The relationship between cannabidiol and psychosis ...

0 downloads 0 Views 332KB Size Report
The relationship between cannabidiol and psychosis: A review. CORRESPONDENCE. Thayanne Brandão Guimarães Silva, MD. Departamento de Saúde II.
CANNABIDIOL AND PSYCHOSIS

REVIEW ARTICLE

ANNALS OF CLINICAL PSYCHIATRY 2015;27(2):134-141

The relationship between cannabidiol and psychosis: A review Thayanne Brandão Guimarães Silva, MD Cássio Queiroz Balbino, MD Department of Health State University of Southwestern Bahia, Jequié Bahia, Brazil

Anderson Fábio Moura Weiber, MD Brazilian Psychiatric Association Brazilian Medical Association Department of Health State University of Southwestern Bahia, Jequié Bahia, Brazil

Cannabis sativa is the most widely used illicit drug in the world. There is concern about its harmful effects, especially because of increasing potency, which has been reported globally. These effects seem to result from the relationship among its components, notably delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which have opposite effects. THC is considered responsible for the main psychotropic effects of the drug, while CBD seems to antagonize these effects, particularly those that induce psychosis. BACKGROUND:

We performed a PubMed literature review of research discussing the association of cannabidiol and psychosis published from 2006 to July 2014. METHODS:

RESULTS: The effects of Cannabis seem to depend on several variables related

to the type of plant, its strength, usage patterns, and intersubjective variations. CBD could be used to treat several conditions, including psychosis, when the current treatment is associated with significant side effects. Because of the complexity of the subject, including limitations and contradictions in studies available to date, further research involving the possible antipsychotic effect and other potential positive effects of Cannabis are needed. There also are noteworthy differences between the research design parameters and recreational use of Cannabis. CONCLUSIONS:

CORRESPONDENCE

Thayanne Brandão Guimarães Silva, MD Departamento de Saúde II Universidade Estadual do Sudoeste da Bahia Avenida José Moreira Sobrinho, S/N Bairro Jequiezinho Jequié, Bahia, Brazil 45210-506 E-MAIL

[email protected]

134

INTRODUCTION Atakan1 and Schoeler and Bhattacharyya2 found that Cannabis sativa, also known as marijuana, is the most widely used illicit drug in the world, especially in Western societies3; individuals often start using Cannabis in

May 2015 | Vol. 27 No. 2 | Annals of Clinical Psychiatry

ANNALS OF CLINICAL PSYCHIATRY

adolescence.2 Cannabis has been used and cultivated for at least 6,000 years. However, studies involving its pharmacological properties are more recent, from the end of the last century.4 Cannabis resin (“hash”5 or hashish6) has 2% to 4% of delta-9-tetrahydrocannabinol (THC), the substance associated with psychotomimetic symptoms and a similar proportion of cannabidiol (CBD), the main non-psychotropic ingredient of the plant. Herbal Cannabis5 (marijuana),6 contains a similar percentage of THC as resin but no CBD.5 In herbal or resin forms, the average CBD content can exceed that of THC.1 However, sinsemilla (“skunk”5 or genetically modified strains of the plant5) increasingly has taken over the market in many areas. At the same time, the THC concentration in sinsemilla and, to a lesser extent, herbal Cannabis has been rising consistently. Potency of Cannabis has been increasing.1 As individuals who use different strains of Cannabis manifest different psychological symptoms,7 concerns about health effects have been increasing, especially with those who are susceptible to its harmful effects.1 Higher THC levels found in the hair of daily users was associated with increased depression and anxiety and poorer word recall and source memory. In contrast, higher CBD in hair was associated with lower psychosis-like symptoms and better recognition memory.1 However, Cannabis users often are unaware of the ratio of CBD to THC because CBD has no psychotomimetic effect in humans.7 Nevertheless, users usually prefer the Cannabis strains with higher THC content because it is the main constituent responsible for the desired effect of being “stoned.”1 Because of the lack of literature on recent discoveries about these issues and the relevance of this subject, including the possibility of new therapeutic alternatives for health problems and addressing the adverse effects of therapeutic agents, we performed a literature review on the association between cannabidiol and psychosis.

