1–  https://www.ncbi.nlm.nih.gov/pubmed/12640322

[Cannabis and schizophrenia: demographic and clinical correlates].

CONCLUSION:

The socio-demographic characteristics of cannabis abuse or dependence in schizophrenia are similar to those found in general population. Cannabis using schizophrenic patients were more likely to be younger and male than non users. The duration of hospitalization was significantly longer for the group with cannabis abuse. Prevalence of suicide attempts in schizophrenia is closely correlated to cannabis abuse.

2– https://www.ncbi.nlm.nih.gov/pubmed/28832666

Cannabis use in male and female first episode of non-affective psychosis patients: Long-term clinical, neuropsychological and functional differences.

CONCLUSION:

Despite knowing that there is a relationship between cannabis use and psychosis, due to the high prevalence of cannabis use among male FEP patients, the results showed that there were very few differences in clinical and neurocognitive outcomes between men and women who used cannabis at the start of treatment compared to those who did not.

3– https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908416/

“Hallucinations” Following Acute Cannabis Dosing: A Case Report and Comparison to Other Hallucinogenic Drugs

Conclusion: Acute cannabis exposure in a healthy adult male resulted in self-reported hallucinations that rated high in magnitude on several subscales of the HRS. However, the hallucinatory experience in this case was qualitatively different than that typically experienced by participants receiving classic and atypical hallucinogens, suggesting that the hallucinatory effects of cannabis may have a unique pharmacological mechanism of action. This type of adverse event needs to be considered in the clinical use of cannabis.

4–   http://www.aslal.it/cannabis

Cannabis

Problemi
Da un punto di vista farmacologico, il THC ha una tossicità acuta praticamente trascurabile. Non sono documentati casi di morte direttamente dovuti ad una dose eccessiva di THC.
Da un punto di vista psicologico, invece, può causare reazioni di panico, ansia e depersonalizzazione.
Anche le prestazioni nello studio o nel lavoro possono venire ridotte, dati gli effetti del THC sull’apprendimento e sulla memoria.
Avrebbe, invece, effetti positivi sulle associazioni mentali, che diventano più ricche, varie ed originali.
Fumare marijuana, inoltre, porta inevitabilmente nei polmoni sostanze cancerogene dovute alla combustione.
Come tutti i farmaci potentemente psicoattivi, il THC può essere controindicato o pericoloso se si devono compiere lavori di precisione o che richiedono attenzione, vigilanza, coordinamento dei movimenti e prontezza dei riflessi. In particolare, non si dovrebbe guidare l’auto o usare attrezzi o macchinari pericolosi sotto gli effetti della canapa.
A lungo termine porta a disinteresse ed apatia (sindrome amotivazionale).

5— https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(87)92620-1/fulltext

Cannabis and Schizophrenia A longitudinal Study of Swedish Conscripts

CONCLUSION:

This study showed a 6-fold increased risk of development of Schizophrenia in users of cannabis compared to non-users.

6— https://www.ncbi.nlm.nih.gov/pmc/articles/PMC135490/

 Self reported cannabis use as a risk factor for schizophrenia in Swedish conscripts of 1969: historical cohort study

Conclusions:

Cannabis use is associated with an increased risk of developing schizophrenia, consistent with a causal relation. This association is not explained by use of other psychoactive drugs or personality traits relating to social integration.

7– https://www.ncbi.nlm.nih.gov/pubmed/12537032

Cannabis dependence and psychotic symptoms in young people.

CONCLUSIONS:

The results show that the development of cannabis dependence is associated with increased rates of psychotic symptoms in young people even when pre-existing symptoms and other background factors are taken into account.

8– https://www.mdedge.com/psychiatry/article/62537/does-marijuana-contribute-psychotic-illness/page/0/2

Does marijuana contribute to psychotic illness?

Marijuana can cause psychotic illness, particularly in persons at risk. Treat both the psychosis and substance use. Psychoeducation might be as effective as cannabis-specific treatments. Patients with a psychotic illness who use marijuana have a worse prognosis than nonusers.

9– https://www.ncbi.nlm.nih.gov/pmc/articles/PMC539839/

Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people

Discussion Exposure to cannabis during adolescence and young adulthood increases the risk of psychotic symptoms later in life. The findings confirm earlier suggestions that this association is stronger for individuals with predisposition for psychosis2,6 and stronger for the more severe psychotic outcomes.2,6 Frequent use of cannabis was associated with higher levels of risk in a dose-response fashion. Associations were independent of other variables known to increase the risk for psychosis. Also, the effect of cannabis remained significant after we corrected for baseline use of other drugs, tobacco, and alcohol. Finally, the data did not support the self medication hypothesis as baseline predisposition for psychosis did not significantly predict cannabis use at follow up.

 

10— https://onlinelibrary.wiley.com/doi/epdf/10.1111/jcpp.12765

Cannabis use and psychotic-like experiences trajectories during early adolescence: the coevolution and potential mediators

 

Conclusions:  Depression symptoms partially mediated the longitudinal link between cannabis use and PLE in adolescents, suggesting that there may be a preventative effect to be gained from targeting depression symptoms, in addition to attempting to prevent cannabis use in youth presenting increasing psychotic experiences.

11– https://www.cambridge.org/core/journals/development-and-psychopathology/article/adolescent-cannabis-use-change-in-neurocognitive-function-and-highschool-graduation-a-longitudinal-study-from-early-adolescence-to-young-adulthood/409F2E21BE7E216535404A4BF9EB1038

Adolescent cannabis use, change in neurocognitive function, and high-school graduation: A longitudinal study from early adolescence to young adulthood

Findings support prevention efforts aimed at delaying onset and reducing frequency of CU.

12– https://www.ncbi.nlm.nih.gov/pubmed/12413646

Cannabis use and dimensions of psychosis in a nonclinical population of female subjects.

CONCLUSION:

This cross-sectional study supports the hypothesis that exposure to cannabis may induce the emergence of positive psychotic symptoms in subjects without clinical psychosis, and additionally suggests that cannabis users exhibit greater levels of negative symptoms. Prospective studies are required to explore the direction of causality and the impact of cannabis on the course of psychotic experiences in subjects from the general population.

13– https://www.ncbi.nlm.nih.gov/pubmed/15369572

Early adolescent cannabis exposure and positive and negative dimensions of psychosis.

CONCLUSIONS:

These results add credence to the hypothesis that cannabis contributes to the population level of expression of psychosis. In particular, exposure early in adolescence may increase the risk for the subclinical positive and negative dimensions of psychosis, but not for depression.

14– https://www.ncbi.nlm.nih.gov/pubmed/19900684

Temporal relationship of first-episode non-affective psychosis with cannabis use: a clinical verification of an epidemiological hypothesis.

CONCLUSIONS:

Our results are in favor of a catalytic role for cannabis use in the onset of psychosis.

15– https://www.ncbi.nlm.nih.gov/pubmed/19748375

[Cannabis and psychosis: search of a causal link through a critical and systematic review].

CONCLUSION:

The objective of this article was to examine whether cannabis use can be an independent risk factor for chronic psychotic disorders, by using established criteria of causality. Data extracted from the selected studies showed that cannabis use may be an independent risk factor for the development of psychotic disorders. Early screening of the vulnerability to psychotic disorder should permit improved focus on prevention and information about the specific risks related to cannabis use among this population.

16– https://www.ncbi.nlm.nih.gov/pubmed/30115639

The adverse health effects and harms related to marijuana use: an overview review.

INTERPRETATION:

Harm was associated with most outcomes assessed. These results should be viewed with concern by physicians and policy-makers given the prevalence of use, the persistent reporting of a lack of recognition of marijuana as a possibly harmful substance and the emerging context of legalization for recreational use.

17— https://www.ncbi.nlm.nih.gov/pubmed/28644037

 Lower-Risk Cannabis Use Guidelines: A Comprehensive Update of Evidence and Recommendations.

MAIN RESULTS:

For most recommendations, there was at least “substantial” (i.e., good-quality) evidence. We developed 10 major recommendations for lower-risk use: (1) the most effective way to avoid cannabis use-related health risks is abstinence, (2) avoid early age initiation of cannabis use (i.e., definitively before the age of 16 years), (3) choose low-potency tetrahydrocannabinol (THC) or balanced THC-to-cannabidiol (CBD)-ratio cannabis products, (4) abstain from using synthetic cannabinoids, (5) avoid combusted cannabis inhalation and give preference to nonsmoking use methods, (6) avoid deep or other risky inhalation practices, (7) avoid high-frequency (e.g., daily or near-daily) cannabis use, (8) abstain from cannabis-impaired driving, (9) populations at higher risk for cannabis use-related health problems should avoid use altogether, and (10) avoid combining previously mentioned risk behaviors (e.g., early initiation and high-frequency use).

18– https://www.ncbi.nlm.nih.gov/pubmed/26785806

Marijuana use in the immediate 5-year premorbid period is associated with increased risk of onset of schizophrenia and related psychotic disorders.

CONCLUSIONS:

These data provide evidence of a clear temporal relationship between escalations in use in the five years pre-onset and an increased rate of onset, demonstrate that the strength of the association is similar pre- and post-onset of prodromal symptoms, and determine that early adult use may be just as important as adolescent use in these associations.

19–  https://pure.mpg.de/rest/items/item_2102999/component/file_2102998/content

Specific attentional dysfunction in adults following early start of cannabis use

Conclusions: These data suggest that beginning cannabis use during early adolescence may lead to enduring effects on specific attentional functions in adulthood. Apparently, vulnerable periods during brain development exist that are subject to persistent alterations by interfering exogenous cannabinoids

20– https://ajp.psychiatryonline.org/doi/10.1176/appi.ajp.2016.15070878

Concurrent and Sustained Cumulative Effects of Adolescent Marijuana Use on Subclinical Psychotic Symptoms

These results suggest that regular marijuana use may significantly increase the risk that an adolescent will experience persistent subclinical psychotic symptoms.

21– https://www.sciencedaily.com/releases/2016/03/160304092006.htm

Cannabis use in psychotic patients linked to 50 percent higher hospital admission risk

 

Summary:

Cannabis use among people experiencing a first episode of psychotic illness is linked to a 50 per cent heightened risk of hospital admission — including compulsory detention (sectioning) — as well as longer inpatient stay, reveals the largest study of its kind.

