Tag Archives: CBD

Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders.

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Abstract

“Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ(9)-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca(2+)) increase, etc.), on CBD behavioural effects.”

http://www.ncbi.nlm.nih.gov/pubmed/23108553

Nonpsychotropic Cannabinoid Receptors Regulate Microglial Cell Migration

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“During neuroinflammation, activated microglial cells migrate toward dying neurons, where they exacerbate local cell damage. The signaling molecules that trigger microglial cell migration are poorly understood. In this paper, we show that pathological overstimulation of neurons by glutamate plus carbachol dramatically increases the production of the endocannabinoid 2-arachidonylglycerol (2-AG) but only slightly increases the production of anandamide and does not affect the production of two putative endocannabinoids, homo-γ-linolenylethanolamide and docosatetraenylethanolamide. We further show that pathological stimulation of microglial cells with ATP also increases the production of 2-AG without affecting the amount of other endocannabinoids. Using a Boyden chamber assay, we provide evidence that 2-AG triggers microglial cell migration. This effect of 2-AG occurs through CB2 and abnormal-cannabidiol-sensitive receptors, with subsequent activation of the extracellular signal-regulated kinase 1/2 signal transduction pathway. It is important to note that cannabinol and cannabidiol, two nonpsychotropic ingredients present in the marijuana plant, prevent the 2-AG-induced cell migration by antagonizing the CB2 and abnormal-cannabidiol-sensitive receptors, respectively. Finally, we show that microglial cells express CB2 receptors at the leading edge of lamellipodia, which is consistent with the involvement of microglial cells in cell migration. Our study identifies a cannabinoid signaling system regulating microglial cell migration. Because this signaling system is likely to be involved in recruiting microglial cells toward dying neurons, we propose that cannabinol and cannabidiol are promising nonpsychotropic therapeutics to prevent the recruitment of these cells at neuroinflammatory lesion sites.”

“Because marijuana produces remarkable beneficial effects, patients with multiple sclerosis, for example, commonly use this plant as a therapeutic agent; however, we still lack essential information on the mechanistic basis of these beneficial effects.”

“The marijuana plant, Cannabis sativa, contains >60 cannabinoid compounds, the best known being Δ9-tetrahydrocannabinol (THC), cannabinol (CBN), and cannabidiol (CBD) (for review, see. Cannabinoid compounds produce their biological effects by acting through at least three cannabinoid receptors (see Table1). These include the cloned cannabinoid CB1 receptors, which are expressed predominately in the CNS, the cloned cannabinoid CB2 receptors, which are expressed predominately by immune cells, and the abnormal-cannabidiol-sensitive receptors (hereafter referred to as abn-CBD receptors). The latter receptors have not been cloned yet, but they have been pinpointed pharmacologically in mice lacking CB1 and CB2 receptors and are also known as anandamide (AEA) receptors.”

“We also show that CBN and CBD, two nonpsychotropic bioactive compounds of marijuana, may antagonize the 2-AG-induced recruitment of microglial cells. This is in agreement with the fact that nabilone, a synthetic analog of THC, produces minimal palliative effects against multiple sclerosis symptoms, whereas smoking cannabis is reported to be beneficial. Therefore, our results suggest that bioactive cannabinoids present in the marijuana plant, such as CBN and CBD, are likely to underlie the increased efficacy of cannabis versus nabilone and therefore hold promise as nonpsychotropic therapeutics to treat neuroinflammation.”

http://www.jneurosci.org/content/23/4/1398.long

Addiction and the pharmacology of cannabis: implications for medicine and the law.

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Abstract

“The topic of drug addiction or misuse of drugs has numerous far-reaching ramifications into areas such as neuroscience, medicine and therapeutics, toxicology, epidemiology, national and international economics and politics, and the law. The general principles of drug addiction are first summarised. A recurring and intrinsic problem is lack of adequate characterisation of the independent variable, namely the drug taken. Secondly, it is not feasible to allocate subjects randomly to treatments. Thirdly, the heterogeneity of different forms of addiction precludes facile generalisations. “A problem drug user is anyone who experiences social, psychological, physical, or legal problems related to intoxication, and/or regular excessive consumption, and/or dependence as a consequence of their use of drugs” (UK Advisory Council on Misuse of Drugs, 1982). Cannabis is a genus of flowering plants whose products are used as recreational drugs. Claims have been made for a range of therapeutic properties. Its two main active principles are delta9 – tetrahydrocannabinol (THC) and cannabidiol (CBD). These compounds have contrasting pharmacological properties. THC is suspected of causing psychotic phenomena, but CBD seems more sedative and may even be antipsychotic. The past use of cannabis, particularly the concentrations of THC and CBD, can be monitored with hair analysis. Recent studies involving the administration of THC and CBD to human subjects are reviewed. Suggestions are made for further research into the pharmacology and toxicology of CBD. Such data may also point to a more rational evidence-based approach to the legal control of cannabis preparations.”

http://www.ncbi.nlm.nih.gov/pubmed/19306615

A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation.

