The Impact of Cannabidiol on Psychiatric and Medical Conditions
c Corresponding Author: Thersilla Oberbarnscheidt, Department of Psychiatry, Western Psychiatric Hospital, University of Pittsburgh, UPMC Health, Pittsburgh, PA, USA. Email: [email protected]
This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
The authors declare that data supporting the findings of this study are available within the article.
Cannabidiol (CBD) is a substance chemically derived from Cannabis sativa and discussed to be non-psychoactive. According to the FDA, marijuana is classified as a schedule I substance; however, hemp which is defined as extracts from marijuana including cannabinoids containing less than 0.3% tetrahydrocannabinol (THC), is excluded from that controlled substance act and available at local convenience stores in the US as it is seen as an herbal supplement. CBD is purported to be used for various medical and psychiatric conditions: depression, anxiety, post-traumatic stress disorder, Alzheimer’s or other cognitive illnesses as well as pain. There is also a new trend to use CBD for the treatment of opioid use disorder. The one CBD product on the market that is FDA approved for the treatment of childhood epilepsy forms Dravet and Lennox-Gastaut syndromes is available under the name Epidiolex. There is a significant difference between this medication and the over-the-counter CBD products that contain very inconsistent strengths of CBD, if they contain it at all, and vary in percentage even from sample to sample. Frequently the so-called CBD products are not containing any CBD at all, but mostly containing THC. This article is a systematic review of literature reviewing the available clinical data on CBD, for use in various medical and psychiatric conditions with focus on a review of the pharmacology and toxicity. Resources used were ORVID, PubMed, MEDLINE, PsychINFO, EMBASE with keywords CBD, cannabidiol, hemp and cannabinoids.
CBD, also called cannabidiol, is chemically derived from hemp (Cannabis sativa), which is the most commonly used illicit drug both nationally and internationally .
It was first obtained from American hemp and Egyptian hashish in 1940 . In its natural form cannabis consists of the two most well-known active chemicals tetrahydrocannabinol (THC) and CBD as well as about 480 other active cannabinoids (CBs) that are not yet well researched. The THC in the cannabis is the psychoactive ingredient with toxicity. The THC content in a product labeled as CBD is supposed to contain less than 0.3% dry weight of THC in its leaves and buds .
Even though CBD use is a global problem, this article will focus on the current situation and trend within the US. Marijuana as well as CBD is purported for use in the US for the self-treatment of numerous medical and psychiatric conditions as a so-called “medicine”. It is commonly used for depression, anxiety, seizures, nausea, appetite enhancer, anti-inflammatory, pain or the new trend to self-treat opioid use disorder .
Against the usual course of a medication development, both substances have not been scientifically investigated or developed prior to their use, but were determined by claims in the general public of their medicinal value . Possible toxic effects and drug-drug interactions should be considered, and consumers should be educated about the risks and safety concerns regarding this substance, which are currently not publicized.
Due to CBD being exempt from federal regulations by the in 2018 passed US farm bill, it is easily accessible and available at convenience stores throughout the US .
The sale and marketing of CBD and CBD-containing products are very important economic factors as sales reached $2 billion US dollars in 2018 and are rising .
Of the US population, 9% of the people less than 35 years of age reported the use of CBD at least once, 6.4% of the people between 45 and 55 years and 3.7% of the people over 55 years of age .
The question for public health is if CBD is really non-psychoactive and as safe as it is advertised in the general-public?
Pharmacological Action of CBD
CBD can be ingested in various routes. It is available in the form of oils, lotions, edibles, teas or smoked ( Figs. 1 , ,2) 2 ) . It is rarely administered intravenously but that route is possible .
CBD chemical structure (source: PUBCHEM ). CBD: cannabidiol.
Chemical structure of THC for comparison (source: PUBCHEM ). THC: tetrahydrocannabinol.
CBD undergoes a significant first pass metabolism in the liver after ingestion. The bioavailability after oral consumption is estimated 6%, and after smoking is estimated to be about 6-31% .
CBD’s primary active metabolite is 7-hydroxy-CBD (7-OH-CBD) . The half-life of CBD depends on the route of administration. Smoked, the half-life is about 27 – 35 h, after oral ingestion 2 – 5 days and the shortest after intravenous injection with about 18 – 33 h .
CBD is very lipophilic, similar to cannabis, and easily passes the blood-brain barrier. It gets quickly distributed into adipose tissue and other organs. Due to its lipophilic quality, CBD accumulates in the adipose tissue particularly in patients with high adiposity and is redistributed into the circulation at a later point . The amount used varies in a wide spectrum: administered doses in studies range from 5 – 1,500 mg/day orally up to 30 mg intravenously .
CBD does bind to the CB receptors, normally activated by endogenous CBs including anandamide and 2-arachidonylglycerol. There are two specific CB receptors identified. Unlike THC that binds to CB1 receptors that are mostly located in the brain, CBD binds mostly to CB2 receptors that are found on cells of the immune system, which include T and B lymphocytes, macrophages and monocytes which are not as highly expressed in the central nervous system .
The activation of those receptors decreases the release of neurotransmitters glutamate, gamma-aminobutyric acid (GABA), serotonin and norepinephrine and provides synaptic control of upstream neurotransmission [17-19].
CBD acts on several other receptor types. Those include receptors of the serotonin system 5HT 1A/2A/3A, glutamate, TRPV-a (vanilloid) receptors, agonist activity on alpha-1 adrenergic receptors as well as mu-opioid receptors .
In addition, CBD acts on the adenosine levels by reducing the adenosine reuptake, which has been associated with neuroprotection and anti-inflammatory processes in the brain .
CBD also acts directly on the cerebral vasculature by inhibiting the nitric oxide synthase protein expression as well as inhibition of calcium transport across membranes. Through this mechanism it causes vasodilatation .
CBD has shown in vitro studies to be a potent inhibitor with cytochrome P450 enzymes such as CYP1A2, CYP2B6, CYP2C9, CYP2D6 and CYP3A4 [23-36]. These enzymes are also responsible for the metabolization of various other medications. Therefore, CBD will most likely interfere with the serum levels of other medications such as antibiotics, antipsychotics, antidepressants and blood thinners as well as many more. Studies about these interactions are yet lacking. The interactions with CBD and other medications are summarized in Table 1 [23-36].
|Enzyme||Medication that interacts||Effect|
|CYP3A4 substrate||Immunosuppressants, antidepressants, opioids, statins, benzodiazepines||Increases toxic effects/levels of substrate|
|CYP3A4 inhibitor||Ketoconazole, loperamide, nefazodone, cimetidine, verapamil||Increases level/toxicity of CBD|
|CYP3A4 inducer||Phenytoin, topiramate, carbamazepine, rifampicin, efavirenz, pioglitazone||Decreases bioavailability of CBD
Reduces effect/level of CBD
|CYP2C19 substrate||Proton pump inhibitor, antidepressants, antiepileptics, clopidogrel, propranolol, warfarin, cyclophosphamide||Increases toxic effects/level of substrate|
|CYP2C19 inhibitor||Cimetidine, proton pump inhibitors, fluvoxamine, clopidogrel, fluconazole||Increases level/toxicity of CBD|
|CYP2C19 inducer||Phenobarbital, phenytoin, St. John’s Wort, rifampicin, carbamazepine||Decreases bioavailability of CBD
Reduces effect/level of CBD
|CYP2C8/9||Buprenorphine, montelukast, celecoxib, phenobarbital, phenytoin, warfarin, valsartan||Increases toxic effects/levels of substrate|
It is possible to ingest quantities of CBD that will cause a fatal overdose but very large doses are required for that to occur in human . The toxicity levels for CBD can be found in the federal government’s Toxicology Data Network . The lethality risk with toxic substances is usually measured in the LD50 which is the amount of substance needed to kill 50% of the population .
There are three studies citied regarding the LD50 determination of CBD [37-12]: 1) In 1946, the LD50 for CBD in dogs was determined to be greater than 254 mg per kg of body weight, when administered intravenously. 2) In 1975, an LD50 was established in mice at 50 mg per kg of body weight, when administered intravenously. 3) In 1981, a report in Toxicology and Applied Pharmacology showed the LD50 for CBD to be 212 mg per kg of body weight when administered intravenously in monkeys.
More recently, a 2011 article in the journal “Current Drug Safety” observed toxic levels of CBD in rhesus monkeys when administered orally. Doses over 200 mg per kg of body weight proved to be fatal in some monkeys by way of respiratory arrest and cardiac failure, while 300 mg per kg of body weight resulted in “rapid death” .
For reference, consider a relatively “average sized” human at 75 kg (approximately 165 lbs). By these numbers, it would take roughly 18,750 mg (18.75 g) of CBD consumed within a very short amount of time to result in any potentially fatal effects. By comparison, most typical CBD oil users consume no more than 100 mg of the compound, and that is throughout the course of an entire day .
CBD’s Effect on Medical and Psychiatric Conditions
Table 2 [14, 42-85] gives an overview of the toxic effects of CBD that are further discussed more in detail.
Some of the listed effects are more acute in nature, and others are more chronic.
Anaphylaxis and rashes are usually occurring immediately after ingestion. Also, dizziness as well as vomiting, diarrhea and dry mouth occur shortly after ingestion.
Depending on the route of ingestion, the toxic effects occur faster with increased bio-availability. The effects on mood and thoughts as well as sleep and immune-system will be discussed more in detail below. The toxic effects can occur even with very small doses of CBD depending on the user’s sensitivity but are more like to occur in higher doses. Users with impaired liver function are at higher risk to experience toxic effects than healthy individuals. There are no data available yet to differentiate reliably between the risks of different age groups, gender or ethnicity.
Anxiety/post-traumatic stress disorder (PTSD)
Anxiety and PTSD are very common psychiatric disorders in the US and are associated with substance use. While cannabis with its THC content has shown to be anxiogenic during intoxication as well as withdrawal, CBD has been discussed to have some anxiolytic potential [42, 43].