22– https://www.jneurosci.org/content/34/16/5529

Cannabis Use Is Quantitatively Associated with Nucleus Accumbens and Amygdala Abnormalities in Young Adult Recreational Users

“The results of this study indicate that in young, recreational marijuana users, structural abnormalities in gray matter density, volume, and shape of the nucleus accumbens and amygdala can be observed. Pending confirmation in other cohorts of marijuana users, the present findings suggest that further study of marijuana effects are needed to help inform discussion about the legalization of marijuana. These results extend prior studies showing that drugs of abuse that are known to elevate DA release are associated with structural abnormalities in the brain and related disruptions in behavior.”

23– https://www.ncbi.nlm.nih.gov/pubmed/21982932?dopt=Abstract

Grey matter alterations associated with cannabis use: results of a VBM study in heavy cannabis users and healthy controls.

“…These findings indicate that associations between heavy cannabis use and altered brain structure are complex. Differential patterns of structural changes for various cannabis use levels imply that alterations in brain structure are associated with specific characteristics of cannabis use and dependence.”

24– https://www.ncbi.nlm.nih.gov/pubmed/11742222?dopt=Abstract

Delta 9-tetrahydrocannabinol induces the apoptotic pathway in cultured cortical neurones via activation of the CB1 receptor.

Abstract

Delta 9-tetrahydrocannabinol, the principal psychoactive component of marijuana, exerts a variety of effects on the CNS, including impaired cognitive function and neurobehavioural deficits. The mechanisms underlying these neuronal responses to tetrahydrocannabinol are unclear but may involve alterations in neuronal viability. Tetrahydrocannabinol has been shown to influence neuronal survival but the role of the cannabinoid receptors in the regulation of neuronal viability has not been fully clarified. In this study we demonstrate that tetrahydrocannabinol promotes the release of cytochrome c, activates caspase-3, promotes cleavage of the DNA repair enzyme poly-ADP ribose polymerase and induces DNA fragmentation in cultured cortical neurones. These effects of tetrahydrocannabinol were completely abrogated by the CB(1) receptor antagonist AM-251. The findings of this study demonstrate that tetrahydrocannabinol induces apoptosis in cortical neurones in a manner involving the CB1 subtype of cannabinoid receptor.

25– https://www.ncbi.nlm.nih.gov/pubmed/25868590

Neuropathological alterations in drug abusers : The involvement of neurons, glial, and vascular systems.

Abstract

Because the effects of drug abuse on the cellular elements of the human brain have not been studied systematically, an investigation was performed using histology, immunohistochemistry, and morphometry. The main cortical and subcortical brain areas of 50 polydrug deaths were analyzed as compared with controls.In the brains of drug abusers, a significant neuronal loss was present. Interestingly, the number of glial fibrillary acidic protein (GFAP)-positive astrocytes was reduced. the numerical density of perivascular and parenchymal microglia was increased in the white matter and in most subcortical regions. In the white matter there were widespread β-amyloid precursor protein deposits. Furthermore, there was a prominent vascular hyalinosis, endothelial cell proliferation, and a loss of immunoreactivity for collagen type IV within the vascular basal lamina.The neuronal loss seems to be the result of a direct impairment of nerve cells and, indirectly, to a damage of astrocytes, axons, and the microvasculature. The reduction of GFAP-positive astrocytes is also indicative of a drug-induced damage. The axonal injury suggests a toxic-metabolic drug effect, whereas the concomitant activation of microglia is indicative of a long-standing progressive process. The noninflammatory vasculopathy can be considered as the morphological substrate of a disturbed blood-brain barrier. Our findings demonstrate that drugs of abuse initiate a cascade of interacting toxic, vascular, and hypoxic factors that finally result in widespread disturbances within the complex network of central nervous system cell-cell interactions.

26– https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033190/

Gone to Pot – A Review of the Association between Cannabis and Psychosis

ABSTRACT

Cannabis is the most commonly used illicit drug worldwide, with ~5 million daily users worldwide. Emerging evidence supports a number of associations between cannabis and psychosis/psychotic disorders, including schizophrenia. These associations-based on case-studies, surveys, epidemiological studies, and experimental studies indicate that cannabinoids can produce acute, transient effects; acute, persistent effects; and delayed, persistent effects that recapitulate the psychopathology and psychophysiology seen in schizophrenia. Acute exposure to both cannabis and synthetic cannabinoids (Spice/K2) can produce a full range of transient psychotomimetic symptoms, cognitive deficits, and psychophysiological abnormalities that bear a striking resemblance to symptoms of schizophrenia. In individuals with an established psychotic disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences on the course of the illness. Several factors appear to moderate these associations, including family history, genetic factors, history of childhood abuse, and the age at onset of cannabis use. Exposure to cannabinoids in adolescence confers a higher risk for psychosis outcomes in later life and the risk is dose-related. Individuals with polymorphisms of COMT and AKT1 genes may be at increased risk for psychotic disorders in association with cannabinoids, as are individuals with a family history of psychotic disorders or a history of childhood trauma. The relationship between cannabis and schizophrenia fulfills many but not all of the standard criteria for causality, including temporality, biological gradient, biological plausibility, experimental evidence, consistency, and coherence. At the present time, the evidence indicates that cannabis may be a component cause in the emergence of psychosis, and this warrants serious consideration from the point of view of public health policy.

27– https://www.ncbi.nlm.nih.gov/pubmed/28644037

Lower-Risk Cannabis Use Guidelines: A Comprehensive Update of Evidence and Recommendations.

AUTHORS’ CONCLUSIONS:

Evidence indicates that a substantial extent of the risk of adverse health outcomes from cannabis use may be reduced by informed behavioral choices among users. The evidence-based Lower-Risk Cannabis Use Guidelines (LRCUG) serve as a population-level education and intervention tool to inform such user choices toward improved public health outcomes. However, the LRCUG ought to be systematically communicated and supported by key regulation measures (e.g., cannabis product labeling, content regulation) to be effective. All of these measures are concretely possible under emerging legalization regimes, and should be actively implemented by regulatory authorities. The population-level impact of the LRCUG toward reducing cannabis use-related health risks should be evaluated. Public health implications. Cannabis control regimes are evolving, including legalization in North America, with uncertain impacts on public health. Evidence-based LRCUG offer a potentially valuable population-level tool to reduce the risk of adverse health outcomes from cannabis use among (especially young) users in legalization contexts, and hence to contribute to improved public health outcomes.

 

28– https://www.ncbi.nlm.nih.gov/pubmed/14987627

Are oral cannabinoids safe and effective in refractory neuropathic pain?

Abstract

Although cannabinoids have anti-hyperalgesic effects in animal models of nerve injury, there are currently very few prospective trials of the efficacy of cannabinoids in neuropathic pain in humans. This open label prospective study investigated the safety, tolerability and analgesic benefit of oral Delta-9-tetrahydrocannabinol (THC) titrated to a maximal dosage of 25 mg/day in 8 consecutive patients with chronic refractory neuropathic pain. Spontaneous ongoing and paroxysmal pain, allodynia and paresthesias were assessed. The sensory and affective components of pain using the McGill pain questionnaire, quality of life, mood, anxiety and functionality were also evaluated. Seven patients suffered from side effects necessitating premature arrest of the drug in 5 of them. THC (mean dosage: 16.6+/-6.5 mg/day) did not induce any significant effects on ongoing and paroxysmal pain, allodynia, quality of life, anxiety/depression scores and functional impact of pain. These results do not support an overall benefit of THC in pain and quality of life in patients with refractory neuropathic pain.

29– https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736954/

Cannabis, a complex plant: different compounds and different effects on individuals

 

Cannabis is a complex plant, with major compounds such as delta-9-tetrahydrocannabinol and cannabidiol, which have opposing effects. The discovery of its compounds has led to the further discovery of an important neurotransmitter system called the endocannabinoid system. This system is widely distributed in the brain and in the body, and is considered to be responsible for numerous significant functions. There has been a recent and consistent worldwide increase in cannabis potency, with increasing associated health concerns. A number of epidemiological research projects have shown links between dose-related cannabis use and an increased risk of development of an enduring psychotic illness. However, it is also known that not everyone who uses cannabis is affected adversely in the same way. What makes someone more susceptible to its negative effects is not yet known, however there are some emerging vulnerability factors, ranging from certain genes to personality characteristics. In this article we first provide an overview of the biochemical basis of cannabis research by examining the different effects of the two main compounds of the plant and the endocannabinoid system, and then go on to review available information on the possible factors explaining variation of its effects upon different individuals.

30– https://www.ncbi.nlm.nih.gov/pubmed/19729208

Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb.

Abstract

Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetrahydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetrahydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.

31– https://www.ncbi.nlm.nih.gov/pubmed/20645411

Cannabidiol induces intracellular calcium elevation and cytotoxicity in oligodendrocytes.

Abstract

Heavy marijuana use has been linked to white matter histological alterations. However, the impact of cannabis constituents on oligodendroglial pathophysiology remains poorly understood. Here, we investigated the in vitro effects of cannabidiol, the main nonpsychoactive marijuana component, on oligodendrocytes. Exposure to cannabidiol induced an intracellular Ca(2+) rise in optic nerve oligodendrocytes that was not primarily mediated by entry from the extracellular space, nor by interactions with ryanodine or IP(3) receptors. Application of the mitochondrial protonophore carbonylcyanide-p-trifluoromethoxyphenylhydrazone (FCCP; 1 μM) completely prevented subsequent cannabidiol-induced Ca(2+) responses. Conversely, the increase in cytosolic Ca(2+) levels elicited by FCCP was reduced after previous exposure to cannabidiol, further suggesting that the mitochondria acts as the source of cannabidiol-evoked Ca(2+) rise in oligodendrocytes. n addition, brief exposure to cannabidiol (100 nM-10 μM) led to a concentration-dependent decrease of oligodendroglial viability that was not prevented by antagonists of CB(1), CB(2), vanilloid, A(2A) or PPARγ receptors, but was instead reduced in the absence of extracellular Ca(2+). The oligodendrotoxic effect of cannabidiol was partially blocked by inhibitors of caspase-3, -8 and -9, PARP-1 and calpains, suggesting the activation of caspase-dependent and -independent death pathways. Cannabidiol also elicited a concentration-dependent alteration of mitochondrial membrane potential, and an increase in reactive oxygen species (ROS) that was reduced in the absence of extracellular Ca(2+). Finally, cannabidiol-induced cytotoxicity was partially prevented by the ROS scavenger trolox. Together, these results suggest that cannabidiol causes intracellular Ca(2+) dysregulation which can lead to oligodendrocytes demise.

32– https://www.ncbi.nlm.nih.gov/pubmed/1922895

Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels.

