Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug
“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.”
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.”
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.”
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.”
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.”
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).”
Cannabis as an adjunct to or substitute for opiates in the treatment of chronic pain.
Abstract
“There is a growing body of evidence to support the use of medical cannabis as an adjunct to or substitute for prescription opiates in the treatment of chronic pain. When used in conjunction with opiates, cannabinoids lead to a greater cumulative relief of pain, resulting in a reduction in the use of opiates (and associated side-effects) by patients in a clinical setting. Additionally, cannabinoids can prevent the development of tolerance to and withdrawal from opiates, and can even rekindle opiate analgesia after a prior dosage has become ineffective. Novel research suggests that cannabis may be useful in the treatment of problematic substance use. These findings suggest that increasing safe access to medical cannabis may reduce the personal and social harms associated with addiction, particularly in relation to the growing problematic use of pharmaceutical opiates. Despite a lack of regulatory oversight by federal governments in North America, community-based medical cannabis dispensaries have proven successful at supplying patients with a safe source of cannabis within an environment conducive to healing, and may be reducing the problematic use of pharmaceutical opiates and other potentially harmful substances in their communities.”
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.”
The endocannabinoid system as a target for the treatment of cannabis dependence
“Cannabinoid replacement therapy and CB1 receptor antagonism are two potential treatments for cannabis dependence that are currently under investigation. However, abuse liability and adverse side effects may limit the scope of each of these approaches. A potential alternative stems from the recognition that (i) frequent cannabis use may cause an adaptive downregulation of brain endocannabinoid signaling, and (ii) that genetic traits that favor hyperactivity of the endocannabinoid system in humans may decrease susceptibility to cannabis dependence. These findings suggest in turn that pharmacological agents that elevate brain levels of the endocannabinoid neurotransmitters, anandamide and 2-arachidonoylglycerol (2-AG), might alleviate cannabis withdrawal and dependence. One such agent, the fatty-acid amide hydrolase (FAAH) inhibitor URB597, selectively increases anandamide levels in the brain of rodents and primates. Preclinical studies show that URB597 produces analgesic, anxiolytic-like and antidepressant-like effects in rodents, which are not accompanied by overt signs of abuse liability. In this article, we review evidence suggesting that (i) cannabis influences brain endocannabinoid signaling; and (ii) FAAH inhibitors such as URB597 might offer a possible therapeutic avenue for the treatment of cannabis withdrawal.”
“Direct modulation of CB1receptors as a treatment for cannabis dependence”
“Even though, as we have seen above, direct activation of CB1 receptors may yield variable behavioral responses, low-dosage oral Δ9-THC has shown promise in the management of human cannabis withdrawal. The rationale for this approach is that controlled replacement of Δ9-THC for smoked cannabis may reduce the severity of withdrawal symptoms and allow a dependent individual to remain abstinent. Additionally, given that dependent subjects are experienced with cannabis, and Δ9-THC is administered at low doses, administration of the latter is unlikely to result in the anxiety responses observed with inexperienced users or high dosages. Consistent with this idea, two independent clinical studies have shown that low-dose oral Δ9-THC attenuates withdrawal symptom scores and is minimally intoxicating in non-treatment seeking daily cannabis users.””
“Several therapeutic modalities are currently being considered to treat cannabis dependence, including activation or deactivation of CB1receptors. While these stategies show promise in measures of cannabis withdrawal and abstinence, they may also create problems of abuse liability or adverse emotional effects. An additional approach might be to enhance endogenous anandamide signaling using agents that attenuate the deactivation of this endocannabinoid transmitter.”
“Increasing anandamide signaling with deactivation inhibitors, such as the FAAH blocker URB597, potentiates stress coping behaviors in animals, indicating a role for anandamide in physiopathological context of stress-related responses. Similarly, elevation of anandamide in specific brain regions opposes the anhedonic effects of stress and promotes normal positive responses to pleasurable stimuli in rodents. It is reasonable to hypothesize that these effects could act to blunt the negative affect and stress, which is common during cannabis withdrawal, thus allowing cannabis dependent individuals to successfully abstain from drug use.”