METHODS

Cannabis plant Cannabis is a complex plant containing >600 chemical components.1,2 It has 2 main subspecies: Cannabis indica and Cannabis sativa. Indica-dominant strains are short and have broad, dark green leaves; sativadominant plants usually are taller with thin, pale-green leaves.1 Natural compounds of the Cannabis plant are known as phytocannabinoids.1 Cannabis sativa contains >80 different cannabinoids,8 which are recognized for both their toxic and potential therapeutic effects.2 There are 4 major compounds: delta-8-tetrahydrocannabinol, cannabinol, THC, and CBD. THC and CBD are responsible for another difference among Cannabis plant’s subspecies: the indicadominant strains have higher CBD content compared with the sativa plants, which have higher levels of THC, making the latter preferred by users.1

THC THC is the main psychoactive constituent of Cannabis1,9 and is considered responsible for most, if not all, of the effects associated with its use,9 especially its addictive properties.3 THC was isolated in 1964, 1 year after CBD.1 THC has been identified and synthesized10 and widely researched in animals and humans.1 THC may be responsible for the anxiogenic effects of Cannabis and can induce sedation and psychotic symptoms.7 THC and other cannabinoids have biphasic effects on anxiety with lower doses generally being anxiolytic and higher doses being anxiogenic.11 As the main component of smoked Cannabis,7 THC could exacerbate pre-existing psychotic symptoms, anxiety, and memory impairments in patients with schizophrenia. THC also is thought to be the Cannabis sativa ingredient responsible for the increased risk of developing schizophrenia with regular Cannabis use, and could have neurotoxic and neuroprotective effects.11

CBD

Our article is based on a literature search using PubMed from February to July 2014. We located publications from as early as 2006, using the keywords cannabidiol and psychosis, according to the Medical Subject Headings terms description. The search yielded 14 full-text, Englishlanguage results and reference lists were analyzed.

AACP.com

RESULTS

CBD is the second most abundant constituent of Cannabis sativa12 and the main non-psychotropic phytocannabinoid in the plant, corresponding to 40% of its extract.13 Unlike THC, CBD does not impair memory or other cognitive functions. CBD could be used to treat Cannabis-induced psychopathology, and as an anxiolytic or an antipsychotic for symptoms not caused by Cannabis use.11

Annals of Clinical Psychiatry | Vol. 27 No. 2 | May 2015

135

CANNABIDIOL AND PSYCHOSIS

Endocannabinoid system Almost 3 decades after THC was isolated and identified, cannabinoid receptors (CB-Rs) in the brain were described and cloned,10 and naturally occurring substances that attach to these receptors, called endocannabinoids9 or endogenous cannabinoids, were isolated and identified.10 Endogenous cannabinoids correspond to a family of lipid messengers that target the same cell surface receptors engaged by THC in Cannabis.14 The discovery of Cannabis compounds led to the discovery of the endocannabinoid system, a relevant neurotransmitter system widely distributed in the brain and elsewhere in the body. It has been associated with several significant functions, serving multiple regulatory roles in neuronal, vascular, metabolic, immune, and reproductive systems.1 This system was named the “cannabinoid receptor system” because THC is a partial agonist,1 and it seems to exist as a complete system with multiple CB-Rs and endocannabinoid transmitter anandamide-related compounds.15 The endocannabinoid system is formed by endocannabinoids, which are responsible for activating the CB-Rs under normal psychological circumstances, along with CB-Rs and the enzymes involved in synthesis and degradation of these substances.9 The highest densities of CB-Rs are found in brain regions implicated in schizophrenia, including the prefrontal cortex, basal ganglia, hippocampus, and anterior cingulate cortex.15 Two of these receptors are CB1 and CB2 receptors.9 They have different distributions in the body, with CB1-R predominating in the CNS,9 particularly in the brain in the substantia nigra, the basal ganglia, limbic system, hippocampus, and cerebellum. However CB1-R also is expressed in the peripheral nervous system, liver, thyroid, uterus, bones, and testicular tissue.1 CB2-R mainly is found in the immune system,9 spleen, and the gastrointestinal system and, to some extent, in the brain and peripheral nervous system. Both also are expressed in human placenta and seem to participate in regulating serotonin transporter activity.1 Because THC and other direct-acting cannabinoid agonists can induce psychotic symptoms in healthy volunteers and patients with schizophrenia, it has been suggested that hyperactivity of the endocannabinoid system might contribute to psychotic states. On the other hand, an opposite view—namely that certain components of the endocannabinoid system might have a protective role in schizophrenia—was suggested by studies with antipsychotic-naïve patients with schizophrenia. This research