Abstract

Cannabinoids and the endocannabinoid system have attracted considerable interest for therapeutic applications. Nevertheless, the mechanism of action of one of the main nonpsychoactive phytocannabinoids, cannabidiol (CBD), remains elusive despite potentially beneficial properties as an anti-convulsant and neuroprotectant. Here, we characterize the mechanisms by which CBD regulates Ca(2+) homeostasis and mediates neuroprotection in neuronal preparations. Imaging studies in hippocampal cultures using fura-2 AM suggested that CBD-mediated Ca(2+) regulation is bidirectional, depending on the excitability of cells. Under physiological K(+)/Ca(2+) levels, CBD caused a subtle rise in [Ca(2+)](i), whereas CBD reduced [Ca(2+)](i) and prevented Ca(2+) oscillations under high-excitability conditions (high K(+) or exposure to the K(+) channel antagonist 4AP). Regulation of [Ca(2+)](i) was not primarily mediated by interactions with ryanodine or IP(3) receptors of the endoplasmic reticulum. Instead, dual-calcium imaging experiments with a cytosolic (fura-2 AM) and a mitochondrial (Rhod-FF, AM) fluorophore implied that mitochondria act as sinks and sources for CBD’s [Ca(2+)](i) regulation. Application of carbonylcyanide-p-trifluoromethoxyphenylhydrazone (FCCP) and the mitochondrial Na(+)/Ca(2+) exchange inhibitor, CGP 37157, but not the mitochondrial permeability transition pore inhibitor cyclosporin A, prevented subsequent CBD-induced Ca(2+) responses. In established human neuroblastoma cell lines (SH-SY5Y) treated with mitochondrial toxins, CBD (0.1 and 1 microm) was neuroprotective against the uncoupler FCCP (53% protection), and modestly protective against hydrogen peroxide- (16%) and oligomycin- (15%) mediated cell death, a pattern also confirmed in cultured hippocampal neurons. Thus, under pathological conditions involving mitochondrial dysfunction and Ca(2+) dysregulation, CBD may prove beneficial in preventing apoptotic signaling via a restoration of Ca(2+) homeostasis.

33– https://www.ncbi.nlm.nih.gov/pubmed/23836028

Spicing things up: synthetic cannabinoids.

Abstract

RATIONALE:

Recently, products containing synthetic cannabinoids, collectively referred to as Spice, are increasingly being used recreationally.

OBJECTIVES:

The availability, acute subjective effects-including self-reports posted on Erowid-laboratory detection, addictive potential, and regulatory challenges of the Spice phenomenon are reviewed.

RESULTS:

Spice is sold under the guise of potpourri or incense. Unlike delta-9-tetrahydrocannabinol, the synthetic cannabinoids present in Spice are high-potency, high-efficacy, cannabinoid receptor full agonists. Since standard urine toxicology does not test for the synthetic cannabinoids in Spice, it is often used by those who want to avoid detection of drug use. These compounds have not yet been subjected to rigorous testing in humans. Acute psychoactive effects include changes in mood, anxiety, perception, thinking, memory, and attention. Adverse effects include anxiety, agitation, panic, dysphoria, psychosis, and bizarre behavior. Psychosis outcomes associated with Spice provide additional data linking cannabinoids and psychosis. Adverse events necessitating intervention by Poison Control Centers, law enforcement, emergency responders, and hospitals are increasing. Despite statutes prohibiting the manufacture, distribution, and sale of Spice products, manufacturers are replacing banned compounds with newer synthetic cannabinoids that are not banned.

CONCLUSIONS:

There is an urgent need for better research on the effects of synthetic cannabinoids to help clinicians manage adverse events and to better understand cannabinoid pharmacology in humans. The reported psychosis outcomes associated with synthetic cannabinoids contribute to the ongoing debate on the association between cannabinoids and psychosis. Finally, drug detection tests for synthetic cannabinoids need to become clinically available.

34– https://www.ncbi.nlm.nih.gov/pubmed/26386480

Association Between Cannabis and Psychosis: Epidemiologic Evidence.

Abstract

Associations between cannabis use and psychotic outcomes are consistently reported, but establishing causality from observational designs can be problematic. We review the evidence from longitudinal studies that have examined this relationship and discuss the epidemiologic evidence for and against interpreting the findings as causal. We also review the evidence identifying groups at particularly high risk of developing psychosis from using cannabis. Overall, evidence from epidemiologic studies provides strong enough evidence to warrant a public health message that cannabis use can increase the risk of psychotic disorders. However, further studies are required to determine the magnitude of this effect, to determine the effect of different strains of cannabis on risk, and to identify high-risk groups particularly susceptible to the effects of cannabis on psychosis. We also discuss complementary epidemiologic methods that can help address these questions.

 

35– https://www.ncbi.nlm.nih.gov/pubmed/23491968

Pathways to psychosis in cannabis abuse.

Abstract

Cannabis has been implicated as a risk factor for the development of schizophrenia, but the exact biological mechanisms remain unclear. In this review, we attempt to understand the neurobiological pathways that link cannabis use to schizophrenia. This has been an area of great debate; despite similarities between cannabis users and schizophrenia patients, the evidence is not sufficient to establish cause-and-effect. There have been advances in the understanding of the mechanisms of cannabis dependence as well as the role of the cannabinoid system in the development of psychosis and schizophrenia. The neurobiological mechanisms associated with the development of psychosis and effects from cannabis use may be similar but remain elusive. In order to better understand these associations, this paper will show common neurobiological and neuroanatomical changes as well as common cognitive dysfunction in cannabis users and patients of schizophrenia. We conclude that epidemiologic evidence highlights potential causal links; however, neurobiological evidence for causality remains weak.

36– http://www.biblioteca.cij.gob.mx/articulos/PatronDeUsoYDependencia/Fersgussonetal-Cannabios-GatewayHypothesis.pdf

Cannabis use and other illicit drug use: testing the cannabis gateway hypothesis

ABSTRACT Aim To examine the associations between the frequency of cannabis use and the use of other illicit drugs. Design A 25-year longitudinal study of the health, development and adjustment of a birth cohort of 1265 New Zealand children. Measurements Annual assessments of the frequency of cannabis use were obtained for the period 14–25 years, together with measures of the use of other illicit drugs from the same time period. Findings The frequency of cannabis use was associated significantly with the use of other illicit drugs, other illicit drug abuse/ dependence and the use of a diversity of other drugs. This association was found to be particularly strong during adolescence but declined rapidly as age increased. Statistical control for confounding by both fixed and time dynamic factors using random- and fixed-effects regression models reduced the strength of association between frequency of cannabis use and other illicit drug use, but a strong association between frequency of cannabis use and other illicit drug use remained even after control for non-observed and time-dynamic sources of confounding. Conclusions Regular or heavy cannabis use was associated with an increased risk of using other illicit drugs, abusing or becoming dependent upon other illicit drugs, and using a wider variety of other illicit drugs. The risks of use, abuse/dependence, and use of a diversity of other drugs declined with increasing age. The findings may support a general causal model such as the cannabis gateway hypothesis, but the actual causal mechanisms underlying such a gateway, and the extent to which these causal mechanisms are direct or indirect, remain unclear.

37– https://www.ncbi.nlm.nih.gov/pubmed/11157424

Psychiatric effects of cannabis.

Abstract

BACKGROUND:

Cannabis is commonly regarded as an innocuous drug and the prevalence of lifetime and regular use has increased in most developed countries. However, accumulative evidence highlights the risks of dependence and other adverse effects, particularly among people with pre-existing psychiatric disorders.

AIMS:

To re-evaluate the adverse effects of cannabis in the general population and among vulnerable individuals, including those with serious psychiatric disorders.

METHOD:

A wide-ranging review of the topics related to these issues. Results and conclusions An appreciable proportion of cannabis users report short-lived adverse effects, including psychotic states following heavy consumption, and regular users are at risk of dependence. People with major mental illnesses such as schizophrenia are especially vulnerable in that cannabis generally provokes relapse and aggravates existing symptoms. Health workers need to recognise, and respond to, the adverse effects of cannabis on mental health.

38– https://www.ncbi.nlm.nih.gov/pubmed/12181101

Cannabis use and psychosis: a longitudinal population-based study.

Abstract

Cannabis use may increase the risk of psychotic disorders and result in a poor prognosis for those with an established vulnerability to psychosis. A 3-year follow-up (1997-1999) is reported of a general population of 4,045 psychosis-free persons and of 59 subjects in the Netherlands with a baseline diagnosis of psychotic disorder. Substance use was assessed at baseline, 1-year follow-up, and 3-year follow-up. Baseline cannabis use predicted the presence at follow-up of any level of psychotic symptoms (adjusted odds ratio (OR) = 2.76, 95% confidence interval (CI): 1.18, 6.47), as well as a severe level of psychotic symptoms (OR = 24.17, 95% CI: 5.44, 107.46), and clinician assessment of the need for care for psychotic symptoms (OR = 12.01, 95% CI: 2.24, 64.34). The effect of baseline cannabis use was stronger than the effect at 1-year and 3-year follow-up, and more than 50% of the psychosis diagnoses could be attributed to cannabis use. On the additive scale, the effect of cannabis use was much stronger in those with a baseline diagnosis of psychotic disorder (risk difference, 54.7%) than in those without (risk difference, 2.2%; p for interaction = 0.001). Results confirm previous suggestions that cannabis use increases the risk of both the incidence of psychosis in psychosis-free persons and a poor prognosis for those with an established vulnerability to psychotic disorder.

 

39– https://www.ncbi.nlm.nih.gov/pubmed/26903403

Changes in Cannabis Potency Over the Last 2 Decades (1995-2014): Analysis of Current Data in the United States.

Abstract

BACKGROUND:

Marijuana is the most widely used illicit drug in the United States and all over the world. Reports indicate that the potency of cannabis preparation has been increasing. This report examines the concentration of cannabinoids in illicit cannabis products seized by the U.S. Drug Enforcement Administration over the last 2 decades, with particular emphasis on Δ(9)-tetrahydrocannabinol and cannabidiol.

METHODS:

Samples in this report were received over time from materials confiscated by the Drug Enforcement Administration and processed for analysis using a validated gas chromatography with flame ionization detector method.

RESULTS:

Between January 1, 1995, and December 31, 2014, 38,681 samples of cannabis preparations were received and analyzed. The data showed that although the number of marijuana samples seized over the last 4 years has declined, the number of sinsemilla samples has increased. Overall, the potency of illicit cannabis plant material has consistently increased over time since 1995 from ~4% in 1995 to ~12% in 2014. The cannabidiol content has decreased on average from ~.28% in 2001 to <.15% in 2014, resulting in a change in the ratio of Δ(9)-tetrahydrocannabinol to cannabidiol from 14 times in 1995 to ~80 times in 2014.

