4. Diazepam (2.5 mg/kg) increased both the percentage of entries and time spent on open arms and the total number of entries.
5. The results confirm previous findings with CBD and indicate that its derivative HU-219 may possess a similar anxiolytic-like profile.
6. Results from HU-252 and HU-261 are less apparent and suggest that the compounds may increase general exploratory activity in a limited range of doses.”
Cannabidiol Reduces the Anxiety Induced by Simulated Public Speaking in Treatment-Naïve Social Phobia Patients
“Generalized Social Anxiety Disorder (SAD) is one of the most common anxiety conditions with impairment in social life. Cannabidiol (CBD), one major non-psychotomimetic compound of the cannabis sativa plant, has shown anxiolytic effects both in humans and in animals. This preliminary study aimed to compare the effects of a simulation public speaking test (SPST) on healthy control (HC) patients and treatment-naïve SAD patients who received a single dose of CBD or placebo…
Pretreatment with CBD significantly reduced anxiety, cognitive impairment and discomfort in their speech performance, and significantly decreased alert in their anticipatory speech. The placebo group presented higher anxiety, cognitive impairment, discomfort, and alert levels when compared with the control group…
…because of the absence of psychoactive or cognitive effects, to its safety and tolerability profiles, and to its broad pharmacological spectrum, CBD is possibly the cannabinoid that is most likely to have initial findings in anxiety translated into clinical practice…
… the effects of a single dose of CBD, observed in this study in the face of one of the main SAD’s phobic stimuli, is a promising indication of a rapid onset of therapeutic effect in patients with SAD.”
Effects of Cannabidiol (CBD) on Regional Cerebral Blood Flow
“Animal and human studies have suggested that cannabidiol (CBD) may possess anxiolytic properties…These results suggest that CBD has anxiolytic properties, and that these effects are mediated by an action on limbic and paralimbic brain areas…
Cannabidiol (CBD) constitutes up to 40% of Cannabis sativa and has quite different psychological effects to the plant’s best known constituent, 
9-tetrahydrocannabinol (9-THC)
In particular, in animal studies CBD has effects similar to anxiolytic drugs…”
Cannabidiol: an overview of some pharmacological aspects.
“Over the past few years, considerable attention has focused on cannabidiol (CBD), a major nonpsychotropic constituent of cannabis.
The authors present a review on the chemistry of CBD and discuss the anticonvulsive, antianxiety, antipsychotic, antinausea, and antirheumatoid arthritic properties of CBD.
CBD does not bind to the known cannabinoid receptors, and its mechanism of action is yet unknown. It is possible that, in part at least, its effects are due to its recently discovered inhibition of anandamide uptake and hydrolysis and to its antioxidative effect.”
Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report.
“Animal and human studies indicate that cannabidiol (CBD), a major constituent of cannabis, has anxiolytic properties. However, no study to date has investigated the effects of this compound on human pathological anxiety and its underlying brain mechanisms. The aim of the present study was to investigate this in patients with generalized social anxiety disorder (SAD) using functional neuroimaging. Regional cerebral blood flow (rCBF) at rest was measured twice using (99m)Tc-ECD SPECT in 10 treatment-naïve patients with SAD. In the first session, subjects were given an oral dose of CBD (400 mg) or placebo, in a double-blind procedure. In the second session, the same procedure was performed using the drug that had not been administered in the previous session. Within-subject between-condition rCBF comparisons were performed using statistical parametric mapping. Relative to placebo, CBD was associated with significantly decreased subjective anxiety (p < 0.001), reduced ECD uptake in the left parahippocampal gyrus, hippocampus, and inferior temporal gyrus (p < 0.001, uncorrected), and increased ECD uptake in the right posterior cingulate gyrus (p < 0.001, uncorrected).
These results suggest that CBD reduces anxiety in SAD and that this is related to its effects on activity in limbic and paralimbic brain areas.”