In animal studies, the systemic administration of CBD had caused a decrease in neurons associated with fear (c-Fos positive neurons) and a direct infusion of CBD in the amygdala neurons has led to decreased anxiety-related behaviors . Another animal model showed that CBD modifies the cerebral blood flow in brain areas that play a role in anxiety symptoms: amygdala, hippocampus, hypothalamus as well as cingulate cortex .
Several human studies have shown some positive results of CBD in anxiety conditions as well. The effect of CBD on the amygdala was studied in brain imaging studies and showed a decrease in activation in the amygdala after administration of CBD .
A placebo-controlled study by Crippa et al showed a decrease in social anxiety symptoms but also sedation in a small group of 10 patients receiving CBD. The patients in this clinical study were treatment naive and with 10 participants the study was small .
Another study by Bergamaschi among 24 treatment naive patients looked at the effect of 600 mg CBD during a public speaking test and noticed a reduction in anxiety, cognitive impairment as well as discomfort in speech performance .
Furthermore, a study by Das et al including 48 healthy volunteers was evaluated for anxiety provoking electric shock anticipation and received either pure CBD without THC or placebo. The results showed that CBD increases extinction learning which might play a role in therapeutic approaches for anxiety disorder treatment .
The lifetime prevalence for PTSD in the US is about 6.1% of the population. The treatment has been mostly consistent of antidepressants as well as Prazosin for nightmares. CBD has been reported in case-control studies to be beneficial for nightmare symptoms associated with PTSD .
In another small study of 11 patients with PTSD, oral CBD was administered open-labeled and the patient’s PTSD symptoms were evaluated initially and on consecutive days up to 8 weeks after utilizing the PCL-5 test and score. Ninety-one percent of the patients reported a decrease in nightmare symptoms. None of the patients reported side effects .
However, despite these studies with small patient numbers, utilizing the pure form of CBD, there are also several case reports of CBD-induced anxiety symptoms as a toxic side effect from the substance.
As part of CBD’s ability to control the cerebral neurotransmission of serotonin and norepinephrine and its active binding to 5HT-1 A receptors , CBD is thought to also have an effect on depression. In addition, CBD stimulates the synaptic plasticity and neurogenesis which also plays a role in the development and treatment of depression [17-20].
Some animal models have shown some promising results. A mouse depression model showed significant antidepressant-like effect after administration of CBD. The animals showed increased engagement on pleasurable activities .
However, in humans, there are very limited studies available. In vitro, CBD is found to be a microglial stabilizer which is similar to the medication lithium which could be beneficial for depression and mood stabilization .
In humans, there are only few case studies published of individual patients with a history of depression who have previously been on traditional treatment with selective serotonin reuptake inhibitor (SSRI) who successfully tried CBD products and experienced a significant improvement in their depressive symptoms .
Caution with these studies is warranted. The studies are utilizing a controlled CBD form without any significant THC content, studies have small patient numbers and the follow-up windows are short. Major toxic effects have been reported with the use of CBD, being more depressed one of them and even suicidal ideations [52, 56].
The pack insert of the FDA approved form of CBD Epidiolex lists depression and suicidal ideation as a possible adverse reaction. In the largest placebo-controlled clinical trial among 27,863 patients treated with Epidiolex and 16,029 patients treated with placebo, the risk of suicidal ideations was increased 1 in every 530 patient and four suicides occurred in the Epidiolex treated group versus none in the placebo group .
There are no compatible data available comparing OTC CBD with placebo regarding increased risk of suicidality.
In studies using animal models for schizophrenia, CBD has shown to improve psychotic symptoms . Zuardi et al looked at the effect of CBD on stereotypy induced by dopaminergic agonist in rodents and found that CBD decreased those similarly to haldol . In a mice model, CBD was compared with haloperidol and clozapine and was found to be equivalent in inhibition of the hyperlocomotion induced by amphetamines and ketamines . In comparison to the conventional medication haloperidol and clozapine, CBD did not induce any catatonia, not even in doses as high as 480 mg/kg. Most commonly, doses of 120 – 240 mg/kg were needed to show any effect, which points to a lower potency of CBD .
There are very few and limited studies available in humans. Boggs et al looked at the effect of CBD at 600 mg in schizophrenia and reported that the medication was well tolerated and did not worsen mood or suicidality but was ineffective in treating cognitive impairment and other neuropsychiatric complications of schizophrenia .
Another double-blind, randomized clinical trial compared CBD with amisulpride and noted similar clinical improvement with less side effects . In the study, 33 patients with schizophrenia were followed over a 4-week period and received either amisulpride or CBD. Both patient groups improved similarly utilizing the positive and negative syndrome scale (PANSS) score with some superiority in improvement of the negative symptoms in the CBD group .
Leweke et al conducted a study looking at the effect of CBD on visual hallucinations induced by nabilone in healthy volunteers. CBD showed to decrease the degree in visual hallucinations . This study since it uses a synthetic form of THC to induce psychosis, as well as other research groups, has raised the questions if CBD might have antagonizing effects to the negative psychotropic effects of THC and might be potentially protective of the side effects of THC .
The study populations in these studies are mostly small and the follow-up is short or only monitored in a one-time event. The number of available studies is very limited, and mostly there are individual case reports published [61, 65-67].
Alzheimer’s disease (AD)
CBD has some pharmacological characteristics that might point to be benefit in the treatment of AD. Libro at al showed that CBD is able to prevent the development of amyloid plaques in vitro. The group pre-treated a gingiva tissue sample with CBD and looked at the change in mesenchymal stem cells, meaning that it could possibly be beneficial in the treatment of AD. Also, CBD regulates the expression of GDK3b a central factor implemented in the molecular pathogenesis of AD .
In animal models, CBD has shown to prevent glutamate-induced excitotoxicity and to reduce inflammatory mediators and well as reduce lipid peroxidase. In addition, the active binding to CB2 receptors was causing a down-regulation in microglial activation in animal in vivo studies. In a mouse model with hippocampal gliosis induced by injection of human Aβ-fragment, CBD inhibited the glial cell activation and proinflammatory mediator release in a dose-dependent manner.
In a rat model, CBD stimulated the hippocampal neurogenesis which would technically mean that CBD reverses the disease .
In case reports of traumatic brain injuries, CBD has been found to reduce brain damage after cerebral trauma by improving the metabolic activity . Those findings have been confirmed in magnetic resonance imaging (MRI) and positron emission tomography (PET) studies. Studies are ongoing that evaluate this effect in persons with high risk concussion rates, for example, football players.
CBD has been frequently associated with the side effect of sedation which would be very negative in patients with AD and lead to other medical complications due to decreased activity in this elderly population. More studies need to be done to show efficacy of CBD in AD or other forms of dementia.
Epilepsy and seizures
The use of CBD for the treatment of seizures has been researched since the 1970s. Overall the idea is to utilize CBD’s effect on neuronal hyperactivity which means excessive neuronal firing as it occurs in seizure disorders . The exact mechanism of CBD’s action on epilepsy is unknown. In vitro, CBD has shown to decrease epileptiform local field potentials, their amplitude and duration .
In animal models, predominantly mice, it has shown some positive effects in few studies but no effect in most others. Studies performed in rats by Jones et al have shown anticonvulsant effects in partial pilocarpine and penicillin-induced seizures. In chronic epilepsy studies in animals have been less optimistic, showing little to no effect on the seizure activity .
In humans, the data are very limited for the natural form of CBD. The only FDA approved CBD medication for childhood seizures, Dravet and Lennox-Gastaut syndromes, is Epidiolex, which is a synthetic substance with a purity of 98% CBD and less than 0.15% THC. Difference to the over-the-counter (OTC) CBDs is that Epidiolex is showing the same content of CBD and dose in one unit to the other. The two FDA approved conditions are both very severe and devastating forms of childhood seizures where seizures are most commonly refractory to traditional pharmaceutical treatment forms and children develop encephalopathy with intellectual disability and neurodevelopmental problems early on in their lives [74-77]. Epidiolex is an FDA approved medication, prescribed by physicians, and patients will be evaluated and monitored. In contrast this is not the case with the OTC form of CBD.
Researches regarding the effect of CBD on sleep are still in its infancy. Endocannabinoids have been shown to play a role in the circadian rhythm, therefore CBD is thought to have an effect on sleep [78-80].
In animal models, studies have been performed to show the effect of CBD on the sleep quality as well as the sleep cycle . In rats, studies have shown that high doses of CBD lead to increased total percentage of sleep. In another rodent model, high dose CBD led to increased rapid eye movement (REM) sleep latency, while the low dose CBD showed a decrease with no effect shown on the non-rapid eye movement (NREM) sleep .
Only few and small numbered human studies are available to show the effect of CBD on sleep. The sedating effect of CBD appears to be dose dependent. Low dose of CBD has been found to be more stimulating, while higher doses have a sedating effect. Two studies by Nicholson and Zuadi et al showed that a CBD dose of 160 mg/day to increase sleep time in persons suffering insomnia as well as decrease nightly arousals while a lower dose again showed increased wakefulness [79, 80]. Basic research in humans showed an overall increase in the total amount of sleep with several sleep disorders [79, 80].
There are no data available yet to show the effects of CBD abstinence syndrome on sleep as it is described with THC to cause prolonged insomnia as a symptom or prolonged withdrawal . Long-term and chronic use for insomnia bears the risk for development of dependence to CBD.
From pre-clinical studies, CBD is discussed to have protective effects against striatal degeneration . In animal studies CBD has shown promising capabilities to reduce striatal dopamine hypersensitivity which is mediating chorea [83, 84]. This has been shown predominantly in rats. CBD also reduced the aggressive behaviors in rats treated with neurotoxin L-pyroglutamate which is one possible pathophysiological model for the aggressive behaviors seen in Huntington’s disease .