CONCLUSIONS:

There is a shift in the production of illicit cannabis plant material from regular marijuana to sinsemilla. This increase in potency poses higher risk of cannabis use, particularly among adolescents.

40– https://www.ncbi.nlm.nih.gov/pubmed/17355521

Patterns, predictors and impact of substance use in early psychosis: a longitudinal study.

Abstract

OBJECTIVE:

The purpose was to determine the prevalence of substance use and its impact on outcome 3 years after presentation for a first-episode of psychosis.

METHOD:

Subjects were 203 consecutive admissions to an early psychosis program. Assessments included substance use, positive, negative and depressive symptoms and social functioning. Assessments occurred at baseline, and 1-, 2- and 3-year follow-ups.

RESULTS:

The prevalence of substance misuse was high with 51% having a substance use disorder (SUD), 33% with cannabis SUD and 35% with an alcohol SUD. Numbers with an alcohol SUD declined considerably by 1 year and for cannabis SUD by 2 years. Substance misuse was significantly associated with male gender, young age and age of onset and cannabis misuse with increased positive symptoms.

CONCLUSION:

This study confirms the high rates of substance misuse, in particular cannabis, in first-episode psychosis. It further demonstrates that these rates can be reduced.

41— https://www.researchgate.net/publication/281901749_Cannabis_psychosis_gender_matters

Cannabis psychosis, gender matters.

Purpose – The purpose of this paper is to draw together key literature and analyses of data on admissions for cannabis psychosis in National Health Service hospitals in England (extracted from Hospital Episode Statistics (HES)) to highlight what is known about gender differences in cannabis psychosis and point towards suggestions for improving gender-sensitive treatment and future research. Design/methodology/approach – Analysis of British Crime Survey data and HES data were used in combination with data from previously published epidemiological studies to compare gender differences. Findings – Male cannabis users outnumber female users by 2:1, a similar gender ratio is found for those admitted to hospital with a diagnosis of schizophrenia or psychosis. However this ratio increases significantly for those admitted to hospital with a diagnosis of cannabis psychosis, with males outnumbering females by 4:1. Research limitations/implications – Consistent patterns in gender ratios for people admitted to hospital with cannabis psychosis over a period of 11 years are reported, it is not clear why this gender difference persists but it warrants further investigation which would be aided by improved gender recording at a systemic level. Practical implications – This review brings into focus the marked gender differences in cannabis psychosis. Attending to gender is important for research and treatment with the aim of improving understanding and providing gender-sensitive services. Originality/value – This paper adds to the literature on gender differences in cannabis psychosis.

42– https://www.ncbi.nlm.nih.gov/pubmed/?term=glutamate+and+dopamine+in+cannabis+users

Decreased spontaneous eye blink rates in chronic cannabis users: evidence for striatal cannabinoid-dopamine interactions.

Abstract

Chronic cannabis use has been shown to block long-term depression of GABA-glutamate synapses in the striatum, which is likely to reduce the extent to which endogenous cannabinoids modulate GABA- and glutamate-related neuronal activity. The current study aimed at investigating the effect of this process on striatal dopamine levels by studying the spontaneous eye blink rate (EBR), a clinical marker of dopamine level in the striatum. 25 adult regular cannabis users and 25 non-user controls matched for age, gender, race, and IQ were compared. Results show a significant reduction in EBR in chronic users as compared to non-users, suggesting an indirect detrimental effect of chronic cannabis use on striatal dopaminergic functioning. Additionally, EBR correlated negatively with years of cannabis exposure, monthly peak cannabis consumption, and lifetime cannabis consumption, pointing to a relationship between the degree of impairment of striatal dopaminergic transmission and cannabis consumption history.

43– https://www.ncbi.nlm.nih.gov/pubmed/24696078

The link between dopamine function and apathy in cannabis users: an [18F]-DOPA PET imaging study.

Abstract

RATIONALE:

Cannabis is the most widely used illicit drug in the world, and regular use has been associated with reduced motivation, i.e. apathy. Regular long-term cannabis use has been associated with reduced dopamine synthesis capacity. The mesolimbic dopaminergic system mediates the processing of incentive stimuli by modifying their motivational value, which in turn is modulated by endocannabinoid signalling. Thus, it has been proposed that dopaminergic dysfunction underlies the apathy associated with chronic cannabis use.

OBJECTIVES:

The aim of this study was to examine the relationship between dopaminergic function and subjective apathy in cannabisusers.

METHODS:

We measured dopamine synthesis capacity (indexed as the influx rate constant K i(cer)) via 3,4-dihydroxy-6-[(18)F]-fluoro-l-phenylalanine positron emission tomography and subjective apathy using the self-rated Apathy Evaluation Scale (AES-S) in 14 regular cannabis users.

RESULTS:

All subjects scored in excess of 34 points on the AES-S (median [interquartile range] 59.5 [7.5]), indicative of significant apathy based on normative data. K i (cer) was inversely correlated to AES-S score in the whole striatum and its associative functional subdivision (Spearman’s rho = -0.64, p = 0.015 [whole striatum]; rho = -0.69, p = 0.006 [associative]) but not in the limbic or sensorimotor striatal subdivisions. There were no significant relationships between AES-S and current cannabis consumption (rho = 0.28, p = 0.34) or age of first cannabis use (rho = 0.25, p = 0.40).

CONCLUSIONS:

These findings indicate that the reduction in striatal dopamine synthesis capacity associated with chronic cannabis use may underlie reduced reward sensitivity and a motivation associated with chronic cannabis use.

44– https://www.ncbi.nlm.nih.gov/pubmed/23820822

Dopaminergic function in cannabis users and its relationship to cannabis-induced psychotic symptoms.

Abstract

BACKGROUND:

Cannabis is the most widely used illicit drug globally, and users are at increased risk of mental illnesses including psychotic disorders such as schizophrenia. Substance dependence and schizophrenia are both associated with dopaminergic dysfunction. It has been proposed, although never directly tested, that the link between cannabis use and schizophrenia is mediated by altered dopaminergic function.

METHODS:

We compared dopamine synthesis capacity in 19 regular cannabis users who experienced psychotic-like symptoms when they consumed cannabis with 19 nonuser sex- and age-matched control subjects. Dopamine synthesis capacity (indexed as the influx rate constant [Formula: see text] ) was measured with positron emission tomography and 3,4-dihydroxy-6-[(18)F]-fluoro-l-phenylalanine ([(18)F]-DOPA).

RESULTS:

Cannabis users had reduced dopamine synthesis capacity in the striatum (effect size: .85; t36 = 2.54, p = .016) and its associative (effect size: .85; t36 = 2.54, p = .015) and limbic subdivisions (effect size: .74; t36 = 2.23, p = .032) compared with control subjects. The group difference in dopamine synthesis capacity in cannabis users compared with control subjects was driven by those users meeting cannabisabuse or dependence criteria. Dopamine synthesis capacity was negatively associated with higher levels of cannabis use (r = -.77, p < .001) and positively associated with age of onset of cannabis use (r = .51, p = .027) but was not associated with cannabis-induced psychotic-like symptoms (r = .32, p = .19).

CONCLUSIONS:

These findings indicate that chronic cannabis use is associated with reduced dopamine synthesis capacity and question the hypothesis that cannabis increases the risk of psychotic disorders by inducing the same dopaminergic alterations seen in schizophrenia.

45– https://www.ncbi.nlm.nih.gov/pubmed/27628967

Salience attribution and its relationship to cannabis-induced psychotic symptoms.

(https://psychology.iresearchnet.com/social-psychology/social-cognition/salience/)

Abstract

BACKGROUND:

Cannabis is a widely used drug associated with increased risk for psychosis. The dopamine hypothesis of psychosis postulates that altered salience processing leads to psychosis. We therefore tested the hypothesis that cannabis users exhibit aberrant salience and explored the relationship between aberrant salience and dopamine synthesis capacity.

METHOD:

We tested 17 cannabis users and 17 age- and sex-matched non-user controls using the Salience Attribution Test, a probabilistic reward-learning task. Within users, cannabis-induced psychotic symptoms were measured with the Psychotomimetic States Inventory. Dopamine synthesis capacity, indexed as the influx rate constant K i cer , was measured in 10 users and six controls with 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine positron emission tomography.

RESULTS:

There was no significant difference in aberrant salience between the groups [F 1,32 = 1.12, p = 0.30 (implicit); F 1,32 = 1.09, p = 0.30 (explicit)]. Within users there was a significant positive relationship between cannabis-induced psychotic symptom severity and explicit aberrant salience scores (r = 0.61, p = 0.04) and there was a significant association between cannabis dependency/abuse status and high implicit aberrant salience scores (F 1,15 = 5.8, p = 0.03). Within controls, implicit aberrant salience was inversely correlated with whole striatal dopamine synthesis capacity (r = -0.91, p = 0.01), whereas this relationship was non-significant within users (difference between correlations: Z = -2.05, p = 0.04).

CONCLUSIONS:

Aberrant salience is positively associated with cannabis-induced psychotic symptom severity, but is not seen in cannabis   users overall. This is consistent with the hypothesis that the link between cannabis use and psychosis involves alterations in salience processing. Longitudinal studies are needed to determine whether these cognitive abnormalities are pre-existing or caused by long-term cannabis use.

 

46–https://www.ncbi.nlm.nih.gov/pubmed/23820822

Dopaminergic function in cannabis users and its relationship to cannabis-induced psychotic symptoms.

CONCLUSIONS:

These findings indicate that chronic cannabis use is associated with reduced dopamine synthesis capacity and question the hypothesis that cannabis increases the risk of psychotic disorders by inducing the same dopaminergic alterations seen in schizophrenia.

47– https://www.ncbi.nlm.nih.gov/pubmed/14694348

Repeated, intermittent delta(9)-tetrahydrocannabinol administration to rats impairs acquisition and performance of a test of visuospatial divided attention.