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Abstract

“Δ 9-tetrahydrocannabinol (Δ 9-THC) is the main compound of the Cannabis Sativa responsible for most of the effects of the plant. Another major constituent is cannabidiol (CBD), formerly regarded to be devoid of pharmacological activity. However, laboratory rodents and human studies have shown that this cannabinoid is able to prevent psychotic-like symptoms induced by high doses of Δ 9- THC. Subsequent studies have demonstrated that CBD has antipsychotic effects as observed using animal models and in healthy volunteers. Thus, this article provides a critical review of the research evaluating antipsychotic potential of this cannabinoid. CBD appears to have pharmacological profile similar to that of atypical antipsychotic drugs as seem using behavioral and neurochemical techniques in animal models. Additionally, CBD prevented human experimental psychosis and was effective in open case reports and clinical trials in patients with schizophrenia with a remarkable safety profile. Moreover, fMRI results strongly suggest that the antipsychotic effects of CBD in relation to the psychotomimetic effects of Δ 9-THC involve the striatum and temporal cortex that have been traditionally associated with psychosis. Although the mechanisms of the antipsychotic properties are still not fully understood, we propose a hypothesis that could have a heuristic value to inspire new studies. These results support the idea that CBD may be a future therapeutic option in psychosis, in general and in schizophrenia, in particular.”

http://www.ncbi.nlm.nih.gov/pubmed/22716160

Safety and side effects of cannabidiol, a Cannabis sativa constituent.

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“Cannabidiol (CBD), a major nonpsychotropic constituent of Cannabis, has multiple pharmacological actions, including anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, little is known about its safety and side effect profile in animals and humans. This review describes in vivo and in vitro reports of CBD administration across a wide range of concentrations, based on reports retrieved from Web of Science, Scielo and Medline. The keywords searched were “cannabinoids”, “cannabidiol” and “side effects”. Several studies suggest that CBD is non-toxic in non-transformed cells and does not induce changes on food intake, does not induce catalepsy, does not affect physiological parameters (heart rate, blood pressure and body temperature), does not affect gastrointestinal transit and does not alter psychomotor or psychological functions. Also, chronic use and high doses up to 1,500 mg/day of CBD are reportedly well tolerated in humans. Conversely, some studies reported that this cannabinoid can induce some side effects, including inhibition of hepatic drug metabolism, alterations of in vitro cell viability, decreased fertilization capacity, and decreased activities of p-glycoprotein and other drug transporters. Based on recent advances in cannabinoid administration in humans, controlled CBD may be safe in humans and animals. However, further studies are needed to clarify these reported in vitro and in vivo side effects.”

Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug

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“The use Cannabis sativa(cannabis) extracts as medicine was described in China and India before the birth of Christ. The therapeutic use of cannabis was introduced in Western medicine in the first half of the 19th century and reached its climax in the last two decades of the same century. At the turn of the century, several pharmaceutical companies were marketing cannabis extracts and tinctures which were prescribed by doctors for many different complaints including pain, whooping cough and asthma, and as a sedative/hypnotic agent. However, the use of cannabis as a medicine almost completely disappeared at about the middle of the 20th century. The main reasons for this disappearance were the variable potency of cannabis extracts, the erratic and unpredictable individual responses, the introduction of synthetic and more stable pharmaceutical substitutes such as aspirin, chloral hydrate and barbiturates, the recognition of important adverse effects such as anxiety and cognitive impairment, and the legal restrictions to the use of cannabis-derived medicines .”

“Today this situation has changed considerably. The main active psychotropic constituent of cannabis, D9-tetrahydrocannabinol (D9-THC), was isolated, identified and synthesized in the 1960’s. Almost three decades later, cannabinoid receptors in the brain were described and cloned and the endogenous cannabinoids were isolated and identified. As a result of these discoveries the interest in cannabis research has remarkably increased. For instance, the number of publications using the key word “brain”, compiled by the ISI Web of Knowledge, increased 26 times from 1960-1964 to 2000-2004, while the number of publications about `cannabis’ increased 78.5 times during the same period. As a consequence, the research on the use of cannabis as medicine has been renewed.”