A genetic mouse model has shown neuroprotective properties of CBD towards the striatal degeneration through selective binding to CB2 receptors .
Few clinical studies have looked at the effect of CBD on Huntington’s disease and not shown beneficial value in the medicinal properties of CBD in the treatment of this devastating disease .
A study done by Consroe et al compared CBD versus placebo. The group used a mean dose of 700 mg CBD daily on 15 patients with Huntington’s disease. The group did not find any significant difference in chorea severity, side effects and lab tests after 6 weeks of treatment .
CBD is commonly used for pain without any scientific evidence nor FDA approval. Preclinical studies have proposed hat CBD might be useful in the treatment of chronic pain conditions .
However, clinical studies have been unconvincing so far. In Naftali’s study, CBD at 10 mg per day dose was shown ineffective in the treatment of Chron’s disease . Also, another study by Ben showed that CBD was ineffective at 40 mg per day dose in the treatment of chronic neuropathic pain. Other people suggested CBD to be useful in the treatment of cancer pain but studies supporting this statement are yet to be done . None of the available studies are long-term and showing relevant beneficial clinical effect to advocate for the use of CBD in pain conditions.
Opioid use disorder (OUD)
In the US approximately 2.5 million people have been diagnosed with an OUD and about 80 people each day die of overdose. OUD is a burden for each individual person, their families and the society. The annual costs associated with OUD are estimated 78 billon US dollars .
The conventional medication assisted treatments available for OUD including methadone, buprenorphine as well as naltrexone, have been of value but also associated with their own challenges. Those medications are regulated and require the person to be enrolled in a treatment program, which is time-consuming and associated with a negative stigma. This bears grounds to investigate for alternatives, easier accessible and less controlled treatment options for OUD .
Blogs on the internet are attracting an increasing number of people with OUD and discuss the use of CBD during withdrawal as well as ongoing maintenance treatment. CBD is advertised as safe and with low lethality even in combination with strong opioid agonists .
In animal studies, CBD has been shown to reduce the rewarding effects of opioids and it also reduces the heroin-seeking behaviors. CBD acts on the same receptors that heroin does and antagonizes the heroin’s effect on CB1 and glutamate receptors .
The data from Colorado are concerning, with the increased use of CBs and THC, there has been a corresponding increase in opioid use and no decrease in opioid use since the legalization [92, 93].
However, there are only limited case reports available in humans regarding the use of CBD in OUD or small numbered clinical studies that are not allowing a broad statement regarding CBD’s efficacy in the treatment of OUD.
The treatment of OUD with CBD bears particularly a risk, as the amount of CBD taken is not dosed in a controlled setting and for someone who has lost control over a substance prior might have difficulties dosing CBD as well.
CBD and addiction
CBD is unlike THC not binding to the cerebral CB1 receptor which is responsible for the rewarding effects of cannabis in its natural form and for the feeling of euphoria. Many articles state that CBD is a non-psycho-active substance [3-5]. However, it must have some degree of psycho-activity if it alters people’s mood, anxiety as well as cognition.
As with many other substances listed in the DSM V for substance use disorders, it is also possible with CBD to experience a loss of control and a compulsive use. Even though the risk of lethality is very low, it does not mean it is impossible to become addicted to the substance [37, 38, 94].
Withdrawal symptoms are not well described in the literature but however, most likely a person who takes CBD regularly for insomnia, will experience rebound insomnia if he stops .
Similar exacerbating effects are to be expected when CBD is no longer taken for depression or anxiety [12, 42]. Studies about the withdrawal symptoms from CBD and their course are yet to be published. Only case reports exist.
Under Federal Law, marijuana is still listed as a schedule I substance which means that the substance is not accepted for medical use and has a high potential for abuse. In comparison, cocaine is a schedule II substance since it is used as an anesthetic medically .
The Drug Enforcement Administration (DEA) has specific criteria for a drug to be considered a medication [3, 6]: 1) The drugs chemistry must be known and reproducible; 2) The drug must have shown efficacy in well-controlled clinical study; 3) The drug must have shown safety; 4) It must be accepted by qualified experts and scientific evidence must be widely available.
CBD falls under the regulation of the “Farm Bill” (the agriculture improvement act of 2018, Pub. L. 115-334) which was signed in December 2018. This bill defines hemp as the cannabis plant, any part of it including extracts and cannabinoids with a THC concentration of less than 0.3% dry weight. “Hemp” was removed from the controlled substance act under federal law and is federally not considered a controlled substance [95, 96].
Especially problematic is the purity of the content that can be purchased currently. The requirements for quality control as well as labeling vary significantly from state to state. For example, California requires laboratory testing for medical and recreational cannabis and cannabis products while other states, for example, Arizona, do not mandate any laboratory testing [97, 98].
Over the last several years, including 2019, the FDA has issued several warning letters about unapproved new drugs on the market that allegedly contain CBD. The FDA had tested the content of these products and found a discrepancy of the claimed ingredients on the label and the actual content. Ninety percent of the tested CBD products contained much less CBD that what was posted on the label or no CBD at all, but the majority of tested products did contain a greater content of THC than claimed [99-103].
The FDA explicitly writes on their webpage that these products are not FDA approved for the diagnosis, cure, mitigation, treatment, or prevention of any disease and warns customers to beware purchasing or using any such products [37, 38].
The FDA further states that no food products can enter inter-state commerce and that CBD is not a safe food additive. CBD and other CBD or cannabis derived products should not be considered as dietary supplements as they contain pharmacologically active ingredients. Also, the FDA warns about the various dosing contents as there have been potentially toxic doses reported in certain food, for example, gummi bears containing 1,500 mg of CBD [37, 38].
The interest in cannabis products and CBD has exploded nationally over the last decade and the current trend is to legalize marijuana and make CBD available without strict regulations or control to the general public. CBD can nowadays be purchased online, in natural food stores, pet stores or retail outlet without a physician prescription despite claims for use in medical conditions.
Cannabis and CBD are almost seen as a “wonder drug” in the eye of the general public and claimed to help with conditions that are difficult to treat with established medications: AIDS, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington’s disease and might also mirror some mistrust and frustration in the medications that are currently available as FDA approved medications.
In the case of OUD treatment, people might try to use CBD to avoid being associated with the stigma of treatment for OUD. Buprenorphine and methadone clinics are still seen with some degree of negative stigma even amongst physicians. Affected people try to self-treat with other substances and consult blogs on the internet rather than professional treatment. There are also cases reported of CBD use for other use disorder for example alcohol or tobacco. The use of CBD in these cases bears the risk of potentially developing a new addiction or dependence in the process of substituting one drug with another. Data from Colorado since legalization are alarming and pointing to an increase of opioid use since the increased use of CBs and since legalization of marijuana. Well-established treatments for OUDs are available and should be preferred and advertised.
CBD might have some medicinal value, but main problem is that there is little established research nor control or regulation over the CBD product and people do not know what they are getting when they purchase CBD. CBD products vary highly in compositions and concentrations even from one unit to the other. The FDA issued warning letters about CBD products being falsely labeled and distributed.
The THC content is legally limited to be less than 0.3% but the reality shows that CBD products often contain higher amounts of THC and therefore the user gets put at risk to experience all the toxic side effects that are associated with marijuana and THC. The list of those toxic side effects includes attention-deficit/hyperactivity disorder (ADHD) like symptoms, cognitive impairment, aggression, behavior changes, paranoia, depression, anxiety, cancers and more.
The studies looking at the clinical effect of CBD on certain psychiatric and medical conditions utilize pure forms of CBD that had prior been tested of its contents for its ingredients and concentration, but this is not the form that the general public purchases in a convenience store.
The only form that is FDA approved CBD product that is considered a medication is the Epidiolex. The difference in calling it a “medication” is that one unit is consistent with the next and that it contains always the same dose. For OTC CBD this is not the case, the content varies as well as the psychoactive effect.
Given the inconsistency in the OTC CBD product, there are no dosing recommendations available for each claimed condition and they are not prescribed like a FDA approved medication and there is no physician follow-up.
Also, the use of CBD bears a risk for the user to develop toxic side effects from other medications that they are taking as prescribed as those might develop higher serum concentrations through the interaction of CBD with several CYP P 450 enzymes.
Persons with organ transplants are at risk of increased toxic effects from their immunosuppressant which might lead to organ failure, toxic levels of anticoagulants might lead to acute bleeding, and someone who is prescribed suboxone might experience sedation or respiratory depression even though he/she was previously on a stable dose.
After reviewing the literature, CBD is claimed as a psychoactive substance with effects on mood and behaviors and therefore bears the risk to develop an addiction.
Long-term studies in larger patient cohorts are needed to investigate the addictive potential of CBD.
More studies need to be done in humans in a controlled setting to determine the medicinal value of CBD for various diagnoses in order to be able to make clear recommendations.
Preclinical studies have shown some promising data regarding the medicinal value of CBD but studies in human are not consistent in outcome and controversial in their design. More studies need to be performed in human with larger sample sizes and longer follow-up periods.
Dosing guidelines for CBD need to be established for different indications and follow-up with a physician. The current situation, where the user does not know what they are actually getting in the product, makes CBD unsafe and the risk outweighs the benefit of recommending or using that substance. Especially the content of CBD needs to be under stricter regulations with lab monitoring to determine and guarantee a particular dose or content or CBD and to exclude a higher content of THC than the 0.3% that are allowed by law. Currently there is no consistency in the content of the CBD product.
It is dangerous to assume that the CBD is a “miracle drug” without any safety concerns given the list of potential toxic reactions. Particularly the sedating effect appears to be concerning and limiting in its use.
Cross-interactions with other medications need to be investigated to rule out toxicity in co-morbid patients taken numerous prescribed medications.