Abstract

The residual neuropsychological effects of marijuana abuse in man indicate a dysfunction of the attentional/executive systems. Moreover, experimental investigations suggest that repeated, intermittent (subchronic) Delta(9)-tetrahydrocannabinol (THC), the main psychoactive ingredient of marijuana, alters neurotransmission in the frontal cortex of rats and humans, a key neural site mediating attention and executive functions. In the present studies, the acquisition and performance of a test of visuospatial attention (the lateralized reaction time task) after subchronic THC administration (10.0 mg/kg twice daily for 14 days) was examined. Rats previously administered THC showed impairments in this self-paced version of the classic multiple-choice serial reaction time task, which persisted 14 days after the final drug administration. Longer time points were not examined. These attentional impairments were transiently reversible with an acute amphetamine (0.5 mg/kg) challenge. These behavioral data demonstrate that chronic THC administration to rats induces an attentional deficit, similar to that observed in humans who abuse marijuana. Finally, amphetamine’s ability to reverse the attentional impairments provides indirect evidence that monoaminergic deficits may be linked to the cognitive dysfunction.

48– https://www.ncbi.nlm.nih.gov/pubmed/10208322

Specific attentional dysfunction in adults following early start of cannabis use.

Abstract

RATIONALE AND OBJECTIVE:

The present study tested the hypothesis that chronic interference by cannabis with endogenous cannabinoid systems during peripubertal development causes specific and persistent brain alterations in humans. As an index of cannabinoid action, visual scanning, along with other attentional functions, was chosen. Visual scanning undergoes a major maturation process around age 12-15 years and, in addition, the visual system is known to react specifically and sensitively to cannabinoids.

CONCLUSIONS:

These data suggest that beginning cannabis use during early adolescence may lead to enduring effects on specific attentional functions in adulthood. Apparently, vulnerable periods during brain development exist that are subject to persistent alterations by interfering exogenous cannabinoids.

49– https://www.ncbi.nlm.nih.gov/pubmed/12633916

Early-onset cannabis use and cognitive deficits: what is the nature of the association?

Abstract

BACKGROUND:

Individuals who initiate cannabis use at an early age, when the brain is still developing, might be more vulnerable to lasting neuropsychological deficits than individuals who begin use later in life.

CONCLUSIONS:

Early-onset cannabis users exhibit poorer cognitive performance than late-onset users or control subjects, especially in VIQ, but the cause of this difference cannot be determined from our data. The difference may reflect (1). innate differences between groups in cognitive ability, antedating first cannabis use; (2). an actual neurotoxic effect of cannabis on the developing brain; or (3). poorer learning of conventional cognitive skills by young cannabis users who have eschewed academics and diverged from the mainstream culture.

50– https://www.ncbi.nlm.nih.gov/pubmed/28823723

Understanding marijuana’s effects on functional connectivity of the default mode network in patients with schizophrenia and co-occurring cannabis use disorder: A pilot investigation.

Abstract

Nearly half of patients with schizophrenia (SCZ) have co-occurring cannabis use disorder (CUD), which has been associated with decreased treatment efficacy, increased risk of psychotic relapse, and poor global functioning. While reports on the effects of cannabis on cognitive performance in patients with SCZ have been mixed, study of brain networks related to executive function may clarify the relationship between cannabis use and cognition in these dual-diagnosis patients. In the present pilot study, patients with SCZ and CUD (n=12) and healthy controls (n=12) completed two functional magnetic resonance imaging (fMRI) resting scans. Prior to the second scan, patients smoked a 3.6% tetrahydrocannabinol (THC) cannabis cigarette or ingested a 15mg delta-9-tetrahydrocannabinol (THC) pill. We used resting-state functional connectivity to examine the default mode network (DMN) during both scans, as connectivity/activity within this network is negatively correlated with connectivity of the network involved in executive control and shows reduced activity during task performance in normal individuals. At baseline, relative to controls, patients exhibited DMN hyperconnectivity that correlated with positive symptom severity, and reduced anticorrelation between the DMN and the executive control network (ECN). Cannabinoid administration reduced DMN hyperconnectivity and increased DMN-ECN anticorrelation. Moreover, the magnitude of anticorrelation in the controls, and in the patients after cannabinoid administration, positively correlated with WM performance. The finding that DMN brain connectivity is plastic may have implications for future pharmacotherapeutic development, as treatment efficacy could be assessed through the ability of therapies to normalize underlying circuit-level dysfunction.

51— https://www.ncbi.nlm.nih.gov/pubmed/15976013

The environment and schizophrenia: the role of cannabis use.

Abstract

Cannabis use is associated with poor outcome in existing schizophrenia and may precipitate psychosis in individuals with preexisting liability. To investigate the overall effect size and consistency of the association between cannabis and psychosis, a meta-analysis from prospective studies was carried out. The pooled odds ratio was 2.1 (95% CI: 1.7-2.5) and could not be explained by confounding or reverse causality. Evidence suggests that cannabis is a component cause in the development and prognosis of psychosis, in which mechanisms of gene-environment interaction are most likely to explain this association. Potential new methods to directly link genetic liability to the effects of cannabis are discussed.

52— https://www.ncbi.nlm.nih.gov/pubmed/20513854

Psychosis reactivity to cannabis use in daily life: an experience sampling study.

Abstract

BACKGROUND:

Little is known about the experiential dynamics of the interaction between cannabis and vulnerability to psychosis.

AIMS:

To examine the effects of cannabis on psychotic symptoms and mood in patients with psychosis and healthy controls.

METHOD:

Patients with a psychotic disorder (n = 42) and healthy controls (n = 38) were followed in their daily lives using a structured time-sampling technique.

RESULTS:

Daily life cannabis use predicted subsequent increases in positive affect and in patients, but not in controls, decreases in negative affect. In patients, but not in controls, cannabis use predicted increased levels of hallucinatory experiences. Mood-enhancing properties of cannabis were acute, whereas psychosis-inducing effects were sub-acute. There was no direct evidence for self-medication effects in daily life.

CONCLUSIONS:

Patients with psychosis are more sensitive to both the psychosis-inducing and mood-enhancing effects of cannabis. The temporal dissociation between acute rewarding effects and sub-acute toxic influences may be instrumental in explaining the vicious circle of deleterious use in these patients.

53– https://www.bmj.com/content/332/7534/172

Cannabis and psychosis

54– https://www.ncbi.nlm.nih.gov/pubmed/19386576

Rate of cannabis use disorders in clinical samples of patients with schizophrenia: a meta-analysis.

Abstract

OBJECTIVE:

Our aim was to review recent studies and estimate the rate of cannabis use disorders (CUDs) in schizophrenia, as well as to examine the factors affecting this rate.

METHODS:

We conducted an electronic search of 3 literature databases and a manual search of articles from 1996 to 2008. The key words used were “schizophreni*,” “psychos*s,” “psychotic,” “cannabis abuse,” “cannabis dependence,” “cannabis use disorder,” “substance use disorder,” “substance abuse,” “substance dependence,” and “dual diagnosis.” Articles that reported diagnoses according to the Diagnostic and Statistical Manual of Mental Disorders or International Classification of Diseases were included. Regression analysis was used to examine how estimated rates of CUDs are affected by various study characteristics such as the classification system, inpatient vs outpatient status, study location, proportion of males, age of the sample, or duration of illness.

RESULTS:

Thirty-five studies met our search criteria. The median current rate of CUDs was 16.0% (interquartile range [IQR] = 8.6-28.6, 10 studies), and the median lifetime rate was 27.1% (IQR = 12.2-38.5, 28 studies). The median rate of CUDs was markedly higher in first-episode vs long-term patients (current 28.6%/22.0%, lifetime 44.4%/12.2%, respectively) and in studies where more than two-thirds of the participants were males than in the other studies (33.8%/13.2%). CUDs were also more common in younger samples than in the others (current 38.5%/16.0%, lifetime 45.0%/17.9%).

CONCLUSIONS:

Approximately every fourth schizophrenia patient in our sample of studies had a diagnosis of CUDs. CUDs were especially common in younger and first-episode patient samples as well as in samples with a high proportion of males.

55— https://www.ncbi.nlm.nih.gov/pubmed/28803095

Acute effects of smoked marijuana in marijuana smokers at clinical high-risk for psychosis: A preliminary study.

Abstract

Marijuana use is associated with psychosis, but its effects are understudied in individuals with preexisting risk for psychotic disorders. This preliminary study examined the acute psychological and physiological effects of smoked marijuana (0.0% or 5.5% Δ9-THC) in marijuana users at clinical high-risk (CHR; n = 6) to develop a psychotic disorder, and those not at risk (n = 6), under controlled laboratory conditions. CHR marijuana users exhibited temporary increases in psychotic-like states and decreases in neurocognitive performance during marijuana intoxication but control marijuana smokers did not. These findings, if replicated, may support a psychotogenic role for marijuana in CHR individuals.

56— https://www.ncbi.nlm.nih.gov/pubmed/18185500

Blunted psychotomimetic and amnestic effects of delta-9-tetrahydrocannabinol in frequent users of cannabis.

Abstract

Cannabis is one of the most widely used illicit substances and there is growing interest in the association between cannabis use and psychosis. Delta-9-Tetrahydrocannabinol (Delta-9-THC) the principal active ingredient of cannabis has been shown to induce psychotomimetic and amnestic effects in healthy individuals. Whether people who frequently use cannabis are either protected from or are tolerant to these effects of Delta-9-THC has not been established. In a 3-day, double-blind, randomized, placebo-controlled study, the dose-related effects of 0, 2.5, and 5 mg intravenous Delta-9-THC were studied in 30 frequent users of cannabis and compared to 22 healthy controls. Delta-9-THC (1) produced transient psychotomimetic effects and perceptual alterations; (2) impaired memory and attention; (3) increased subjective effects of ‘high’; (4) produced tachycardia; and (5) increased serum cortisol in both groups. However, relative to controls, frequent users showed blunted responses to the psychotomimetic, perceptual altering, cognitive impairing, anxiogenic, and cortisol increasing effects of Delta-9-THC but not to its euphoric effects. Frequent users also had lower prolactin levels. These data suggest that frequent users of cannabis are either inherently blunted in their response to, and/or develop tolerance to the psychotomimetic, perceptual altering, amnestic, endocrine, and other effects of cannabinoids.

57– https://www.ncbi.nlm.nih.gov/pubmed/26286840

Does Cannabis Cause, Exacerbate or Ameliorate Psychiatric Disorders? An Oversimplified Debate Discussed.

Abstract

There have been extensive policy shifts in the legality of recreational and therapeutic use of cannabis in the United States, as well as a steady increase in the number of people using the drug on a regular basis. Given these rapid societal changes, defining what is known scientifically about the consequences of cannabis use on mental health takes on added public health significance. The purpose of this circumspectives piece is to discuss evidence of cannabis’ effects on two psychiatric conditions: post-traumatic stress disorder and psychotic disorders. Dr Haney and Dr Evins will discuss two viewpoints regarding the benefit and harm of cannabis use for these conditions, while outlining what remains unproven and requires further testing to move the field forward.

