The endocannabinoid system: emotion, learning and addiction.

Abstract

“The identification of the cannabinoid receptor type 1 (CB1 receptor) was the milestone discovery in the elucidation of the behavioural and emotional responses induced by the Cannabis sativa constituent Delta(9)-tetrahydrocannabinol. The subsequent years have established the existence of the endocannabinoid system. The early view relating this system to emotional responses is reflected by the fact that N-arachidonoyl ethanolamine, the pioneer endocannabinoid, was named anandamide after the Sanskrit word ‘ananda’, meaning ‘bliss’. However, the emotional responses to cannabinoids are not always pleasant and delightful. Rather, anxiety and panic may also occur after activation of CB1 receptors. The present review discusses three properties of the endocannabinoid system as an attempt to understand these diverse effects. First, this system typically functions ‘on-demand’, depending on environmental stimuli and on the emotional state of the organism. Second, it has a wide neuro-anatomical distribution, modulating brain regions with different functions in responses to aversive stimuli. Third, endocannabinoids regulate the release of other neurotransmitters that may have even opposing functions, such as GABA and glutamate. Further understanding of the temporal, spatial and functional characteristics of this system is necessary to clarify its role in emotional responses and will promote advances in its therapeutic exploitation.”

http://www.ncbi.nlm.nih.gov/pubmed/18422832

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

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

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

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

 “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.

Abstract

“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

Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study

“The two main constituents of cannabis, cannabidiol and Δ 9-tetrahydrocannabinol (THC), have opposing effects both pharmacologically and behaviourally when administered in the laboratory. Street cannabis is known to contain varying levels of each cannabinoid.”

“We have recently found evidence to suggest that use of strains richer in cannabidiol may protect cannabis users from the chronic psychotic-like effects of THC. Given the opposing neuropharmacological actions of THC and cannabidiol – the former is a partial agonist whereas the latter is an antagonist at CB1 and CB2 receptors – we hypothesised that cannabidiol may also protect users against other harmful effects of the drug such as cognitive impairment and psychosis-like effects. The current study set out to test these hypotheses by employing a novel methodology that enabled analysis of cannabinoids in the cannabis actually smoked by each individual user.”

“The constituents of street cannabis have changed over the past 20 years with high THC, low-cannabidiol strains now dominating the market. Our findings suggest that this increases the cognitive harms to cannabis users. The research reported here also contributes to the growing body that suggests a range of potential therapeutic uses of cannabidiol, including the ability to modulate the acute amnestic effects of THC. Given the widespread use of cannabis across the globe, there are clear public health implications of this study. In terms of harm reduction, users should be made aware of the higher risk of memory impairment associated with smoking low-cannabidiol strains of cannabis like skunk and encouraged to use strains containing higher levels of cannabidiol.”

Conclusions

“The antagonistic effects of cannabidiol at the CB1 receptor are probably responsible for its profile in smoked cannabis, attenuating the memory-impairing effects of THC. In terms of harm reduction, users should be made aware of the higher risk of memory impairment associated with smoking low-cannabidiol strains of cannabis like ‘skunk’ and encouraged to use strains containing higher levels of cannabidiol.”

http://bjp.rcpsych.org/content/197/4/285.long

Prescribing cannabis for harm reduction

“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/

Cannabidiol for the treatment of cannabis withdrawal syndrome: a case report.

Abstract

“What is known and Objective:  Cannabis withdrawal in heavy users is commonly followed by increased anxiety, insomnia, loss of appetite, migraine, irritability, restlessness and other physical and psychological signs. Tolerance to cannabis and cannabis withdrawal symptoms are believed to be the result of the desensitization of CB(1) receptors by THC. Case summary:  This report describes the case of a 19-year-old woman with cannabis withdrawal syndrome treated with cannabidiol (CBD) for 10 days. Daily symptom assessments demonstrated the absence of significant withdrawal, anxiety and dissociative symptoms during the treatment. What is new and Conclusion:  CBD can be effective for the treatment of cannabis withdrawal syndrome.”

http://www.ncbi.nlm.nih.gov/pubmed/23095052

Marijuana Compound Effective In Treating Tourette’s Syndrome, Study Says

“Thursday, 15 May 2003

Hanover, Germany: A primary compound in marijuana, delta-9-tetrahydrocannabinol (THC), is effective in reducing “tics” in patients suffering from Tourette’s Syndrome (TS), according to clinical trail data published in a recent edition of the Journal of Clinical Psychiatry. Tourette’s Syndrome is a complex neuropsychiatric disorder characterized by motor tics (sudden spasms especially in the facial muscles, neck and shoulders) and one or more vocal tics.

Twenty-four patients participated in the double-blind placebo-controlled trial over a period of six weeks. Treatment with up to 10 mg of THC resulted in significant improvement of tic severity, authors wrote. No serious adverse effects to the treatment were reported.

In a separate article published in Neuropsychopharmacology, authors elaborated, “No detrimental effect was seen on learning curve, interference, recall and recognition of word lists, immediate visual memory span, and divided attention” from THC during or after the treatment.

The 24-patient study confirmed previous smaller patient trials that also found THC to be effective in the treatment of tics and behavioral problems in patients with Tourette’s Syndrome.”

http://norml.org/news/2003/05/15/marijuana-compound-effective-in-treating-tourette-s-syndrome-study-says

Marijuana Successfully Treats Tourette’s Syndrome, Study Shows

“Thursday, 11 March 1999

German researchers report that the consumption of the marijuana compound THC alleviates symptoms of Tourette’s Syndrome. The researchers published their findings in this month’s issue of the American Journal of Psychiatry.

“Earlier reports suggested beneficial effects in Tourette’s syndrome when smoking marijuana,” the German research team wrote. “We report a successful treatment of Tourette’s syndrome with delta-9-tetrahydocannabinol, the major psychoactive ingredient of marijuana.”

Tourette’s syndrome is a complex neuropsychiatric disorder that is characterized by sudden spasms, so called “tics,” that occur especially in the face, neck, and shoulders.

The researchers found that a 25-year-old patient treated with 10 mg of THC experienced marked improvement of both vocal and motor tics associated with behavioral disorders. “The improvement began 30 minutes after treatment and lasted for about seven hours,” the researchers reported. “No adverse effects occurred.”

Researchers stated, “This is the first report of a successful treatment of Tourette’s syndrome with delta-9-THC.” They said they are planning to confirm their preliminary results in an upcoming double-blind, placebo controlled, crossover study.

NORML board member Dr. Lester Grinspoon of Harvard Medical School called inhaled marijuana’s effects on patients suffering from Tourette’s “impressive,” and said that the drug holds tremendous potential as a course of treatment for the disease.

For more information, please contact either Allen St. Pierre of The NORML Foundation @ (202) 483-8751 or NORML board member Dr. Lester Grinspoon of Harvard Medical School @ (617) 277-3621.”

http://norml.org/news/1999/03/11/marijuana-successfully-treats-tourette-s-syndrome-study-shows