A possible development of an addictive disorder to CBD can from the current knowledge not be excluded and further data on long-term administration, the effects of tolerance and toxicity with administration of higher doses need to be investigated. From experience, if a substance is used over a prolonged period of time, there is a process of habituation involved and consecutively an increase in consumption of the substance.
Also, the claimed absence of psycho-active effects and absence of withdrawal symptoms upon discontinuation of CBD is from current point of view, subject to speculation.
The current trend of decriminalization of marijuana and its products bear the risk to further increase the CBD consumption with associated increase in health problems, violence, criminality and lethality.
Does Cannabidiol Protect Against Adverse Psychological Effects of THC?
This article was submitted to Addictive Disorders and Behavioral Dyscontrol, a section of the journal Frontiers in Psychiatry.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
The recreational use of cannabis can have persistent adverse effects on mental health. Delta-9-tetrahydrocannabinol (THC) is the main psychoactive constituent of cannabis, and most, if not all, of the effects associated with the use of cannabis are caused by THC. Recent studies have suggested a possible protective effect of another cannabinoid, cannabidiol (CBD). A literature search was performed in the bibliographic databases PubMed, PsycINFO, and Web of Science using the keyword “cannabidiol.” After removing duplicate entries, 1295 unique titles remained. Based on the titles and abstracts, an initial selection was made. The reference lists of the publications identified in this manner were examined for additional references. Cannabis is not a safe drug. Depending on how often someone uses, the age of onset, the potency of the cannabis that is used and someone’s individual sensitivity, the recreational use of cannabis may cause permanent psychological disorders. Most recreational users will never be faced with such persistent mental illness, but in some individuals cannabis use leads to undesirable effects: cognitive impairment, anxiety, paranoia, and increased risks of developing chronic psychosis or drug addiction. Studies examining the protective effects of CBD have shown that CBD can counteract the negative effects of THC. However, the question remains of how the laboratory results translate to the types of cannabis that are encountered by real-world recreational users.
Keywords: tetrahydrocannabinol, cannabidiol, cannabis, psychosis, anxiety, drug dependence, cognition
Tetrahydrocannabinol (THC) is the main psychoactive substance in cannabis. Cannabidiol (CBD) is a cannabinoid that appears in cannabis resin but rarely in herbal cannabis. In recent years, many positive attributes have been ascribed to CBD. Is cannabis that contains CBD less harmful than cannabis without CBD? Are people who smoke cannabis resin, therefore, less susceptible to psychosis or less likely to become addicted than are people who smoke herbal marijuana? In this article, several of the health aspects of CBD will be reviewed. The article will focus on the role played by CBD in contributing to the psychological effects that are experienced during recreational cannabis use.
Cannabis sativa contains more than 80 different cannabinoids, of which THC is principally responsible for the pharmacological actions, including the psychoactive effects. THC binds to specific proteins in the brain – the cannabinoid receptors (CB-Rs) (1). Two different receptors have been discovered: the CB1 and CB2 receptors (2, 3). CB1-R is mainly found in the central nervous system (CNS); CB2-R is predominantly present in the immune system (3–5). Endocannabinoids are naturally occurring substances that attach to these receptors (6–8).
Cannabinoid receptors, endocannabinoids, and the enzymes involved in the synthesis and degradation of these substances together form the endocannabinoid system (9). The activation of the CB-Rs affects the actions of various neurotransmitters, such as acetylcholine, dopamine, GABA, glutamate, serotonin, norepinephrine, and endogenous opioids (10, 11). Under normal physiological circumstances, CB-Rs are activated by endocannabinoids (12). The activation of CB-Rs by endocannabinoids inhibits excessive neurotransmitter release. Endocannabinoids are lipid-soluble compounds, which prevent them from traveling long distances within the brain. As a consequence of this feature, endocannabinoids are ideally suited for small-scale, local physiological processes (13).
Tetrahydrocannabinol mimics the effect of endocannabinoids. In contrast to these substances, THC is not rapidly broken down at the site of operation, and it not only works at specific locations but simultaneously activates all CB receptors throughout the brain (14).
The mechanisms by which CBD exerts its effect are not precisely known, but it is clear that the pharmacological actions of CBD follow from many different mechanisms [for reviews, see Ref. (15, 16)]. CBD weakly binds to CB-Rs but is capable of antagonizing the effects of THC, even when the former is present in low doses. By inhibiting the degradation of the endogenous cannabinoid anandamide, CBD intensifies, and prolongs its effect (17). The (extended) presence of anandamide prevents THC from interacting with CB-Rs. CBD also interacts with several other recently discovered CB-Rs, and it is an agonist for the 5-HT1A receptor (18, 19), which may explain some of the antipsychotic and anxiolytic effects of CBD (20). Through its effect on intracellular calcium concentrations, CBD might protect neurons against the possible neurotoxic effects of THC (21). CBD itself has almost no effect on normal physiological processes. Only when a stimulus (such as pain or a shock reaction) or another cannabinoid (such as THC) upsets the normal “tone” of the endocannabinoid system is the effect of CBD expressed (12).
The amount of CBD administered, the ratio of CBD to THC and the timing of administration all seem to be important in determining the possible effects of CBD (22, 23). Most clinical studies on the effects of CBD are not relevant for generalizing to the effects of CBD in “recreational” cannabis users. In many of these studies, the doses that have been used are not relevant to the situation typically encountered by recreational cannabis users.
Clinical research has focused on the physical effects of cannabis use, such as pain relief, appetite promotion, and inflammation. For recreational cannabis users, the substance’s psychological effects are the most important. In many experimental studies, the routes of administration used for both THC and CBD are not comparable to the routes of administration found in recreational cannabis use. The high dosages of CBD that have been used in experimental studies increase the concentration of CBD in the blood to levels that can never be reached by smoking a joint. The method that is most comparable to smoking is exposure through a vaporizer, but little research has been conducted involving the administration of cannabis, THC, or CBD via a vaporizer (24, 25). Therefore, it is unknown to what extent the effects of a single administration procedure can be extrapolated to recreational cannabis users given such differences in usage patterns.
Toxicology of CBD
Research on the pharmacological and toxicological properties of CBD has been performed on different types of animals. In general, the metabolism of CBD in different species seems similar to that observed in humans, but some differences exist (26). It is possible that differences in metabolism and kinetics among different species have been responsible for some of the observed differences in pharmacological and toxicological effects.
Little research has focused on the safety and side effects of CBD in humans. However, several studies have described the effects of CBD for therapeutic applications in clinical trials. Only a few, generally mild side effects have been observed after administration of CBD in these human studies, though a wide range of effects over a wide dose range, including acute and chronic administration, have been examined. Few undesirable effects are reported, and tolerance for CBD does not seem to occur.
Based on an extensive literature review, Bergamaschi and colleagues concluded that CBD, to the extent that it has been studied, is a substance with low toxicity (27). Notably, however, the absence of harmful effects of CBD in humans has been described in research that was not primarily aimed at investigating these same side effects or toxicities of CBD. Because no specific research on these issues has been performed, it is currently impossible to draw conclusions about differences in toxicity between hashish and marijuana.
Chronic cannabis use is associated with psychiatric toxicity and cannabis has been implicated in the etiology of long-term psychiatric conditions (28). Several in vivo brain scanning techniques have been conducted to investigate whether chronic, heavy cannabis use leads to structural changes in the brain [for reviews, see Ref. (29, 30)]. The results of these studies have been relatively inconsistent. In general, no differences in total brain volume between cannabis users and non-users have been found. With respect to CB1 receptor concentrations in different parts of the brain, it can be expected that structural changes after chronic intensive cannabis use would most likely eventually be situated in the orbitofrontal cortex (OCC), the anterior cingulate cortex (ACC), the striatum, the amygdala, and the hippocampus (31–33). In some structural magnetic resonance imaging (sMRI) studies, reductions in the volumes of the hippocampus, the amygdala, and the cerebellum have been found in adult heavy cannabis users when compared with healthy controls (21, 34, 35). Using a PET scan technique, Wilson and colleagues found age-dependent morphological changes in early-onset cannabis users. In subjects who started their cannabis use before the age of 17, it has been found that the ratio of cortical gray to white matter is smaller when compared with subjects who had started using cannabis after their 17th birthdays (36). Structural abnormalities due to chronic cannabis use have been most consistently identified in the hippocampus (21, 34, 35). Using a voxel-based morphometry (VBM) approach, Demirakca and colleagues studied gray matter (GM) concentrations and volumes of the hippocampus in 11 chronic recreational cannabis users and 13 healthy controls and correlated their findings with THC and CBD measurements made from hair analyses. They found that cannabis users showed lower GM volume in the right anterior hippocampus. Higher THC and lower CBD were associated with this hippocampal volume reduction, suggesting neurotoxic effects of THC and neuroprotective effects of CBD.
The conflicting results among volumetric brain studies seem to result from differences in time span (e.g., age of onset), patterns of cannabis use (e.g., frequency, duration of use, cumulative lifetime use), and type of cannabis used (e.g., potency, CBD/THC ratio) (29, 30).
The effects of cannabis on psychological functioning mainly concern psychotic symptoms, anxiety, depression, cognitive functioning, and the potential for abuse and dependency. Several studies show that high doses of cannabis can provoke acute and transient psychotic reactions in both “healthy” users and in people with a certain predisposition for psychosis (37–39). These effects are dose-related (i.e., more THC produces a greater effect) and are stronger and longer-lasting in naive and occasional users than they are in frequent and transient cannabis users. Rottanburg and colleagues were the first to propose a protective effect of CBD on THC-induced psychosis. They suggested that the high incidence of cannabis-related psychosis among their patients occurred because cannabis variants in South Africa are more potent in terms of THC content and because they lack CBD (40).