58– https://www.ncbi.nlm.nih.gov/pubmed/26386480

 

 

59– https://www.ncbi.nlm.nih.gov/pubmed/24274357

Reasons for cannabis use among youths at ultra high risk for psychosis.

Abstract

AIM:

Cannabis use is prevalent in schizophrenia and its risk states, despite its association with anxiety and positive symptoms. While schizophrenia patients report using cannabis for mood enhancement and social motives, it is not known what motivates clinical high risk (CHR) patients to use cannabis.

METHODS:

Among 102 CHR patients, 24 (23%) endorsed cannabis use, and were queried as to reasons for use, using a scale previously administered in schizophrenia patients. We hypothesized a primary motivation for mood enhancement related to anhedonia. We evaluated the ‘self-medication’ hypothesis by examining if motivation for symptom relief was associated with concurrent severity of symptoms.

RESULTS:

The rank order of reasons for use in CHR patients was similar to that previously reported by schizophrenia patients, with mood enhancement and social motives as primary reasons for use, and the motivation to use cannabis for symptom relief comparatively less common. Motivation for mood enhancement had a trend association with anhedonia. Motivation for symptom relief was entirely unrelated to concurrent severity of positive and anxiety symptoms.

CONCLUSION:

As in schizophrenia, CHR patients primarily use cannabis for mood enhancement, especially in the context of decreased motivation to seek pleasure otherwise. Negative symptoms may drive cannabis use in schizophrenia and its risk states, which may exacerbate positive symptoms. By contrast, CHR patients do not report using cannabis to ‘self-medicate’ emergent positive symptoms. The understanding of motives for cannabis use among CHR patients may be informative for treatments aimed at reducing use, such as motivational interviewing.

60— https://www.ncbi.nlm.nih.gov/pubmed/27337422

Cannabis and Neuropsychiatry, 2: The Longitudinal Risk of Psychosis as an Adverse Outcome.

Abstract

Psychosis is one of the most serious among the adverse effects associated with cannabis use. The association between cannabis use and psychosis has been variously explored in a series of recent meta-analyses. The results of these meta-analyses show that persons who develop psychosis experience onset of psychosis about 2-3 years earlier if they are cannabis users; this effect is not observed with alcohol or other substance use. Higher levels of cannabis use are associated with greater risk of psychosis. Current cannabis abuse or dependence (but not past use or lower levels of current use) increases the risk of transition into psychosis in persons at ultrahigh risk of psychosis. About a third of patients with first-episode psychosis are cannabis users, and, at follow-up, about half of these users are found to continue their cannabis use. Continued cannabis use (in those who are treated after developing psychosis) is associated with higher risk of relapse into psychosis, and discontinuation of cannabis use reduces the risk of relapse to that in cannabis nonusers. Finally, persons with psychosis who continue to use cannabis have more severe positive symptoms and poorer levels of functioning. Because experimental studies in humans show that cannabinoids and cannabis can induce psychotic symptoms, it is reasonable to assume that the epidemiologic data indicate a causal effect of cannabis in anticipating, triggering, or exacerbating psychosis in vulnerable individuals and in worsening the course and outcome of the illness in those who continue to use the substance. Given the public health implications of these findings, the trend to legalize medical marijuana must be viewed with concern, and efforts are necessary to educate patients and the public about the serious mental and physical health risks associated with cannabis use and abuse.

61–  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3037578/

An Evidence Based Review of Acute and Long-Term Effects of Cannabis Use on Executive Cognitive Functions

CONCLUSION

Prevalence rates for cannabis use have increased in recent years (SAMHSA 2007), and as such, chronic, heavy cannabis use is a growing health concern. Research on the effects of cannabis on cognition has generally lagged behind studies on the cognitive effects of alcohol, cocaine, methamphetamine and heroin, and only recently appears to be gaining momentum. Even less attention has been given to the effects of cannabis on executive functions. There are some important methodological differences to take into consideration when interpreting the sometimes disparate results of studies of cannabis effects on executive functions, such as the recency, amount, duration and age of onset of cannabis use.

The trajectory of effects of cannabis on executive functions follows an interesting pattern of recovery of some functions and persisting deficits in others (see Table 2). The acute effects of cannabis use are evident in attentional and information processing abilities with recovery of these functions likely after a month or more of abstinence. Decision-making and risk-taking problems aren’t necessarily evident immediately after smoking; however, if cannabis use is heavy and chronic, impairments may emerge that do not remit with abstinence, particularly if heavy use was initiated in adolescence such that maturation of executive functions was not achieved. Acute cannabis use impairs inhibition and promotes impulsivity, and over a period of abstinence, these deficits are most evident in tasks that require concept formation, planning and sequencing abilities. Working memory is significantly impaired following acute exposure to cannabis; however, these deficits resolve with sustained abstinence. Evidence is less clear in regards to verbal fluency abilities; however, research suggests that chronic, heavy use may impact verbal fluency abilities even after long-term abstinence. The long-term effects of cannabis on executive function is most clearly demonstrated when studies use chronic, heavy cannabis users, as opposed to light, occasional users. Yet even occasional cannabis use can acutely impair attention, concentration, decision-making, inhibition, impulsivity and working memory.

An understanding of the effects of cannabis use on executive functions has considerable practical utility in the clinical setting. The consolidation of findings in this review can provide clinicians with an overview of the documented effects of cannabis use on executive functions as they relate to age of onset, duration, quantity and recency of use with consequent treatment implications. With this information, clinicians can inform their patients who are regular, heavy, cannabis users of the cognitive liabilities associated with continued use, and better understand the impairments their cannabis-abusing patients experience in comprehending, processing, and following-through on important health and treatment advice relevant to sustaining their recovery.

62– https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776082/

The Grass Might Be Greener: Medical Marijuana Patients Exhibit Altered Brain Activity and Improved Executive Function after 3 Months of Treatment

ABSTRACT

…Following 3 months of treatment, MMJ patients demonstrated improved task performance accompanied by changes in brain activation patterns within the cingulate cortex and frontal regions. Interestingly, after MMJ treatment, brain activation patterns appeared more similar to those exhibited by healthy controls from previous studies than at pre-treatment, suggestive of a potential normalization of brain function relative to baseline. These findings suggest that MMJ use may result in different effects relative to recreational marijuana (MJ) use, as recreational consumers have been shown to exhibit decrements in task performance accompanied by altered brain activation. Moreover, patients in the current study also reported improvements in clinical state and health-related measures as well as notable decreases in prescription medication use, particularly opioids and benzodiapezines after 3 months of treatment. Further research is needed to clarify the specific neurobiologic impact, clinical efficacy, and unique effects of MMJ for a range of indications and how it compares to recreational MJ use.

63—

Marijuana matters: reviewing the impact of marijuana on cognition, brain structure and function, & exploring policy implications and barriers to research.

Abstract

The neurobiologic effects of cannabis, commonly referred to as ‘marijuana’ (MJ), have been studied for decades. The impact of recreational MJ use on cognition and measures of brain function and structure is outlined, and variables influencing study results are discussed, including age of the consumer, patterns of MJ use, variations in MJ potency, and the presence of additional cannabinoids. Although evidence suggests that chronic, heavy recreational MJ use is related to cognitive decrements and neural changes, particularly when use begins in adolescence, findings from studies of recreational MJ users may not be applicable to medical marijuana (MMJ) patients given differences in demographic variables, product selection, and reasons for use. Although additional research is needed to fully understand the impact of MJ and individual cannabinoids on the brain, current findings are beginning to inform public policy, including considerations for age limits, potential limits for some cannabinoids, and guidelines for use. However, barriers continue to impede researchers’ ability to conduct studies that will guide policy change and provide vital information to consumers and patients regarding best practices and safest methods for use. The need for information is critical, as legalization of MJ for medical and recreational use is increasingly widespread.

64— https://www.ncbi.nlm.nih.gov/pubmed/23810133

Cannabis and psychosis: have we found the missing links?

Abstract

BACKGROUND:

The association between cannabis and psychosis has long been a matter of debate, with cannabis widely perceived as a harmless recreational drug.

METHODS:

Electronic bibliographic databases like PubMed and Google Scholar were searched using the format “(psychosis or schizophrenia or synonyms) and (cannabis or synonyms)”. Cross-linked searches were made taking the lead from key articles. Recent articles and those exploring the genetic factors or gene-environment interaction between cannabis use and psychosis were focussed upon.

RESULTS:

Heavy cannabis use at a n young age, in association with genetic liability to psychosis and exposure to environmental stressors like childhood trauma and urban upbringing increases the risk of psychotic outcome in later life.

CONCLUSION:

Cannabis acts as a component cause of psychosis, that is, it increases the risk of psychosis in people with certain genetic or environmental vulnerabilities, though by itself, it is neither a sufficient nor a necessary cause of psychosis. Although significant progress has been made over the last few years, we are yet to find all the missing links. Further work is necessary to identify all the factors that underlie individual vulnerability to cannabis-related psychosis and to elucidate the biological mechanisms underlying this risk

65– https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033654/

Deficits in striatal dopamine release in cannabis dependence

ABSTRACT

Most drugs of abuse lead to a general blunting of dopamine release in the chronic phase of dependence, which contributes to poor outcome. To test whether cannabis dependence is associated with a similar dopaminergic deficit, we examined striatal and extrastriatal dopamine release in severely cannabis dependent participants (CD), free of any comorbid conditions, including nicotine use. Eleven CD and twelve healthy controls (HC) completed two positron emission tomography scans with [11C]-(+)-PHNO, before and after oral administration of d-amphetamine. CD stayed inpatient for 5–7 days prior to the scans to standardize abstinence. Magnetic Resonance Imaging (MRS) measures of glutamate in the striatum and hippocampus were obtained in the same subjects. Percent change in [11C]-(+)-PHNO binding potential (ΔBPND) was compared between groups and correlations with MRS glutamate, subclinical psychopathological and neurocognitive parameters were examined. CD had significantly lower ΔBPND in the striatum (p=0.002, effect size (ES)=1.48), including the associative striatum (p=0.003, ES=1.39), sensorimotor striatum (p=0.003, ES=1.41), and the pallidus (p=0.012, ES=1.16). Lower dopamine release in the associative striatum correlated with inattention and negative symptoms in CD, and with poorer working memory and probabilistic category learning performance in both CD and HC. No relationships to MRS glutamate and amphetamine-induced subclinical positive symptoms were detected. In conclusion, this study provides evidence that severe cannabis dependence -without the confounds of any comorbidity- is associated with a deficit in striatal dopamine release. This deficit extends to other extrastriatal areas and predicts subclinical psychopathology.