136

found that the symptom intensity experienced by these patients was negatively correlated with cerebrospinal levels of anandamide, known to be involved in regulation of pain, mood, and cognition.14 However, increased anandamide levels also have been found in the cerebrospinal fluid of schizophrenia patients compared with healthy controls.15 By activation of CB-Rs, many other neurotransmitters are affected, such as acetylcholine, dopamine, α-aminobutyric acid, glutamate, serotonin, norepinephrine, and endogenous opioids.1,11 When this occurs by endocannabinoids, there is an inhibition of excessive neurotransmitter release.9 Through these mechanisms, functions such as cognition, memory, motor movements, and pain perception are affected. The complex interactions with other neurotransmitter systems and the ondemand regulatory role on them may interfere with CB-Rs functions. Elevation of intracellular calcium leads to the release of endocannabinoids, such as anandamide and 2-arachidonoylglycerol, from the postsynaptic sites to the synaptic cleft. They then act as retrograde neurotransmitters on presynaptically located CB1-Rs to maintain homeostasis and prevent the excessive neuronal activity. Usually, there is a rapid removal of these endocannabinoids from the extracellular space by cannabinoid transporters, often referred to as anandamide membrane transporters. This contributes to their breakdown by internalizing the molecule and allowing access to fatty acid amide hydrolase (FAAH). Investigators have discovered other receptor candidates associated with this system. It is important to mention that it is possible that some endocannabinoids, THC, and several synthetic CB1-R/CB2-R agonists, and antagonists interact with certain non-CB1, non-CB2 G-protein-coupled receptors, ligand-gated ion channels, and nuclear receptors. This would make the biochemical mechanisms involved in this system even more complex. As many brain areas and neurotransmitter systems are implied in psychotic disorders, particularly in schizophrenia, the same neural regions and the neurotransmitter systems are of great importance. Nevertheless, there isn’t a complete understanding on the diverse functions of the endocannabinoid system yet, although research on this system has been included in the fastest growing fields in psychopharmacology.1

The effects of Cannabis Recreational Cannabis use can lead to persistent adverse effects on mental health.9 Younger users are likely to be

May 2015 | Vol. 27 No. 2 | Annals of Clinical Psychiatry

ANNALS OF CLINICAL PSYCHIATRY

more vulnerable to its impairing effects. Although studies show the age of onset of Cannabis use is decreasing,2 public concern about the adverse effects of regular use of Cannabis on adolescent psychosocial development and mental health is increasing.3 There is evidence indicating a close association between Cannabis consumption and an increased risk for cognitive impairment, depression, anxiety disorders, paranoia, other psychotic symptoms, or even schizophrenia.3,9 Early Cannabis use has been associated with development of schizophrenia spectrum disorder symptoms.1 The relationship between Cannabis and psychosis or schizophrenia has been reported. Marijuana use occurs more often among patients with schizophrenia than among the healthy population, and the extended use of marijuana can trigger psychotic episodes in patients with schizophrenia.15 This relationship seems to depend on many variables, including Cannabis potency.9 There also has been evidence of a relationship between Cannabis dosage and an increased risk of development of a chronic psychotic disorder. However, the reasons and biological basis of differences in susceptibility to the negative effects of Cannabis are unknown, although there are some emerging vulnerability factors.1 Although most recreational users never develop serious or permanent psychological disorders or other health deficits, Cannabis is not considered safe and can cause undesirable effects, mainly on psychological functioning, including persistent mental illness depending on the dosage, the frequency of use, the age of onset, the potency of the Cannabis that is used, and individual sensitivity.9 This is related to variables that range from genes to personality characteristics.1 Between 15% and 50% of users experience transient psychotic symptoms, from a couple of hours to up to a week, and usually recover without requiring intervention, according to some studies.1 Individuals at high-risk for psychosis who exhibited lower cerebrospinal levels of anandamide showed a higher risk for transitioning to frank psychosis.14 Evidence also points to a stronger effect of Cannabis use in individuals predisposed to psychosis at baseline, particularly a positive family history of psychosis and the presence of subclinical psychotic features, compared with healthy individuals.1 Health risks are higher with stronger variants of the plant in patients with psychosis. Individuals at ultra-high risk for psychosis seem to be more sensitive to the psychotogenic effects of Cannabis than users in the general population. The same occurs in Cannabis users with high schizotypy scores, similar to those with schizo-