As early as 1982, there were indications that the psychosis- and anxiety-inducing effects of THC can be suppressed by CBD (41, 42). Several other studies have found support for the antipsychotic effects of CBD. fMRI studies have shown that the effects of THC are correlated with a decrease in brain activity in the striatum. The striatum plays an important role in planning activities, modulating motor activity (movement), and performing cognitive tasks. CBD has been found to increase the activity in this brain area (43). Moreover, in other brain areas, the effects of CBD on neurological activity have been shown to be opposite those of THC.
In one Dutch and three English studies, associations between the consumption of certain types of cannabis and the occurrence of psychotic symptoms were reported (41–47). The results of these “naturalistic” studies suggest that CBD exerts a dampening effect on THC-induced psychotic symptoms. It is not clear for which CBD/THC ratio and for what minimum CBD concentration the protective effects of CBD may be expressed. The main features of these “naturalistic” studies are summarized in Table Table1 1 .
Summary of “naturalistic” studies in which the effects of cannabidiol and cannabis with a high dosis of THC on psychological functions have been investigated.
|Di Forti et al. (47)||“First-episode” psychiatric patients (n = 280)||Self reported frequency and type of cannabis used||The chance that high-potent cannabis (THC) has been used is higher among “first-episode” psychotic patients than among non-psychotics||Also more frequent use in “first-episode” psychotic patients|
|Morgan and Curran (45)||Cannabis users (n = 154)||Grouping based on presence of THC and/or CBD in hair||More psychotic symptoms among THC group in comparison with no THC group and in group with THC and CBD in hair||THC might be psychotogenic and CBD might protect against this effect|
|Schubart et al. (48)||Websurvey among cannabis users (n = 1877)||Grouping based on self reported preference for type of cannabis||Less psychotic symptoms in cannabis users who use cannabis with high level of CBD (hash)||Personal communication with author (Schubart)|
|Morgan et al. (46)||Cannabis users, at least once a month (n = 134)||Choosing cannabis by cannabis user||Acute effects on mood, psychotic symptoms, and cognition||CBD attenuates the THC-induced memory impairment; CBD does not affect psychotomimetic symptoms|
|Morgan et al. (49)||Recreational cannabis users (n = 54) versus daily users (n = 66)||Measuring THC and CBD in hair||THC increases possibility of negative psychotic symptoms, CBD antagonizes (part of) THC-induced effects|
Longitudinal studies that have investigated the relationship between chronic cannabis use and the occurrence of psychosis have shown that cannabis use increases the risk of later psychotic symptoms and disorders by a factor of 2–3. The magnitude of the risk depends on the degree of exposure, the age of onset of cannabis use and the “vulnerability” of the user (50–52). No longitudinal studies have distinguished between the type of cannabis having been used, and no studies give an indication of the THC/CBD ratio.
One case-control study has shown an association between the occurrence of a first psychotic episode and the use of high-potency cannabis (skunk or sinsemilla) (47). Patients with psychotic symptoms had more frequently used skunk or sinsemilla cannabis instead of hashish than had non-patients. Patients experiencing first-episode psychosis were also more likely to be daily users of high-potency cannabis than were controls. This finding suggests that both the daily use and consumption of cannabis with a high-THC and low-CBD content increase the risk of developing psychosis.
Cannabis use can lower the age of a first psychotic episode (53, 54). Epidemiological and clinical studies suggest an adverse effect of cannabis use on the course of the disease in terms of relapse, exacerbation of symptoms and number of hospitalizations (38, 55–57). With the exception of a study by Di Forti et al. (47), no study has investigated the use of different types of cannabis in patients with a psychotic disorder. The extent to which the presence or absence of CBD in cannabis will influence the early occurrence of a first-episode psychosis or to what extent it will affect the course of the disease is, therefore, unknown.
Anxiety and panic attacks are the most commonly reported adverse reactions following the use of cannabis. Inexperience and use in a foreign environment play a major role (58). Though anxiety and panic attacks are often reported, many users take cannabis for its fear-inhibiting effects [for a review, see Ref. (59)]. THC seems to be responsible for the anxiogenic effects of cannabis [e.g., Ref. (58, 60, 61)].
By the early 1980s, it had been shown that THC led to a significant increase of acute anxiety symptoms, while CBD had no effect (42). When CBD and THC were administered together, the anxiogenic effect of THC was halved. This was an important indication that the anxiety-inducing effects of THC could be antagonized by CBD. The results from later studies, however, were inconsistent; the anxiety-reducing effect of CBD was not found in all subsequent studies. Ilan and colleagues investigated the contribution of THC and CBD to the subjective and behavioral effects of smoked marijuana (62). In their study, 23 healthy marijuana users were randomly assigned to a low- or a high-THC group and low or high levels of CBD. In the four sessions under blinded conditions, subjects smoked marijuana cigarettes containing placebo (no active cannabinoids) or cigarettes containing THC with low or high levels of CBD. Compared with the placebo, cannabis caused a slight short-term increase in anxiety symptoms (VAS). These effects were greatest in the high-THC condition and appeared to diminish when the CBD content was high, but this latter effect was not statistically significant. Because this increase in anxiety was generally mild and because not all subjects responded with fear, a follow-up analysis with only the anxious subjects was performed. There was a non-significant trend for less anxiety in the high- versus the low-CBD condition in subjects who reported higher levels of anxiety after smoking the joints. A reason for the absence of significant results in this study might be that neither the THC nor the CBD concentrations were high enough to have significant effects. In the studies in which anxiety-reducing effects were reported, high oral doses of CBD typically were involved. Cannabis that is used for recreational purposes does not contain such high amounts of CBD.
People with cannabis dependence are more likely to suffer from an anxiety disorder and, in particular, from social anxiety disorder [for a review, see Ref. (58)].
So far, studies investigating the relationship between cannabis dependence and anxiety disorders have not clarified the nature of the relationship in question: does cannabis use lead to anxiety disorders or do anxiety disorders lead to the (over-) use of cannabis? There are no studies in which the relationship between cannabis use and anxiety disorders is examined and in which an inquiry about the type of cannabis used or its THC/CBD ratio is included.
In two experiments using patients suffering from social anxiety disorder along with healthy volunteers as controls, the subjects had to speak in front of a video camera, regardless of whether they were under the influence of CBD. In this experimental situation, CBD was effective in preventing symptoms of anxiety, both in healthy volunteers and in patients with social anxiety disorder (41, 63). CBD suppressed the symptoms of anxiety, similar to the action of the sedatives diazepam and ipsapirone. The main features of the studies on humans that have investigated the psychological effects of administering CBD (singularly or in combination with THC) are summarized in Table Table2 2 .
Overview of studies investigating the effect of cannabidiol or cannabidiol in combination with THC on psychological functions in humans. Studies in which cannabis extracts have been used are not included.
|Karniol et al. (64)||Healthy volunteers (n = 40)||30 mg THC (oral); 15, 30 of 60 mg CBD (oral) or in combination with 30 mg THC (both oral)||Antagonizing (part of) the THC-induced effects||CBD decreased the anxiety component of THC effects; no effect of CBD alone|
|Hollister and Gillespie (65)||Healthy volunteers (n = 30)||20 mg THC + 40 mg CBD (both oral)||CBD delays onset of the effect of THC and prolongs the effects of THC|
|Dalton et al. (66)||Healthy volunteers (n = 15)||25 μg/kg BW THC and 150 μg/kg BW CBD via smoking a joint||CBD reduces euphoric effect of THC||Only effective when CBD and THC are administered simultaneously|
|Hollister (67)||Healthy volunteers (n = ?)||CBD 5–30 mg i.v.||No effects|
|Carlini and Cunha (68)||Healthy volunteers||Acute 600 mg CBD; 10 mg/kg/BW CBD 20 days||CBD does not have psychological or physical effects||Light drowsiness after CBD administration|
|Zuardi et al. (42)||Healthy volunteers (n = 8)||0.5 mg/kg BW THC + 1 mg/kg BW CBD (both oral)||CBD antagonizes psychological effects of THC (anxiety)||CBD itself has no effect and does not antagonize the physical effects of THC (HR, BP)|
|Zuardi et al. (69)||Treatment resistant schizophrenic patients (n = 3)||CBD during 29 days upwards from 40 to 1280 mg/day (oral)||CBD does not antagonize symptoms||No side effects of CBD reported|
|Crippa et al. (70)||Healthy volunteers (n = 10)||CBD 400 mg oral||Anxiolytic effects; light mental sedation||SPECT results: effects in left amygdala-hippocampus complex radiating to hypothalamus|
|Leweke et al. (71)||Psychiatric patients (n = 43)||CBD oral 800 mg/day; during 4 weeks||CBD more effective as antipychotic than amsulpride||Less side effects of CBD than with amsulpride|
|Zuardi et al. (72)||PD patients with psychoses||CBD 150 mg/day; during 4 weeks||CBD possibly effective for treatment of PD patients suffering from psychoses||No significant side effects of CBD reported|
|Borgwardt et al. (73), Fusar-Poli et al. (74), Fusar-Poli et al. (75), Bhattacharyya et al. (76) a||Healthy volunteers (n = 15)||CBD oral 600 mg; 10 mg THC (not simultaneously); in comparison with placebo||No effect in contrast with THC; CBD activates other brain areas than THC no effects of CBD in verbal learning task and no induction of psychotic symptoms||No sedation and no inhibition of locomotion by CBD; THC induces psychotic symptoms, anxiety, and sedation|
|Zuardi et al. (77)||Patients with bipolar disorder (n = 2)||CBD oral 600 – 1200 mg/day during 25 days||CBD has no effect on symptoms||No side effects of CBD reported|
|Bhattacharyya et al. (43)||Healthy volunteers (n = 6)||CBD 5 mg i.v. immediately followed by 1.25 mg THC i.v.||CBD antagonizes THC-induced psychotic symptoms||CBD and THC have opposite effects on regional brain function|
|Bergamaschi et al. (78)||Healthy controls (n = 12) and patients with social phobia (n = 24)||CBD oral 600 mg||Reduction of anxiety scores in patients, no effect in controls||No physical effects or side effects of CBD reported|
|Crippa et al. (79)||Patients with social phobia (n = 10)||CBD oral 400 mg||No effect on psychological scores||No physical effects; SPECT: CBD exerts its effects via limbic and paralimbic areas|
|Nicholson et al. (80)||Healthy volunteers (n = 8)||CBD 5 mg + THC 5 mg; CBD 15 mg + THC 15 mg, via mouth spray||THC (15 mg) increases drowsiness, antagonized by CBD (15 mg)|
|Hallak et al. (81)||Schizophrenic patients (n = 28)||CBD oral 300 and 600 mg acute||No positive effects in Stroop Color Word Test||No significant side effects of CBD reported|
|Hallak et al. (82)||Healthy volunteers (n = 10)||CBD oral 600 mg and ketamine i.v.||CBD increases activating effects of ketamine (BPRS); reduction of ketamine-induced depersonalization (CADSS)||No effect of CBD on HR and BP|
a This concerns experiments with one group of 15 subjects from which the results have been spread over four different publications; BP, blood pressure; BW, body weight; CADSS, Clinician Administered Dissociative States Scale; HR, heart rate; i.v., intravenously; PD, Parkinson disease.