DISCUSSION

…In conclusion, this study demonstrates that severe cannabis dependence, with no other psychiatric or drug comorbidities, is associated with deficits in amphetamine-induced dopamine release in the AST, SMST and globus pallidus. The lower dopamine release in the AST might contribute to the association between heavy cannabis use and psychopathology. These results are important in light of the steady increase in daily cannabis use in the U.S.62, along with continually increasing THC potency and the movement to legalize its use, which would expose a wider proportion of the population to the negative impact of cannabis use disorder. In particular, as most of our subjects here initiated cannabis use during their adolescent years, our study suggests that adolescent use of cannabis leading to dependence is associated with a compromised dopaminergic system that may have a negative impact on brain function.

66– https://www.ncbi.nlm.nih.gov/pubmed/23138434

Impulsivity, attention, memory, and decision-making among adolescent marijuana users.

Abstract

RATIONALE:

Marijuana is a popular drug of abuse among adolescents, and they may be uniquely vulnerable to resulting cognitive and behavioral impairments. Previous studies have found impairments among adolescent marijuana users. However, the majority of this research has examined measures individually rather than multiple domains in a single cohesive analysis. This study used a logistic regression model that combines performance on a range of tasks to identify which measures were most altered among adolescent marijuana users.

OBJECTIVES:

The purpose of this research was to determine unique associations between adolescent marijuana use and performances on multiple cognitive and behavioral domains (attention, memory, decision-making, and impulsivity) in 14- to 17-year-olds while simultaneously controlling for performances across the measures to determine which measures most strongly distinguish marijuana users from nonusers.

METHODS:

Marijuana-using adolescents (n = 45) and controls (n = 48) were tested. Logistic regression analyses were conducted to test for: (1) differences between marijuana users and nonusers on each measure, (2) associations between marijuana use and each measure after controlling for the other measures, and (3) the degree to which (1) and (2) together elucidated differences among marijuana users and nonusers.

RESULTS:

Of all the cognitive and behavioral domains tested, impaired short-term recall memory and consequence sensitivity impulsivity were associated with marijuana use after controlling for performances across all measures.

CONCLUSIONS:

This study extends previous findings by identifying cognitive and behavioral impairments most strongly associated with adolescent marijuana users. These specific deficits are potential targets of intervention for this at-risk population.

67– https://www.ncbi.nlm.nih.gov/pubmed/15871146

Cannabis as a risk factor for psychosis: systematic review.

Abstract

Various lines of evidence suggest an association between cannabis and psychosis. Five years ago, the only significant case-control study addressing this question was the Swedish Conscript Cohort. Within the last few years, other studies have emerged, allowing the evidence for cannabis as a risk factor to be more systematically reviewed and assessed. Using specific search criteria on Embase, PsychINFO and Medline, all studies examining cannabis as an independent risk factor for schizophrenia, psychosis or psychotic symptoms, published between January 1966 and January 2004, were examined. Additional studies were also reviewed from references found in retrieved articles, reviews, and a cited reference search (ISI-Web of Science). Studies selected for meta-analysis included: (i) case-control studies where exposure to cannabis preceded the onset of schizophrenia or schizophrenia-like psychosis and (ii) cohort studies of healthy individuals recruited before the median age of illness onset, with cannabis exposure determined prospectively and blind to eventual diagnosis. Studies of psychotic symptoms were also tabulated for further discussion. Eleven studies were identified examining the relationship between cannabis use and psychosis. Seven were included in the meta-analysis, with a derived odds ratio (fixed effects) of 2-9 (95 % confidence interval = 2.4-3.6). No evidence of publication bias or heterogeneity was found. Early use of cannabis did appear to increase the risk of psychosis. For psychotic symptoms, a dose-related effect of cannabis use was seen, with vulnerable groups including individuals who used cannabis during adolescence, those who had previously experienced psychotic symptoms, and those at high genetic risk of developing schizophrenia. In conclusion, the available evidence supports the hypothesis that cannabis is an independent risk factor, both for psychosis and the development of psychotic symptoms. Addressing cannabis use, particularly in vulnerable populations, is likely to have beneficial effects on psychiatric morbidity.

68— https://www.ncbi.nlm.nih.gov/pubmed/25242813

[Does the use of cannabis increase the risk for psychosis and the development of schizophrenia?].

Abstract

Over the past 30 years evidence has been growing that cannabis use increases the risk for psychosis which could develop into schizophrenia in a proportion of cases. Over the past decade many studies have been published which clarify the association between cannabis use and psychosis. The aim of this review is to examine this association. A systematic search yielded 14 cohort studies carried out in 9 cohorts and 9 case-control studies. When the results of these studies are taken together they unambiguously support that cannabis use is an independent risk factor for psychosis and may also give rise to chronic psychotic disorders like schizophrenia. A dose dependent link is present because more frequent use associates with greater risk. The studies also show that cannabis-use in adolescence is associated with greater risk of developing psychosis than commencing the use of cannabis in adulthood. Further studies are needed to explain this association since psychotic disorders take years to evolve and it remains difficult to measure both the explanatory and the response variable and their complex relationship. The results emphasize the need to enhance public knowledge on the possible consequences of cannabis use and the fact that it cannot be predicted who will experience transient psychosis and who will develop a chronic psychotic disorder.

69— https://www.ncbi.nlm.nih.gov/pubmed/23139065

[Can cannabis use increase the risk for schizophrenic psychoses?].

Abstract

BACKGROUND:

In recent years, cannabis has been increasingly discussed as one of the most important environmental risk factors for developing schizophrenic psychoses. This is mainly due to the following observations. (i) Cannabis at high doses can cause acute transient psychotic symptoms even in healthy individuals. (ii) Patients with schizophrenia abuse cannabis more often than age-matched healthy controls.

OBJECTIVES:

It is still controversial whether cannabis use can cause schizophrenic psychoses that would not have occurred otherwise. In our review, we have critically evaluated the evidence for a causal link between cannabis use and schizophrenic psychoses.

METHODS:

A systematic literature review in PubMed, ISI Web of Science and PsycINFO was carried out using the following keywords: cannabis, marijuana, THC, hashish, psychosis, schizophrenia.

CONCLUSIONS:

We have concluded that although a causal relationship between cannabis use and schizophrenic psychoses cannot be definitely proven, the available evidence strongly supports its plausibility. Furthermore, the results of the review indicate that cannabis might cause psychosis especially in individuals with a predisposition for schizophrenia and in adolescents with an early onset of cannabis use.

70— https://www.ncbi.nlm.nih.gov/pubmed/18981338

Familial predisposition for psychiatric disorder: comparison of subjects treated for cannabis-induced psychosis and schizophrenia.

Abstract

CONTEXT:

Cannabis-induced psychosis is considered a distinct clinical entity in the existing psychiatric diagnostic systems. However, the validity of the diagnosis is uncertain.

OBJECTIVES:

To establish rate ratios of developing cannabis-induced psychosis associated with predisposition to psychosis and other psychiatric disorders in a first-degree relative and to compare them with the corresponding rate ratios for developing schizophrenia spectrum disorders.

DESIGN:

A population-based cohort was retrieved from the Danish Psychiatric Central Register and linked with the Danish Civil Registration System. History of treatment of psychiatric disorder in family members was used as an indicator of predisposition to psychiatric disorder. Rate ratios of cannabis-induced psychosis and schizophrenia associated with predisposition to psychiatric disorders were compared using competing risk analyses.

SETTING:

Nationwide population-based sample of all individuals born in Denmark between January 1,1955, and July 1, 1990 (N = 2,276,309). Patients During the 21.9 million person-years of follow-up between 1994 and 2005, 609 individuals received treatment of a cannabis-induced psychosis and 6476 received treatment of a schizophrenia spectrum disorder.

RESULTS:

In general, the rate ratios of developing cannabis-induced psychosis and schizophrenia spectrum disorder associated with predisposition to schizophrenia spectrum disorder, other psychoses, and other psychiatric disorders in first-degree relatives were of similar magnitude. However, children with a mother with schizophrenia were at a 5-fold increased risk of developing schizophrenia and a 2.5-fold increased risk of developing cannabis-induced psychosis. The risk of a schizophrenia spectrum disorder following a cannabis-induced psychosis and the timing of onset were unrelated to familial predisposition.

CONCLUSIONS:

Predisposition to both psychiatric disorders in general and psychotic disorders specifically contributes equally to the risk of later treatment because of schizophrenia and cannabis-induced psychoses. Cannabis-induced psychosis could be an early sign of schizophrenia rather than a distinct clinical entity.

71— https://www.ncbi.nlm.nih.gov/pubmed/29083450

The Potential of Cannabidiol Treatment for Cannabis Users With Recent-Onset Psychosis. 

Abstract

A major factor associated with poor prognostic outcome after a first psychotic break is cannabis misuse, which is prevalent in schizophrenia and particularly common in individuals with recent-onset psychosis. Behavioral interventions aimed at reducing cannabis use have been unsuccessful in this population. Cannabidiol (CBD) is a phytocannabinoid found in cannabis, although at low concentrations in modern-day strains. CBD has a broad pharmacological profile, but contrary to ∆9-tetrahydrocannabinol (THC), CBD does not activate CB1 or CB2 receptors and has at most subtle subjective effects. Growing evidence indicates that CBD acts as an antipsychotic and anxiolytic, and several reports suggest neuroprotective effects. Moreover, CBD attenuates THC’s detrimental effects, both acutely and chronically, including psychotogenic, anxiogenic, and deleterious cognitive effects. This suggests that CBD may improve the disease trajectory of individuals with early psychosis and comorbid cannabis misuse in particular-a population with currently poor prognostic outcome and no specialized effective intervention.

72–  https://www.ncbi.nlm.nih.gov/pubmed/22290115

Dopamine release in chronic cannabis users: a [11c]raclopride positron emission tomography study.

Abstract

BACKGROUND:

Low striatal dopamine 2/3 receptor (D(2/3)) availability and low ventrostriatal dopamine (DA) release have been observed in alcoholism and cocaine and heroin dependence. Less is known about the dopaminergic system in cannabis dependence. We assessed D(2/3) availability and DA release in abstinent cannabis users compared with control subjects and explored relationships to cannabis use history using [(11)C]raclopride positron emission tomography and an amphetamine challenge paradigm.