AACP.com

typal personality disorder, who are more susceptible to develop psychosis-like experiences at the time of use, along with unpleasant side effects.1 It has been reported that high dosages of THC in Cannabis can cause acute and transient psychotic reactions even in users without psychosis. Research has shown that these effects are more intense and last longer in naïve and occasional users compared with frequent users.9 An association between the use of high-potency Cannabis and occurrence of a first psychotic episode has been documented.9 People experiencing a first episode of psychosis used higher-potency Cannabis for longer durations and greater frequency compared with healthy controls.1 Moreover, patients with psychotic symptoms seem to use “skunk” or sinsemilla Cannabis more often than hashish compared with non-psychotic patients. Evidence suggests that Cannabis use has an adverse effect on the course of schizophrenia, such as relapse, exacerbation of symptoms, and quantity of hospitalizations.9 Cannabis and THC dosedependently cause cognitive and psychomotor function impairments, along with memory, (selective) attention, locomotion, perception, and response impairments,16-18 especially during the first hour after smoking and 1 to 2 hours after oral intake, when the effects are stronger.7 There is increasing evidence of dysfunction in the endogenous cannabinoid system in patients with schizophrenia as well as its association with the typical cognitive impairment of the disorder. Cannabinoid agonists impair many cognitive functions, especially memory and attention, and similarities have been reported between the cognitive impairment seen in schizophrenia and that induced by Cannabis intoxication. This can contribute to development of novel pharmacological approaches.15 The complex nature of schizophrenia—a disorder that involves multiple brain neurotransmitters, including endogenous cannabinoids—has hampered research for safe and effective drugs for its treatment.14 Many pharmaceutical companies have marketed Cannabis extracts and tinctures, which were prescribed by doctors for many conditions, such as pain, whooping cough, and asthma, besides its use as a sedative/hypnotic agent.10 However, this type of application of Cannabis disappeared by the middle of the 20th century. It happened mainly because of the variable potency of Cannabis extracts; 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,

Annals of Clinical Psychiatry | Vol. 27 No. 2 | May 2015

137

CANNABIDIOL AND PSYCHOSIS

such as anxiety and cognitive impairment; and the legal restrictions to the use of Cannabis-derived medicines.10 Cannabis extracts and synthetic cannabinoids are considered illegal substances.19

CBD–THC ratio Winton-Brown et al12 found that CBD has no significant symptomatic effects. Despite this, CBD has been associated with a possible protective effect and it can even counteract the negative effects of THC.9,13 It has been suggested that CBD in Cannabis samples, for example, could protect users against occurrence of THC-induced acute psychotic episodes.13 Pretreatment with CBD was associated with a less acute induction of psychotic symptoms by THC.1,11 A pretreatment design effectively is similar to combined administration; however, it doesn’t exclude the possibility of CBD having a beneficial effect on THC-induced psychotic symptoms if administered subsequently.11 But, as previously explained, CBD is found only in Cannabis resin, rarely appearing in herbal Cannabis.9,13 However, 1 study20 found that CBD itself has no effect and doesn’t antagonize the physical effects of THC, including effects on heart rate and blood pressure that have been observed by other researchers.9 Rottanburg et al21 first proposed a protective effect of CBD on THC-induced psychosis in a 1982 study. They suggested that South African Cannabis variants, which have a higher THC content and lack CBD, are associated with the high incidence of Cannabis-related psychosis among their patients. In addition, the CBD–THC ratio probably influences the risk of abuse. A study cited by Dalton et al22 suggests that CBD reduces the euphoric effect of THC when both are administered together. Using different time spans (age of onset) or patterns of Cannabis use—how often, how long, cumulative lifetime use, types of Cannabis (potency, CBD–THC ratio)—several researchers have reported conflicting results involving brain studies. Some indicate that structural changes after chronic, intensive Cannabis use are situated in the orbitofrontal cortex, the anterior cingulate cortex, the striatum, the amygdala, and the hippocampus. Indeed, reductions in the volumes of some of these areas, such as the hippocampus, amygdala and cerebellum, in heavy Cannabis adult users compared with healthy controls, have been reported. The CBD-THC ratio was important in a study that associated higher THC and lower CBD with hippocampal volume reduction, suggesting neurotoxic effects of THC and neuroprotective effects of CBD. However, the