Several studies have shown that cannabis and THC dose-dependently cause cognitive and psychomotor function impairments along with memory, (selective) attention, locomotion, perception, and response impairments (83–85). The effects occur most strongly during the first hour after smoking a joint and between 1 and 2 h after oral intake. Little experimental research exists on the effects of CBD alone or in conjunction with THC on cognitive and psychomotor functions. The studies performed so far show few “protective” effects of CBD on cognitive functions. Morgan and colleagues identified a few such effects on memory functions, but the research on this aspect of CBD has inconsistent findings (45, 49).
Although no human studies have specifically investigated the long-term effects of the combined effect of THC and CBD on cognitive functioning, there are indications that CBD may have some neuroprotective properties. In some neurodegenerative diseases that are often associated with declines in cognitive functioning, such as Alzheimer’s and Parkinson’s diseases, CBD may have some role in treatment or prevention (86–89).
The ratio of THC to CBD may play a role in the risk of addiction (90). Morgan and colleagues examined whether there is a difference in attentional bias between users of cannabis having a relatively high CBD/THC ratio versus cannabis having a low-CBD/THC ratio. Much weaker attentional bias for cannabis-related stimuli was found for users of cannabis with a high CBD content than for users of cannabis with a low-CBD content. Furthermore, the extent to which both groups appreciated the self-selected drug and the strength of the desire for their drug (“wanting”) were investigated. High CBD content led to diminished appreciation and weaker desire for the drug relative to low-CBD content. The researchers concluded that cannabis with a high CBD content confers less risk for developing an addiction than cannabis with a low-CBD content (90). Whether smoking hashish in practice diminishes addiction risk in comparison with smoking highly potent marijuana should be further investigated.
Cannabis is not a safe drug. Depending on how often someone uses, the age of onset, the potency of the cannabis that is used and someone’s individual sensitivity, the recreational use of cannabis may cause permanent psychological disorders. Many recreational users of cannabis will never be faced with serious or permanent health deficits. However, for some users, the use of cannabis may cause undesirable psychological side effects, such as cognitive impairment, anxiety and paranoia, and an increased risk of developing chronic psychosis and addiction. Despite all of the publicity surrounding cannabis, remarkably few studies have been performed that examined the relationship between a possibly harmful effect of THC and a possibly protective effect of CBD. The few studies that exist on the effects of CBD show that this cannabinoid can counteract some of the negative effects of THC, although their results have not always been consistent. The question remains how the findings from laboratory studies, often employing high doses of CBD and high CBD/THC ratios, can be extrapolated to the typical practices of the recreational cannabis user. Few or no adverse effects of CBD have been proffered, and where CBD has been found to have an effect, it is usually in a “positive” (i.e., salubrious) direction. The evidence favoring a beneficial effect of CBD therefore merits further investigation in studies in which the amounts and ratios of CBD and THC correspond to the daily practices of recreational cannabis use.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
1. Howlett AC, Johnson MR, Melvin LS, Milne GM. Nonclassical cannabinoid analgetics inhibit adenylate cyclase: development of a cannabinoid receptor model . Mol Pharmacol (1988) 33 ( 3 ):297–302 [PubMed] [Google Scholar]
2. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA . Nature (1990) 346 ( 6284 ):561–4 10.1038/346561a0 [PubMed] [CrossRef] [Google Scholar]
3. Munro S, Thomas KL, Bu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids . Nature (1993) 365 ( 6441 ):61–5 10.1038/365061a0 [PubMed] [CrossRef] [Google Scholar]
4. Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, De Costa BR, et al. Cannabinoid receptor localization in brain . Proc Natl Acad Sci U S A (1990) 87 ( 5 ):1932–6 10.1073/pnas.87.5.1932 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
5. Glass M, Dragunow M, Faull RL. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain . Neuroscience (1997) 77 ( 2 ):299–318 10.1016/S0306-4522(96)00428-9 [PubMed] [CrossRef] [Google Scholar]
6. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor . Science (1992) 258 ( 5090 ):1946–9 10.1126/science.1470919 [PubMed] [CrossRef] [Google Scholar]
7. Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain . Biochem Biophys Res Commun (1995) 215 ( 1 ):89–97 10.1006/bbrc.1995.2437 [PubMed] [CrossRef] [Google Scholar]
8. Stella N, Schweitzer P, Piomelli D. A second endogenous cannabinoid that modulates long-term potentiation . Nature (1997) 388 ( 6644 ):773–8 10.1038/42015 [PubMed] [CrossRef] [Google Scholar]
9. Wilson RI, Nicoll RA. Endocannabinoid signaling in the brain . Science (2002) 296 ( 5568 ):678–82 10.1126/science.1063545 [PubMed] [CrossRef] [Google Scholar]
10. Grotenhermen F. Pharmacology of cannabinoids . Neuro Endocrinol Lett (2004) 25 ( 1-2 ):14–23 [PubMed] [Google Scholar]
11. Skaper SD, Di Marzo V. Endocannabinoids in nervous system health and disease: the big picture in a nutshell . Philos Trans R Soc Lond B Biol Sci (2012) 367 ( 1607 ):3193–200 10.1098/rstb.2012.0313 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
12. Alger BE, Kim J. Supply and demand for endocannabinoids . Trends Neurosci (2011) 34 ( 6 ):304–15 10.1016/j.tins.2011.03.003 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
13. Di Marzo V. The endocannabinoid system: its general strategy of action, tools for its pharmacological manipulation and potential therapeutic exploitation . Pharmacol Res (2009) 60 ( 2 ):77–84 10.1016/j.phrs.2009.02.010 [PubMed] [CrossRef] [Google Scholar]
14. Fisar Z. Phytocannabinoids and endocannabinoids . Curr Drug Abuse Rev (2009) 2 ( 1 ):51–75 10.2174/1874473710902010051 [PubMed] [CrossRef] [Google Scholar]
15. Hill AJ, Williams CM, Whalley BJ, Stephens GJ. Phytocannabinoids as novel therapeutic agents in CNS disorders . Pharmacol Ther (2012) 133 :79–97 10.1016/j.pharmthera.2011.09.002 [PubMed] [CrossRef] [Google Scholar]
16. Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb . Trends Pharmacol Sci (2009) 30 :515–27 10.1016/j.tips.2009.07.006 [PubMed] [CrossRef] [Google Scholar]
17. Ligresti A, Cascio MG, Pryce G, Kulasegram S, Beletskaya I, De Petrocellis L, et al. New potent and selective inhibitors of anandamide reuptake with antispastic activity in a mouse model of multiple sclerosis . Br J Pharmacol (2006) 147 ( 1 ):83–91 10.1038/sj.bjp.0706418 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
18. Bisogno T, Maccarrone M, De Petrocellis L, Jarrahian A, Finazzi-Agro A, Hillard C, et al. The uptake by cells of 2-arachidonoylglycerol, an endogenous agonist of cannabinoid receptors . Eur J Biochem (2001) 268 ( 7 ):1982–9 10.1046/j.1432-1327.2001.02072.x [PubMed] [CrossRef] [Google Scholar]
19. Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors . Neurochem Res (2005) 30 ( 8 ):1037–43 10.1007/s11064-005-6978-1 [PubMed] [CrossRef] [Google Scholar]
20. Campos AC, Guimarães FS. Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats . Psychopharmacology (Berl) (2008) 199 ( 2 ):223–30 10.1007/s00213-008-1168-x [PubMed] [CrossRef] [Google Scholar]
21. Demirakca T, Sartorius A, Ende G, Meyer N, Welzel H, Skopp G, et al. Diminished gray matter in the hippocampus of cannabis users: possible protective effects of cannabidiol . Drug Alcohol Depend (2011) 114 ( 2-3 ):242–5 10.1016/j.drugalcdep.2010.09.020 [PubMed] [CrossRef] [Google Scholar]
22. Zuardi AW, Hallak JE, Crippa JA. Interaction between cannabidiol (CBD) and (9)-tetrahydrocannabinol (THC): influence of administration interval and dose ratio between the cannabinoids . Psychopharmacology (Berl) (2012) 219 ( 1 ):247–9 10.1007/s00213-011-2495-x [PubMed] [CrossRef] [Google Scholar]