” A high dose of D9-tetrahydrocannabinol, the main Cannabis sativa (cannabis) component, induces anxiety and psychotic-like symptoms in healthy volunteers. These effects of D9-tetrahydrocannabinol are significantly reduced by cannabidiol (CBD), a cannabis constituent which is devoid of the typical effects of the plant. This observation led us to suspect that CBD could have anxiolytic and/or antipsychotic actions. Studies in animal models and in healthy volunteers clearly suggest an anxiolytic-like effect of CBD. The antipsychotic-like properties of CBD have been investigated in animal models using behavioral and neurochemical techniques which suggested that CBD has a pharmacological profile similar to that of atypical antipsychotic drugs. The results of two studies on healthy volunteers using perception of binocular depth inversion and ketamine-induced psychotic symptoms supported the proposal of the antipsychotic-like properties of CBD. In addition, open case reports of schizophrenic patients treated with CBD and a preliminary report of a controlled clinical trial comparing CBD with an atypical antipsychotic drug have confirmed that this cannabinoid can be a safe and well-tolerated alternative treatment for schizophrenia. Future studies of CBD in other psychotic conditions such as bipolar disorder and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly indicated.”

“In conclusion, results from pre-clinical and clinical studies suggest that CBD is an effective, safe and well-tolerated alternative treatment for schizophrenic patients. Future trials of this cannabinoid in other psychotic conditions such as bipolar disorder (50) and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly needed.”

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-879X2006000400001&lng=en&nrm=iso&tlng=en

Potential antipsychotic properties of central cannabinoid (CB1) receptor antagonists.

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Abstract

“Delta(9)-Tetrahydrocannabinol (Delta(9)-THC), the principal psychoactive constituent of the Cannabis sativa plant, and other agonists at the central cannabinoid (CB(1)) receptor may induce characteristic psychomotor effects, psychotic reactions and cognitive impairment resembling schizophrenia. These effects of Delta(9)-THC can be reduced in animal and human models of psychopathology by two exogenous cannabinoids, cannabidiol (CBD) and SR141716. CBD is the second most abundant constituent of Cannabis sativa that has weak partial antagonistic properties at the CB(1) receptor. CBD inhibits the reuptake and hydrolysis of anandamide, the most important endogenous CB(1) receptor agonist, and exhibits neuroprotective antioxidant activity. SR141716 is a potent and selective CB(1) receptor antagonist. Since both CBD and SR141716 can reverse many of the biochemical, physiological and behavioural effects of CB(1) receptor agonists, it has been proposed that both CBD and SR141716 have antipsychotic properties. Various experimental studies in animals, healthy human volunteers, and schizophrenic patients support this notion. Moreover, recent studies suggest that cannabinoids such as CBD and SR141716 have a pharmacological profile similar to that of atypical antipsychotic drugs. In this review, both preclinical and clinical studies investigating the potential antipsychotic effects of both CBD and SR141716 are presented together with the possible underlying mechanisms of action.”

http://www.ncbi.nlm.nih.gov/pubmed/20218784

Opposite Effects of Δ-9-Tetrahydrocannabinol and Cannabidiol on Human Brain Function and Psychopathology

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 “Pretreatment with CBD prevented the acute induction of psychotic symptoms by Δ-9-tetrahydrocannabinol. Δ-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioral effects, and CBD’s ability to block the psychotogenic effects of Δ-9-THC”

“In healthy individuals, Δ-9-tetrahydrocannabinol (Δ-9-THC), the main psychoactive ingredient of the Cannabis sativa plant, can induce psychotic symptoms and anxiety, and can impair memory and psychomotor control. In patients with schizophrenia, Δ-9-THC may exacerbate existing psychotic symptoms, anxiety and memory impairments, and Δ-9-THC is thought to be the ingredient responsible for the increased risk of developing schizophrenia following regular cannabis use. In contrast, Cannabidiol (CBD), the other major psychoactive constituent of C. sativa, has anxiolytic and possibly antipsychotic properties, does not impair memory or other cognitive functions. Although CBD has been shown to have neuroprotective effects, Δ-9-THC may have neurotoxic as well as neuroprotective effects. Moreover, when co-administered with Δ-9-THC, CBD may be able to reduce some of the symptomatic effects of Δ-9-THC like anxiety and paranoia. CBD may thus have therapeutic potential as a treatment for cannabis-induced psychopathology, and as an anxiolytic and an antipsychotic.”