138

minimum CBD concentration and the CBD-THC ratio necessary for which the protective effects of CBD could be expressed has not been determined. Because of the scarcity of studies concerning different types of Cannabis used by patients with a psychotic disorder, it’s unknown to what extent the presence or absence of CBD in Cannabis influences the early occurrence of a first-episode psychosis or the extent to which it affects the course of the disease.9 Some studies have indicated an association between the effects of THC and a decrease in brain activity in the striatum, the opposite effect demonstrated by CBD.9,11 This area is important in planning activities, modulating motor activity, and performing cognitive tasks.9 Nevertheless, not all studies have corroborated this finding.23 When administered orally and compared with placebo, THC and CBD were reported to have opposite effects on activation of anterior cingulate/medial prefrontal cortex, and lateral prefrontal cortex during verbal recall; in the hippocampus/ parahippocampal gyrus during the response inhibition task; in the amygdala when participants viewed fearful faces; in the superior temporal cortex when participants listened to speech; and in the occipital cortex during visual processing. The last 2 findings are consistent with evidence that Cannabis has marked effect on sensory experiences.11,13 These differences in CBD and THC effects may underlie their different symptomatic and behavioral effects and probably suggest that these distinct effects are not specific to a particular brain system, and could be common to multiple regions and cognitive processes.11 In schizophrenia, functional changes in auditory and visual processing pathways have been implicated in the pathophysiology of auditory and visual hallucinations, respectively. Transient auditory and visual hallucinations are occasionally experienced with Cannabis and appear to be mediated by THC. Single-acute doses of THC and CBD modulate brain function differently in areas that process auditory and visual stimuli and relate to induced psychotic symptoms.12 High CBD content was associated with reduced appreciation and weaker desire for the drug (“wanting”) compared with low-CBD content, which can be related to less risk for developing an addiction. However, it’s unclear if smoking hashish reduces risk of addiction compared with smoking highly potent Cannabis.9

CBD and its antipsychotic effect Available evidence shows therapeutic potential of CBD over a range of non-psychiatric and psychiatric disorders such as anxiety, depression, and psychosis. It has been

May 2015 | Vol. 27 No. 2 | Annals of Clinical Psychiatry

ANNALS OF CLINICAL PSYCHIATRY

demonstrated that CBD inhibits THC-induced anxiety and psychotic-like symptoms, including disconnected thoughts, perceptual disturbance, depersonalization, and resistance to communication.13 It is suggested that CBD could exert antipsychotic effects in patients with schizophrenia, along with its capacity for reducing the psychosislike effects of THC and synthetic analogs.14 However, there is evidence that CBD could have antipsychotic effects in patients who have psychotic symptoms, but not in healthy individuals without pre-existing psychotic phenomena.11 Studies show that although it binds to CB-Rs weakly, even in low doses, CBD can counteract the effects of THC9 when administered simultaneously.15 One of the mechanisms involves inhibition of degradation of anandamide, which prevents THC from interacting with CB-Rs. Acting like this, CBD allows anandamide to intensify and extend its effect.9 Elevation of anandamide levels in cerebrospinal fluid is inversely associated with psychotic symptoms. In addition, enhanced anandamide signaling has been shown to slow the transition from initial prodromal states into frank psychosis, as well as postpone transition from one state to another.14 CBD and the dopamine D2/D3-receptor antagonist amisulpride, a potent atypical antipsychotic, have been shown to be effective and safe and led to significant clinical improvement; however, CBD displayed a markedly superior side-effect profile.14 Patients with schizophrenia treated with CBD presented with higher anandamide serum levels than those receiving amisulpride.13,14 However, further research is necessary to clarify whether this link represents cause and effect. Although serum levels of endocannabinoids have been found to be less effective in early stages of schizophrenia, they have been reported beneficial in chronic cases.14 Many antipsychotic drugs produce side effects, such as motor disturbances (so-called extrapyramidal symptoms), weight gain, and sexual dysfunction, which influence acute compliance and long-term treatment adherence. However, compared with amisulpride, treatment with CBD was associated with significantly fewer extrapyramidal symptoms, less weight gain, and lower prolactin increase, which is a predictor of galactorrhea and sexual dysfunction.14 In addition, CBD was demonstrated to be more effective as an antipsychotic.9 By indirectly activating CB1 receptors via increased levels of anandamide, CBD could modulate neurotransmitters systems related to these receptors. Facilitation of CB1-mediated neurotransmission by CBD also increases adult hippocampal neuro-