23. Arnold JC, Boucher AA, Karl T. The yin and yang of cannabis-induced psychosis: the actions of delta(9)-tetrahydrocannabinol and cannabidiol in rodent models of schizophrenia . Curr Pharm Des (2012) 8 ( 32 ):5113–30 10.2174/138161212802884726 [PubMed] [CrossRef] [Google Scholar]
24. Fischedick J, van der Kooy F, Verpoorte R. Cannabinoid receptor 1 binding activity and quantitative analysis of Cannabis sativa L. smoke and vapor . Chem Pharm Bull (Tokyo) (2010) 58 ( 2 ):201–7 10.1248/cpb.58.201 [PubMed] [CrossRef] [Google Scholar]
25. Zuurman L, Roy C, Schoemaker RC, Hazekamp A, den Hartigh J, Bender JC, et al. Effect of intrapulmonary tetrahydrocannabinol administration in humans . J Psychopharmacol (2008) 22 ( 7 ):707–16 10.1177/0269881108089581 [PubMed] [CrossRef] [Google Scholar]
26. Harvey DJ, Samaram E, Mechoulam R. Comparative metabolism of cannabidiol in dog, rat and man . Pharmacol Biochem Behav (1991) 40 ( 3 ):523–32 10.1016/0091-3057(91)90358-9 [PubMed] [CrossRef] [Google Scholar]
27. Bergamaschi MM, Queiroz RH, Zuardi AW, Crippa JA. Safety and side effects of cannabidiol, a Cannabis sativa constituent . Curr Drug Saf (2011) 6 ( 4 ):237–49 10.2174/157488611798280924 [PubMed] [CrossRef] [Google Scholar]
28. Reece AS. Chronic toxicology of cannabis . Clin Toxicol (Phila) (2009) 47 ( 6) :517–24 10.1080/15563650903074507 [PubMed] [CrossRef] [Google Scholar]
29. Lorenzetti V, Lubman DI, Whittle S, Solowij N, Yucel M. Structural MRI findings in long-term cannabis users: what do we know? Subst Use Misuse (2010) 45 ( 11 ):1787–808 10.3109/10826084.2010.482443 [PubMed] [CrossRef] [Google Scholar]
30. Hermann D, Schneider M. Potential protective effects of cannabidiol on neuroanatomical alterations in cannabis users and psychosis: a critical review . Curr Pharm Des (2012) 18 ( 32 ):4897–905 10.2174/138161212802884825 [PubMed] [CrossRef] [Google Scholar]
31. Breivogel CS, Childers SR. The functional neuroanatomy of brain cannabinoid receptors . Neurobiol Dis (1998) 5 ( 6 Pt B ):417–31 10.1006/nbdi.1998.0229 [PubMed] [CrossRef] [Google Scholar]
32. Ameri A. The effects of cannabinoids on the brain . Prog Neurobiol (1999) 58 :315–48 10.1016/S0301-0082(98)00087-2 [PubMed] [CrossRef] [Google Scholar]
33. Iversen L. Cannabis and the brain . Brain (2003) 126 ( Pt 6 ):1252–70 10.1093/brain/awg143 [PubMed] [CrossRef] [Google Scholar]
34. Matochik JA, Eldreth DA, Cadet JL, Bolla KI. Altered brain tissue composition in heavy marijuana users . Drug Alcohol Depend (2005) 77 ( 1 ):23–30 10.1016/j.drugalcdep.2004.06.011 [PubMed] [CrossRef] [Google Scholar]
35. Yucel M, Zalesky A, Takagi MJ, Bora E, Fornito A, Ditchfield M, et al. White-matter abnormalities in adolescents with long-term inhalant and cannabis use: a diffusion magnetic resonance imaging study . J Psychiatry Neurosci (2010) 35 ( 6 ):409–12 10.1503/jpn.090177 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
36. Wilson W, Mathew R, Turkington T, Hawk T, Coleman RE, Provenzale J. Brain morphological changes and early marijuana use: a magnetic resonance and positron emission tomography study . J Addict Dis (2000) 19 ( 1 ):1–22 10.1300/J069v19n01_01 [PubMed] [CrossRef] [Google Scholar]
37. D’Souza DC. Cannabinoids and psychosis . Int Rev Neurobiol (2007) 2007 ( 78 ):289–326 10.1016/S0074-7742(06)78010-2 [PubMed] [CrossRef] [Google Scholar]
38. D’Souza DC, Sewell RA, Ranganathan M. Cannabis and psychosis/schizophrenia: human studies . Eur Arch Psychiatry Clin Neurosci (2009) 259 ( 7 ):413–31 10.1007/s00406-009-0024-2 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
39. Barkus E, Murray RM. Substance use in adolescence and psychosis: clarifying the relationship . Annu Rev Clin Psychol (2010) 2010 ( 6 ):365–89 10.1146/annurev.clinpsy.121208.131220 [PubMed] [CrossRef] [Google Scholar]
40. Rottanburg D, Robins AH, Ben-Arie O, Teggin A, Elk R. Cannabis-associated psychosis with hypomanic features . Lancet (1982) 2 ( 8312 ):1364–6 10.1016/S0140-6736(82)91270-3 [PubMed] [CrossRef] [Google Scholar]
41. Zuardi AW. Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action . Rev Bras Psiquiatr (2008) 30 ( 3 ):271–80 10.1590/S1516-44462008000300015 [PubMed] [CrossRef] [Google Scholar]
42. Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects . Psychopharmacology (Berl) (1982) 76 ( 3 ):245–50 10.1007/BF00432554 [PubMed] [CrossRef] [Google Scholar]
43. Bhattacharyya S, Morrison PD, Fusar-Poli P, Martin-Santos R, Borgwardt S, Winton-Brown T, et al. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology . Neuropsychopharmacology (2010) 35 ( 3 ):764–74 10.1038/npp.2009.184 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
44. Schubart CD, van Gastel WA, Breetvelt EJ, Beetz SL, Ophoff RA, Sommer IE, et al. Cannabis use at a young age is associated with psychotic experiences . Psychol Med (2010) 7 :1–10 10.1017/S003329171000187X [PubMed] [CrossRef] [Google Scholar]
45. Morgan CJ, Curran HV. Effects of cannabidiol on schizophrenia-like symptoms in people who use cannabis . Br J Psychiatry (2008) 192 ( 4 ):306–7 10.1192/bjp.bp.107.046649 [PubMed] [CrossRef] [Google Scholar]
46. Morgan CJ, Schafer G, Freeman TP, Curran HV. Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study [corrected] . Br J Psychiatry (2010) 197 ( 4 ):285–90 10.1192/bjp.bp.110.077503 [PubMed] [CrossRef] [Google Scholar]
47. Di Forti M, Morgan C, Dazzan P, Pariante C, Mondelli V, Marques TR, et al. High-potency cannabis and the risk of psychosis . Br J Psychiatry (2009) 195 ( 6 ):488–91 10.1192/bjp.bp.109.064220 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
48. Schubart CD, Sommer IE, van Gastel WA, Goetgebuer RL, Kahn RS, Boks MP. Cannabis with high cannabidiol content is associated with fewer psychotic experiences . Schizophr Res (2011) 130 ( 1–3 ):216–21 10.1016/j.schres.2011.04.017 [PubMed] [CrossRef] [Google Scholar]
49. Morgan CJ, Gardener C, Schafer G, Swan S, Demarchi C, Freeman TP, et al. Sub-chronic impact of cannabinoids in street cannabis on cognition, psychotic-like symptoms and psychological well-being . Psychol Med (2011) 29 :1–10 [PubMed] [Google Scholar]
50. Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review . Lancet (2007) 370 :319–28 10.1016/S0140-6736(07)61162-3 [PubMed] [CrossRef] [Google Scholar]
51. Kuepper R, van Os J, Lieb R, Wittchen HU, Höfler M, Henquet C. Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study . BMJ (2011) 342 :d738. 10.1136/bmj.d738 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
52. Griffith-Lendering MF, Wigman JT, Prince van Leeuwen A, Huijbregts SC, Huizink AC, Ormel J, et al. Cannabis use and vulnerability for psychosis in early adolescence – a TRAILS study . Addiction (2013) 108 ( 4 ):733–40 10.1111/add.12050 [PubMed] [CrossRef] [Google Scholar]
53. Dragt S, Nieman DH, Schultze-Lutter F, van der Meer F, Becker H, de Haan L, et al. Cannabis use and age at onset of symptoms in subjects at clinical high risk for psychosis . Acta Psychiatr Scand (2012) 125 ( 1 ):45–53 10.1111/j.1600-0447.2011.01763.x [PubMed] [CrossRef] [Google Scholar]
54. Large M, Sharma S, Compton MT, Slade T, Nielssen O. Cannabis use and earlier onset of psychosis: a systematic meta-analysis . Arch Gen Psychiatry (2011) 68 ( 6 ):555–61 10.1001/archgenpsychiatry.2011.5 [PubMed] [CrossRef] [Google Scholar]
55. Degenhardt L, Roxburgh A, McKetin R. Hospital separations for cannabis- and methamphetamine-related psychotic episodes in Australia . Med J Aust (2007) 186 ( 7 ):342–5 [PubMed] [Google Scholar]
56. Caspari D. Cannabis and schizophrenia: results of a follow-up study . Eur Arch Psychiatry Clin Neurosci (1999) 249 ( 1 ):45–9 10.1007/s004060050064 [PubMed] [CrossRef] [Google Scholar]
57. Linszen DH, Dingemans PM, Lenior ME. Cannabis abuse and the course of recent-onset schizophrenic disorders . Arch Gen Psychiatry (1994) 51 ( 4 ):273–9 10.1001/archpsyc.1994.03950040017002 [PubMed] [CrossRef] [Google Scholar]
58. Crippa JA, Zuardi AW, Martin-Santos R, Bhattacharyya S, Atakan Z, McGuire P, et al. Cannabis and anxiety: a critical review of the evidence . Hum Psychopharmacol (2009) 24 ( 7 ):515–23 10.1002/hup.1048 [PubMed] [CrossRef] [Google Scholar]