METHODS:

Sixteen recently abstinent, psychiatrically healthy cannabis-using participants (27.3 ± 6.1 years, 1 woman, 15 men) and 16 matched control subjects (28.1 ± 6.7 years, 2 women, 14 men) completed two positron emission tomography scans, before and after injection of intravenous d-amphetamine (.3 mg/kg). Percent change in [(11)C]raclopride binding after amphetamine (change in nondisplaceable binding potential, ΔBP(ND)) in subregions of the striatum was compared between groups. Correlations with clinical parameters were examined.

RESULTS:

Cannabis users had an average consumption of 517 ± 465 estimated puffs per month, indicating mild to moderate cannabis dependence. Neither baseline BP(ND) nor ΔBP(ND) differed from control subjects in any region of interest, including ventral striatum. In cannabis-dependent subjects, earlier age of onset of use correlated with lower [ΔBP(ND)] in the associative striatum when controlling for current age.

CONCLUSIONS:

Unlike other addictions, cannabis dependence of mild to moderate severity is not associated with striatal DA alterations. However, earlier or longer duration of use is related to lower DA release in the associative striatum. These observations suggest a more harmful effect of use during adolescence; more research is needed to distinguish effects of chronicity versus onset.

73– https://www.ncbi.nlm.nih.gov/pubmed/28823723

Understanding marijuana’s effects on functional connectivity of the default mode network in patients with schizophrenia and co-occurring cannabis use disorder: A pilot investigation.

Understanding marijuana’s effects on functional connectivity of the default mode network in patients with schizophrenia and co-occurring cannabis use disorder: A pilot investigation.

Abstract

Nearly half of patients with schizophrenia (SCZ) have co-occurring cannabis use disorder (CUD), which has been associated with decreased treatment efficacy, increased risk of psychotic relapse, and poor global functioning. While reports on the effects of cannabis on cognitive performance in patients with SCZ have been mixed, study of brain networks related to executive function may clarify the relationship between cannabis use and cognition in these dual-diagnosis patients. In the present pilot study, patients with SCZ and CUD (n=12) and healthy controls (n=12) completed two functional magnetic resonance imaging (fMRI) resting scans. Prior to the second scan, patients smoked a 3.6% tetrahydrocannabinol (THC) cannabis cigarette or ingested a 15mg delta-9-tetrahydrocannabinol (THC) pill. We used resting-state functional connectivity to examine the default mode network (DMN) during both scans, as connectivity/activity within this network is negatively correlated with connectivity of the network involved in executive control and shows reduced activity during task performance in normal individuals. At baseline, relative to controls, patients exhibited DMN hyperconnectivity that correlated with positive symptom severity, and reduced anticorrelation between the DMN and the executive control network (ECN). Cannabinoid administration reduced DMN hyperconnectivity and increased DMN-ECN anticorrelation. Moreover, the magnitude of anticorrelation in the controls, and in the patients after cannabinoid administration, positively correlated with WM performance. The finding that DMN brain connectivity is plastic may have implications for future pharmacotherapeutic development, as treatment efficacy could be assessed through the ability of therapies to normalize underlying circuit-level dysfunction.

74—https://www.ncbi.nlm.nih.gov/pubmed/24875171  

Executive attention impairment in adolescents with schizophrenia who have used cannabis.

Abstract

OBJECTIVE:

Repeated exposure to cannabis in nonpsychotic adolescents is associated with impairments in executive control of attention, similar to those observed in young adults with first-episode schizophrenia. To assess the impact of recurrent exposure to cannabis on cognitive function, this study characterized attention performance in both nonpsychotic adolescents and adolescents with early-onset schizophrenia (EOS).

METHOD:

The Attention Network Test, a standard procedure that estimates the functional state of neural networks controlling the efficiency of three different attentional behaviors (alerting, orienting, and executive attention), was administered to four groups of participants: (1) adolescents with EOS and comorbid cannabis use disorder (EOS+CUD; n=18), (2) “Pure” schizophrenia (EOS; n=34), (3) “Pure” cannabis use disorder (CUD; n=29), and (4) Healthy controls (HC; n=53). Task performance was examined with a 2×2 design (EOS+ versus EOS- and CUD+ versus CUD-) using multivariate analysis of covariance. Correlative analyses were conducted between executive attention performance and measures of surface area in the right anterior cingulate cortex.

RESULTS:

A significant EOS×CUD interaction was observed. In the executive attention network, adolescents with EOS+CUD showed reduced efficiency relative to adolescents with pure EOS, whereas no group differences were found between adolescents with pure CUD and HC. Less efficient executive attention was significantly associated with smaller surface area in the right caudal anterior cingulate cortex in EOS+CUD.

CONCLUSIONS:

These preliminary data suggest that the presence of CUD has a moderating effect on attentional performance in adolescents with schizophrenia compared to nonpsychotic adolescents. These deficits could have a role in difficulties with self-regulation and predisposition to substance misuse in this patient group. The anatomic substrate of this cognitive deficit may be related to surface area in the right caudal anterior cingulate cortex.

75– https://www.ncbi.nlm.nih.gov/pubmed/24875171

Executive attention impairment in adolescents with schizophrenia who have used cannabis.

Abstract

OBJECTIVE:

Repeated exposure to cannabis in nonpsychotic adolescents is associated with impairments in executive control of attention, similar to those observed in young adults with first-episode schizophrenia. To assess the impact of recurrent exposure to cannabis on cognitive function, this study characterized attention performance in both nonpsychotic adolescents and adolescents with early-onset schizophrenia (EOS).

METHOD:

The Attention Network Test, a standard procedure that estimates the functional state of neural networks controlling the efficiency of three different attentional behaviors (alerting, orienting, and executive attention), was administered to four groups of participants: (1) adolescents with EOS and comorbid cannabis use disorder (EOS+CUD; n=18), (2) “Pure” schizophrenia (EOS; n=34), (3) “Pure” cannabis use disorder (CUD; n=29), and (4) Healthy controls (HC; n=53). Task performance was examined with a 2×2 design (EOS+ versus EOS- and CUD+ versus CUD-) using multivariate analysis of covariance. Correlative analyses were conducted between executive attention performance and measures of surface area in the right anterior cingulate cortex.

RESULTS:

A significant EOS×CUD interaction was observed. In the executive attention network, adolescents with EOS+CUD showed reduced efficiency relative to adolescents with pure EOS, whereas no group differences were found between adolescents with pure CUD and HC. Less efficient executive attention was significantly associated with smaller surface area in the right caudal anterior cingulate cortex in EOS+CUD.

CONCLUSIONS:

These preliminary data suggest that the presence of CUD has a moderating effect on attentional performance in adolescents with schizophrenia compared to nonpsychotic adolescents. These deficits could have a role in difficulties with self-regulation and predisposition to substance misuse in this patient group. The anatomic substrate of this cognitive deficit may be related to surface area in the right caudal anterior cingulate cortex.

76— https://www.ncbi.nlm.nih.gov/pubmed/26970363

Human Laboratory Studies on Cannabinoids and Psychosis.

Abstract

Some of the most compelling evidence supporting an association between cannabinoid agonists and psychosis comes from controlled laboratory studies in humans. Randomized, double-blind, placebo-controlled, crossover laboratory studies demonstrate that cannabinoid agonists, including phytocannabinoids and synthetic cannabinoids, produce a wide range of positive, negative, and cognitive symptoms and psychophysiologic deficits in healthy human subjects that resemble the phenomenology of schizophrenia. These effects are time locked to drug administration, are dose related, and are transient and rarely necessitate intervention. The magnitude of effects is similar to the effects of ketamine but qualitatively distinct from other psychotomimetic drugs, including ketamine, amphetamine, and salvinorin A. Cannabinoid agonists have also been shown to transiently exacerbate symptoms in individuals with schizophrenia in laboratory studies. Patients with schizophrenia are more vulnerable than healthy control subjects to the acute behavioral and cognitive effects of cannabinoid agonists and experience transient exacerbation of symptoms despite treatment with antipsychotic medications. Furthermore, laboratory studies have failed to demonstrate any “beneficial” effects of cannabinoid agonists in individuals with schizophrenia-challenging the cannabis self-medication hypothesis. Emerging evidence suggests that polymorphisms of several genes related to dopamine metabolism (e.g., COMT, DAT1, and AKT1) may moderate the effects of cannabinoid agonists in laboratory studies. Cannabinoid agonists induce dopamine release, although the magnitude of release does not appear to be commensurate to the magnitude and spectrum of their acute psychotomimetic effects. Interactions between the endocannabinoid, gamma-aminobutyric acid, and glutamate systems and their individual and interactive effects on neural oscillations provide a plausible mechanism underlying the psychotomimetic effects of cannabinoids.

77— https://www.ncbi.nlm.nih.gov/pubmed/17349865

Cannabinoids and psychosis.

Abstract

Recent epidemiological studies and advances in understanding of brain cannabinoid function have renewed interest in the long-recognized association between cannabinoids and psychosis. This chapter presents evidence supporting and refuting the association between cannabinoids and psychosis. Cannabinoids can induce acute transient psychotic symptoms or an acute psychosis in some individuals. What makes some individuals vulnerable to cannabinoid-related psychosis is unclear. Also clear is that cannabinoids can also exacerbate psychosis in individuals with an established psychotic disorder, and these exacerbations may last beyond the period of intoxication. Less clear is whether cannabis causes a persistent de novo psychosis. The available evidence meets many but not all the criteria for causality, including dose-response, temporality, direction, specificity, and biological plausibility. On the other hand, the large majority of individuals exposed to cannabinoids do not experience psychosis or develop schizophrenia and the rates of schizophrenia have not increased commensurate with the increase in rates of cannabis use. Similar to smoking and lung cancer, it is more likely that cannabis exposure is a component cause that interacts with other factors, for example, genetic risk, to “cause” schizophrenia. Nevertheless, in the absence of known causes of schizophrenia, the role of component causes such as cannabis exposure (exogenous hypothesis) is important and warrants further study. There is also tantalizing evidence from postmortem, neurochemical, and genetic studies suggesting CB1 receptor dysfunction (endogenous hypothesis) in schizophrenia that warrants further investigation. Further work is necessary to identify those factors that place individuals at higher risk for cannabinoid-related psychosis, to identify the biological mechanisms underlying the risks and to further study whether CB1 receptor dysfunction contributes to the pathophysiology of psychotic disorders.