AACP.com

genesis, a mechanism that could be related to the cognitive deficits found in patients with schizophrenia.13,14 CBD and haloperidol are effective in reducing dopaminergic agonist apomorphine-induced stereotyped behavior in a dose-related manner. Although they increased plasma levels of prolactin, CBD had lower potency. Compared with haloperidol, CBD did not induce catalepsy, even at doses as high as 480 mg/kg.10,13 It is suggested that CBD has an effect profile similar to atypical antipsychotics.13,15 Long et al23 reported that CBD reverses some dopaminergic effects associated with apomorphine, such as stereotypy, prolactin secretion, and palpebral ptosis, while producing none of the catalepsy associated with typical antipsychotics such as haloperidol. In addition, researchers have demonstrated that both CBD and the atypical antipsychotic clozapine, but not haloperidol, increase neuronal activity in the prefrontal cortex. Only haloperidol was capable of increasing activity in the dorsal striatum, which can be related to its motor side effects.13 In mice, CBD was reported to reverse hyperlocomotion produced by amphetamine and ketamine,23 an NMDA (N-methyl-d-aspartate) receptor antagonist,13 without producing catalepsy.23 These findings connect the antipsychotic-like effects of CBD to a glutamate-based model13 and reinforce the potential of CBD to produce few unwanted motor effects.23 CBD has weak affinity for CB1 and CB2 receptors and does not change neural uptake of amine neurotransmitters such as dopamine and serotonin (5-HT) or excite dopaminergic nerve cell firing.23 In contrast, it is capable of producing multiple pharmacological actions over a range of drug concentrations.13 It is suggested that the antipsychotic-like doses of CBD (60 to 120 mg/kg) are higher than those needed to induce anxiolytic-like effects and reverse behavioral deficits induced by the NMDA receptor antagonist MK-801.13 Unlike many other studies, Schubart et al24 conducted their research in a large nonclinical population of young adult Cannabis users, and found a significant inverse relationship between CBD content and self-reported positive symptoms, but not negative symptoms or depression. The authors highlight that a larger effect couldn’t be expected because the dosage of CBD in “joints” is lower than that used for oral administration in treatment studies. Therefore, CBD is considered a potential antipsychotic, especially because of its relatively low side-effect profile. There also is research of CBD that suggests it may offer therapeutic benefits for other conditions, such as

Annals of Clinical Psychiatry | Vol. 27 No. 2 | May 2015

139

CANNABIDIOL AND PSYCHOSIS

inflammation, diabetes, cancer, and neurodegenerative diseases.1,13,14 The ability of CBD to antagonize psychotomimetic and other psychotropic effects of THC constituted an initial stimulus for research assessing CBD pharmacological properties.13 Other studies have demonstrated that CBD was well-tolerated but did not significantly affect hepatic or cardiac functions. Thus, CBD exerts clinically relevant antipsychotic effects associated with marked tolerability and safety compared with available medications.14 On the other hand, CBD can increase THC concentrations in the brain.10 Although CBD delays the onset of the effect of THC, it also prolongs its effect.9 Research indicates that CBD and THC have similar effects but they also can express almost opposite effects, depending on what is involved.1 CBD is proposed to activate or modify the function of a large number of receptors in the CNS, including 5-HT1A receptors (an effect shared by the atypical antipsychotic aripiprazole).13 It may enhance endogenous cannabinoid anandamide signaling indirectly, by inhibiting its intracellular degradation14 catalyzed by the enzyme FAAH and the adenosine transporter, indirectly increasing its levels.13 Therefore, the mechanisms aren’t unique and depend on the effect being assessed, such as anxiolytic, anticompulsive, antidepressant, or antipsychotic-like effects and the drug regime (single vs repeated administration).9,13 The CBD effect also may involve the bell-shaped dose-response curves usually observed.13 Other mechanisms are associated with the interaction between CBD and other recently discovered CB-Rs.9 It is relevant to emphasize the existence of negative outcomes related to the possible antipsychotic effects of CBD. Also, chronic treatment couldn’t modify behavioral changes such as locomotor hyperactivity.13 CBD has been shown to increase activity in many brain sites including the medial prefrontal cortex and the cingulate gyrus, areas involved in attentional processes, which frequently are impaired in schizophrenia. The cognitive impairments, mainly in attention, working memory, and aspects of executive function, mostly are linked to the long-term disability typically caused by the disorder, and available treatments have limited efficacy against them. Hallak et al,15 studying selective attention in people diagnosed with schizophrenia, found worse performance in the patients receiving 600 mg of CBD compared with those receiving placebo or 300 mg of CBD. This could be related to its sedative effect, which would decrease attention. This contention has support in studies that indicate the acute