59. Moreira FA, Wotjak CT. Cannabinoids and anxiety . Curr Top Behav Neurosci (2010) 2 :429–50 10.1007/7854_2009_16 [PubMed] [CrossRef] [Google Scholar]
60. Tambaro S, Bortolato M. Cannabinoid-related agents in the treatment of anxiety disorders: current knowledge and future perspectives . Recent Pat CNS Drug Discov (2012) 7 ( 1 ):25–40 10.2174/157488912798842269 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
61. Karschner EL, Darwin WD, McMahon RP, Liu F, Wright S, Goodwin RS, et al. Subjective and physiological effects after controlled Sativex and oral THC administration . Clin Pharmacol Ther (2011) 89 ( 3 ):400–7 10.1038/clpt.2010.318 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
62. Ilan AB, Gevins A, Coleman M, ElSohly MA, de Wit H. Neurophysiological and subjective profile of marijuana with varying concentrations of cannabinoids . Behav Pharmacol (2005) 16 :487–96 10.1097/00008877-200509000-00023 [PubMed] [CrossRef] [Google Scholar]
63. Zuardi AW, Cosme RA, Graeff FG, Guimaraes FS. Effects of ipsapirone and cannabidiol on human experimental anxiety . J Psychopharmacol (1993) 7 ( 1 Suppl ):82–8 10.1177/026988119300700112 [PubMed] [CrossRef] [Google Scholar]
64. Karniol IG, Shirakawa I, Kasinski N, Pfeferman A, Carlini EA. Cannabidiol interferes with the effects of delta 9-tetrahydrocannabinol in man . Eur J Pharmacol (1974) 28 :172–7 10.1016/0014-2999(74)90129-0 [PubMed] [CrossRef] [Google Scholar]
65. Hollister LE, Gillespie H. Interactions in man of delta-9-tetrahydrocannabinol. II. Cannabinol and cannabidiol . Clin Pharmacol Ther (1975) 18 :80–3 [PubMed] [Google Scholar]
66. Dalton WS, Martz R, Lemberger L, Rodda BE, Forney RB. Influence of cannabidiol on delta-9-tetrahydrocannabinol effects . Clin Pharmacol Ther (1976) 19 :300–9 [PubMed] [Google Scholar]
67. Hollister LE. Cannabidiol and cannabinol in man . Experientia (1973) 29 :825–6 10.1007/BF01946311 [PubMed] [CrossRef] [Google Scholar]
68. Carlini EA, Cunha JM. Hypnotic and antiepileptic effects of cannabidiol . J Clin Pharmacol (1981) 21 :417S–27 10.1002/j.1552-4604.1981.tb02622.x [PubMed] [CrossRef] [Google Scholar]
69. Zuardi AW, Hallak JE, Dursun SM, Morais SL, Sanches RF, Musty RE, et al. Cannabidiol monotherapy for treatment-resistant schizophrenia . J Psychopharmacol (2006) 20 :683–6 10.1177/0269881106060967 [PubMed] [CrossRef] [Google Scholar]
70. Crippa JA, Zuardi AW, Garrido GE, Wichert-Ana L, Guarnieri R, Ferrari L, et al. Effects of cannabidiol (CBD) on regional cerebral blood flow . Neuropsychopharmacology (2004) 29 :417–26 10.1038/sj.npp.1300340 [PubMed] [CrossRef] [Google Scholar]
71. Leweke FM, Koethe D, Pahlisch F, Schreiber D, Gert CW, Nolden BM, et al. Antipsychotic effects of cannabidiol . European Psychiatry (2009) 24 :S207 [Google Scholar]
72. Zuardi AW, Crippa JA, Hallak JE, Pinto JP, Chagas MH, Rodrigues GG, et al. Cannabidiol for the treatment of psychosis in Parkinson’s disease . J Psychopharmacol (2009) 23 :979–83 10.1177/0269881108096519 [PubMed] [CrossRef] [Google Scholar]
73. Borgwardt SJ, Allen P, Bhattacharyya S, Fusar-Poli P, Crippa JA, Seal ML, et al. Neural basis of delta-9-tetrahydrocannabinol and cannabidiol: effects during response inhibition . Biol Psychiatry (2008) 64 :966–73 10.1016/j.biopsych.2008.05.011 [PubMed] [CrossRef] [Google Scholar]
74. Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P, Martin-Santos R, et al. Distinct effects of (delta)9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing . Arch Gen Psychiatry (2009) 66 :95–105 10.1001/archgenpsychiatry.2008.519 [PubMed] [CrossRef] [Google Scholar]
75. Fusar-Poli P, Allen P, Bhattacharyya S, Crippa JA, Mechelli A, Borgwardt S, et al. Modulation of effective connectivity during emotional processing by delta 9-tetrahydrocannabinol and cannabidiol . Int J Neuropsychopharmacol (2010) 13 : 421–32 10.1017/S1461145709990617 [PubMed] [CrossRef] [Google Scholar]
76. Bhattacharyya S, Fusar-Poli P, Borgwardt S, Martin-Santos R, Nosarti C, O’Carroll C, et al. Modulation of mediotemporal and ventrostriatal function in humans by Delta9-tetrahydrocannabinol: a neural basis for the effects of Cannabis sativa on learning and psychosis . Arch Gen Psychiatry (2009) 66 ( 4 ):442–51 10.1001/archgenpsychiatry.2009.17 [PubMed] [CrossRef] [Google Scholar]
77. Zuardi A, Crippa J, Dursun S, Morais S, Vilela J, Sanches R, et al. Cannabidiol was ineffective for manic episode of bipolar affective disorder . J Psychopharmacol (2010) 24 :135–7 10.1177/0269881108096521 [PubMed] [CrossRef] [Google Scholar]
78. Bergamaschi MM, Queiroz RH, Chagas MH, de Oliveira DC, De Martinis BS, Kapczinski F, et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients . Neuropsychopharmacology (2011) 36 :1219–26 10.1038/npp.2011.6 [PMC free article] [PubMed] [CrossRef] [Google Scholar]
79. Crippa JA, Derenusson GN, Ferrari TB, Wichert-Ana L, Duran FL, Martin-Santos R, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report . J Psychopharmacol (2011) 25 :121–30 10.1177/0269881110379283 [PubMed] [CrossRef] [Google Scholar]
80. Nicholson AN, Turner C, Stone BM, Robson PJ. Effect of delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults . J Clin Psychopharmacol (2004) 24 :305–13 10.1097/01.jcp.0000125688.05091.8f [PubMed] [CrossRef] [Google Scholar]
81. Hallak JE, Hado-de-Sousa JP, Crippa JA, Sanches RF, Trzesniak C, Chaves C, et al. Performance of schizophrenic patients in the Stroop Color Word Test and electrodermal responsiveness after acute administration of cannabidiol (CBD) . Rev Bras Psiquiatr (2010) 32 :56–61 10.1590/S1516-44462010000100011 [PubMed] [CrossRef] [Google Scholar]
82. Hallak JE, Dursun SM, Bosi DC, de Macedo LR, Hado-de-Sousa JP, Abrao J, et al. The interplay of cannabinoid and NMDA glutamate receptor systems in humans: preliminary evidence of interactive effects of cannabidiol and ketamine in healthy human subjects . Prog Neuropsychopharmacol Biol Psychiatry (2011) 35 :198–202 10.1016/j.pnpbp.2010.11.002 [PubMed] [CrossRef] [Google Scholar]
83. Ramaekers JG, Berghaus G, van Laar M, Drummer OH. Dose related risk of motor vehicle crashes after cannabis use . Drug Alcohol Depend (2004) 73 ( 2 ):109–19 10.1016/j.drugalcdep.2003.10.008 [PubMed] [CrossRef] [Google Scholar]
84. Ranganathan M, D’Souza DC. The acute effects of cannabinoids on memory in humans: a review . Psychopharmacology (Berl) (2006) 188 ( 4 ):425–44 10.1007/s00213-006-0508-y [PubMed] [CrossRef] [Google Scholar]
85. Hunault CC, Mensinga TT, Böcker KB, Schipper CM, Kruidenier M, Leenders ME, et al. Cognitive and psychomotor effects in males after smoking a combination of tobacco and cannabis containing up to 69 mg delta-9-tetrahydrocannabinol (THC) . Psychopharmacology (Berl) (2009) 204 ( 1 ):85–94 10.1007/s00213-008-1440-0 [PubMed] [CrossRef] [Google Scholar]
86. Hampson AJ, Grimaldi M, Lolic M, Wink D, Rosenthal R, Axelrod J. Neuroprotective antioxidants from marijuana . Ann N Y Acad Sci (2000) 899 :274–82 10.1111/j.1749-6632.2000.tb06193.x [PubMed] [CrossRef] [Google Scholar]
87. Lastres-Becker I, Molina-Holgado F, Ramos JA, Mechoulam R, Fernandez-Ruiz J. Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson’s disease . Neurobiol Dis (2005) 19 ( 1–2 ):96–107 10.1016/j.nbd.2004.11.009 [PubMed] [CrossRef] [Google Scholar]
88. Harvey BS, Ohlsson KS, Maag JL, Musgrave IF, Smid SD. Contrasting protective effects of cannabinoids against oxidative stress and amyloid-beta evoked neurotoxicity in vitro . Neurotoxicology (2012) 33 ( 1 ):138–46 10.1016/j.neuro.2011.12.015 [PubMed] [CrossRef] [Google Scholar]
89. Scuderi C, Filippis DD, Iuvone T, Blasio A, Steardo A, Esposito G. Cannabidiol in medicine: a review of its therapeutic potential in CNS disorders . Phytother Res (2009) 23 ( 5 ):597–602 10.1002/ptr.2625 [PubMed] [CrossRef] [Google Scholar]
90. Morgan CJ, Freeman TP, Schafer GL, Curran HV. Cannabidiol attenuates the appetitive effects of delta 9-tetrahydrocannabinol in humans smoking their chosen cannabis . Neuropsychopharmacology (2010) 35 ( 9 ):1879–85 10.1038/npp.2010.58 [PMC free article] [PubMed] [CrossRef] [Google Scholar]