 “Our data are consistent with a potential therapeutic role for CBD in ameliorating the psychiatric consequences of cannabis use in the general population, and in patients with existing psychiatric disorders, particularly as conventional antipsychotic medication is relatively ineffective for such conditions. It might also have a role in the treatment of psychotic and anxiety disorders independent of cannabis use. From a public health point of view, one worrying implication of our results is that cannabis users may be at an increased risk of acute adverse psychological reactions following cannabis use, in light of the increasingly potent forms of cannabis with decreasing CBD content available on the street.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055598/

Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment.

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“Community-based studies suggest that cannabis products that are high in Δ(9)-tetrahydrocannabinol (THC) but low in cannabidiol (CBD) are particularly hazardous for mental health. Laboratory-based studies are ideal for clarifying this issue because THC and CBD can be administered in pure form, under controlled conditions. In a between-subjects design, we tested the hypothesis that pre-treatment with CBD inhibited THC-elicited psychosis and cognitive impairment. Healthy participants were randomised to receive oral CBD 600mg (n=22) or placebo (n=26), 210 min ahead of intravenous (IV) THC (1.5 mg). Post-THC, there were lower PANSS positive scores in the CBD group, but this did not reach statistical significance. However, clinically significant positive psychotic symptoms (defined a priori as increases ≥3 points) were less likely in the CBD group compared with the placebo group, odds ratio (OR)=0.22 (χ(2)=4.74, p<0.05). In agreement, post-THC paranoia, as rated with the State Social Paranoia Scale (SSPS), was less in the CBD group compared with the placebo group (t=2.28, p<0.05). Episodic memory, indexed by scores on the Hopkins Verbal Learning Task-revised (HVLT-R), was poorer, relative to baseline, in the placebo pre-treated group (-10.6±18.9%) compared with the CBD group (-0.4%±9.7 %) (t=2.39, p<0.05). These findings support the idea that high-THC/low-CBD cannabis products are associated with increased risks for mental health.”

http://www.ncbi.nlm.nih.gov/pubmed/23042808

Prescribing cannabis for harm reduction

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“Neuropathic pain affects between 5% and 10% of the US population and can be refractory to treatment. Opioids may be recommended as a second-line pharmacotherapy but have risks including overdose and death. Cannabis has been shown to be effective for treating nerve pain without the risk of fatal poisoning. The author suggests that physicians who treat neuropathic pain with opioids should evaluate their patients for a trial of cannabis and prescribe it when appropriate prior to using opioids. This harm reduction strategy may reduce the morbidity and mortality rates associated with prescription pain medications.”

“Medicine relies upon the principle of, “First, do no harm,” and one might supplement the axiom to read – “First, do no harm, and second, reduce all the harm you can.” “Harm reduction” or “harm minimization” can be defined in the broadest sense as strategies designed to reduce risk or harm. Those harmed may include the individual, others impacted by the harmed person, and society. The substitution of a safer drug for one that is more dangerous is considered harm reduction. Specific examples of HR include prescribing methadone or buprenorphine to replace heroin, prescribing nicotine patches to be used instead of smoking tobacco, and prescribing intranasal naloxone to patients on opioid therapy to be utilized in case of overdose. Substituting cannabis for prescribed opioids may be considered a harm reduction strategy.”

“Under the Federal Controlled Substance Act “marihuana” is illegal and classified as a schedule I substance-meaning it has a high potential for abuse and no accepted medical use. However, sixteen states and the District of Columbia have legalized cannabis for medicinal use and these include Alaska, Arizona, California, Colorado, Delaware, Hawaii, Maine, Michigan, Montana, Nevada, New Jersey, New Mexico, Oregon, Rhode Island, Vermont, and Washington. Each state law differs but all allow physicians to “authorize” or “recommend” cannabis for specific ailments. This “recommendation” affords legal protections for patients to obtain and use medicinal cannabis, and may be considered the “prescription.””

“Cannabis (Cannabis sativa) and the opium poppy (Papaver somniferum) are both ancient plants that have been used medicinally for thousands of years. The natural and synthetic derivatives of opium, including morphine, are called “opioids.”  “Cannabinoids” is the term for a class of compounds within cannabis of which delta-9-tetrahydrocannabinol (THC) is the most familiar. Besides THC, approximately 100 other cannabinoids have been identified including one of special scientific interest called “cannabidiol” (CBD). The human body produces both endogenous cannabinoids (endocannabinoids) and opioids (endorphins) and contains specific receptors for these substances. There is an extensive literature on opioids but far less on cannabis/cannabinoids (CC).”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295721/