140

administration of CBD has a short-lasting hypnotic effect in rats. The authors highlight that their study, using a single dose of CBD, doesn’t exclude the possibility that chronic use could lead to cognitive improvement, such as with clozapine, which requires a period of adaptation to its sedative effect before its therapeutic action can be observed.15

Neuroprotective effects of CBD It has been suggested that CBD blocks the effects of THC by some intrinsic pharmacological properties. When administered alone, CBD has been shown to produce its own effects, including hypnotic, anticonvulsive, neuroprotective, and hormonal (increased corticosterone and cortisol levels) effects. These effects support the hypothesis that CBD could have anxiolytic and/or antipsychotic effects.10 However, Niesink and van Laar9 verified that CBD has almost no effect on normal physiological processes. It’s necessary a stimulus (such as pain or a shock reaction) or another cannabinoid (such as THC) upsets the normal “tone” of the endocannabinoid system, so the effect of CBD can be expressed.25 CBD also has a potent action in inhibiting oxidative and nitrosative stress. This mechanism has been related to its neuroprotective effects with implications for the treatment of Alzheimer’s, Huntington’s, and Parkinson’s diseases. Findings suggest that CBD can exert CB1- and CB2-independent neuroprotective/antioxidant/antiinflammatory effects.13 Despite the paucity of data on these issues, the limited number of available investigations suggest few “protective” effects of CBD on cognitive functions.9

CONCLUSIONS Being the most commonly used illicit drug globally and having a certain complexity and increasing strength, studies involving Cannabis and its constituents are appropriate and necessary in the context of public health, especially with regard to mental health. With the discovery of CBD, the endocannabinoid system, and other systems involved in the effects of cannabinoids, there is a need for research on the potential therapeutic value of this agent for several clinical conditions—including the psychotic effects induced by Cannabis itself. The therapeutic and neuroprotective effects of Cannabis, as well as its harmful effects, depend on a variety of intrinsic factors within the plant strain. It is especially important to consider the concentrations and ratios

May 2015 | Vol. 27 No. 2 | Annals of Clinical Psychiatry

ANNALS OF CLINICAL PSYCHIATRY

among the plant’s constituents, mainly THC and CBD. The plant’s effects also depend on factors such as exposure time, use patterns, and individual susceptibility factors, which need to be considered in studies and in any debate on the issue. This will help avoid overly biased and hasty conclusions. These aspects also show that there must be a greater homogenization of the variables and parameters involved in further studies to reduce divergence on results, for example, with regard to doses, ratios/strength, administration time/frequency of use, route of administration, age, and individual susceptibility. These facts make clear that studies rarely replicate the usual conditions of recreational Cannabis use. Clearly, there is difficulty in extrapolating the results to the habitual use of Cannabis. Recreational use also is more focused on the plant’s psychological effects, while studies focus more on its physical effects. Mechanisms involved in the intersubjective variation/individual susceptibility and in the effects related to Cannabis components also are not well understood. Because of the complexity involved, including several associated systems, Cannabis components or compounds require extensive investigation, identifying groups that could benefit from Cannabis use or its components, as a therapeutic or even preventive strategy. There are few studies about the safety and side effects profile of CBD in humans and much of the data were found secondarily to the central objective of small studies, making it necessary to conduct more specific studies for each of the issues involved.

All these limitations imply a lack of data about the distinct varieties of Cannabis, and a lack of information regarding the pharmacokinetics involved, essential for better assessment of a substance as a possible therapeutic strategy. Nevertheless, one can consider CBD as a potential therapeutic agent, even for disorders that defy modern medicine, for which available medications are ineffective, insufficient, and/or present side effects that limit their use in clinical practice and negatively influence therapeutic adherence many times. Apparently because it has a satisfactory profile of side effects and safety, CBD can serve as a basis for future therapeutic arsenal, including among antipsychotics. Considering that findings in this area are relatively new and sometimes conflicting, and there is still much to be investigated, it is worth considering current evidence to deepen our knowledge of the effects and mechanisms involved in the action of Cannabis compounds such as CBD. Further research with well-designed and satisfactory samples is needed for better scientific support and future decisions about the use of Cannabis, its different varieties, and its components. Additionally, we recommend further research and exhaustive reading of the references here and additional references found in the studies for better understanding, knowledge, and critical view about these issues. ■ The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products. DISCLOSURES:

REFERENCES 1. Atakan Z. Cannabis, a complex plant: different compounds and different effects on individuals. Ther Adv Psychopharamcol. 2012;2:241-254. 2. Schoeler T, Bhattacharyya S. The effect of cannabis use on memory function: an update. Subst Abuse Rehabil. 2013;4:11-27. 3. Marco EM, García-Gutiérrez MS, Bermúdez-Silva FJ, et al. Endocannabinoid system and psychiatry: in search of a neurobiological basis for detrimental and potential therapeutic effects. Front Behav Neurosci. 2011;5:63. 4. Li H. An archaeological and historical account of cannabis in China. Economic Botany. 1973;28:437-448. 5. Di Forti M, Morgan C, Dazzan P, et al. High-potency cannabis and the risk of psychosis. Br J Psychiatry. 2009;195:488-491. 6. Potter DJ, Clark P, Brown MB. Potency of delta 9–THC and other cannabinoids in cannabis in England in 2005: implications for psychoactivity and pharmacology. J Forensic Sci. 2008;53:90-94. 7. Morgan CJ, Curran HV. Effects of cannabidiol on schizophrenia-like symptoms in people who use cannabis. Br J Psychiatry. 2008;192:306-307. 8. Howlett AC, Johnson MR, Melvin LS, et al. Nonclassical cannabinoid analgetics inhibit adenylate cyclase: development of a cannabinoid receptor model. Mol Pharmacol. 1988;33:297-302. 9. Niesink RJ, van Laar MW. Does cannabidiol protect against adverse psychological effects of THC? Front Psychiatry. 2013;4:130.

AACP.com

10. Zuardi AW, Crippa JA, Hallak JE, et al. Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res. 2006;39:421-419. 11. Bhattacharyya S, Morrison PD, Fusar-Poli P, et al. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology. 2010;35:764-774. 12. Winton-Brown TT, Allen P, Bhattacharyya S, et al. Modulation of auditory and visual processing by delta-9tetrahydrocannabinol and cannabidiol: an FMRI study. Neuropsychopharmacology. 2011;36:1340-1348. 13. Campos AC, Moreira FA, Gomes FV, et al. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond B Biol Sci. 2012;367:3364-3378. 14. Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2:e94. 15. Hallak JE, Machado-de-Sousa JP, Crippa JA, 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. 16. Ramaekers JG, Berghaus G, van Laar M, et al. Dose related risk of motor vehicle crashes after cannabis use. Drug Alcohol Depend. 2004;73:109-119. 17. Ranganathan M, D’Souza DC. The acute effects of cannabinoids on memory in humans: a review. Psychopharmacology (Berl). 2006;188:425-444.

18. Hunault CC, Mensinga TT, Böcker KB, 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;204:85-94. 19. Manzanares J, Julian M, Carrascosa A. Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Curr Neuropharmacol. 2006;4:239-257. 20. Zuardi AW, Shirakawa I, Finkelfarb E, et al. Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology (Berl). 1982;76:245-250. 21. Rottanburg D, Robins AH, Ben-Arie O, et al. Cannabisassociated psychosis with hypomanic features. Lancet. 1982;2:1364-1366. 22. Dalton WS, Martz R, Lemberger L, et al. Influence of cannabidiol on delta-9-tetrahydrocannabinol effects. Clin Pharmacol Ther. 1976;19:300-309. 23. Long LE, Malone DT, Taylor DA. Cannabidiol reverses MK-801-induced disruption of prepulse inhibition in mice. Neuropsychopharmacology. 2006;31:795-803. 24. Schubart CD, Sommer IE, van Gastel WA, et al. Cannabis with high cannabidiol content is associated with fewer psychotic experiences. Schizophr Res. 2011; 130:216-221. 25. Alger BE, Kim J. Supply and demand for endocannabinoids. Trends Neurosci. 2011;34:304-315.

Annals of Clinical Psychiatry | Vol. 27 No. 2 | May 2015

141