The prevalence of psychotic symptoms in kratom (Mitragyna speciosa Korth.) Users in Malaysia.

BACKGROUND: Kratom is a traditional medicinal herb widely used in Malaysia and Thailand. Despite its widespread use and statements by regulatory agencies on the potential for kratom-associated psychosis, there is little data regarding the prevalence of psychotic symptoms among kratom users. This study investigated the prevalence of psychosis among kratom users, described psychotic symptomatology and severity, while examining associations between kratom use characteristics and the occurrence of psychotic symptoms. METHODS: This cross-sectional clinical survey recruited 150 regular kratom users. The Mini International Neuropsychiatric Interview (MINI) and Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-V) diagnostic criteria were used to evaluate psychotic symptomatology among kratom users, and the Brief Psychiatric Rating Scale (BPRS) was used to assess the severity of psychiatric symptoms. Chi-square tests with Yate's correction were performed to determine the association between kratom use characteristics and the occurrence of psychotic symptoms among kratom users in this study. RESULTS: Six out of 150 kratom users (4%) presented with any psychotic symptoms. The psychotic symptoms reported were positive symptoms and thought alienation, with a mean BPRS score of 33 (i.e., mild severity). Variables related to kratom use (such as intake of kratom with diphenhydramine, duration of kratom use, and quantity and frequency of daily kratom use) were not associated with the occurrence of psychotic symptoms among kratom users. CONCLUSION: Although psychotic symptoms could occur among regular kratom users, they were rare and not significantly associated with kratom use characteristics. We found no evidence of elevated psychosis among regular users.

Involvement of posterior cingulate cortex in ketamine-induced psychosis relevant behaviors in rats.

The involvement of posterior cingulate cortex (PCC) on ketamine-induced psychosis relevant behaviors was investigated in rats. Bilateral infusion of muscimol, a GABAA receptor agonist, into the PCC significantly antagonized ketamine-induced deficit in prepulse inhibition of a startle reflex (PPI), deficit in gating of hippocampal auditory evoked potentials, and behavioral hyperlocomotion in a dose dependent manner. Local infusion of ketamine directly into the PCC also induced a PPI deficit. Systemic injection of ketamine (3mg/kg,s.c.) induced an increase in power of electrographic activity in the gamma band (30-100Hz) in both the PCC and the hippocampus; peak theta (4-10Hz) power was not significantly altered, but peak theta frequency was increased by ketamine. In order to exclude volume conduction from the hippocampus to PCC, inactivation of the hippocampus was made by local infusion of muscimol into the hippocampus prior to ketamine administration. Muscimol in the hippocampus effectively blocked ketamine-induced increase of gamma power in the hippocampus but not in the PCC, suggesting independent generation of gamma waves in PCC and hippocampus. It is suggested that the PCC is part of the brain network mediating ketamine-induced psychosis related behaviors.

Adverse Structural and Functional Effects of Marijuana on the Brain: Evidence Reviewed.

The growing use and legalization of cannabis are leading to increased exposures across all age groups, including in adolescence. The touting of its medicinal values stems from anecdotal reports related to treatment of a broad range of illnesses including epilepsy, multiple sclerosis, muscle spasms, arthritis, obesity, cancer, Alzheimer disease, Parkinson disease, post-traumatic stress, inflammatory bowel disease, and anxiety. However, anecdotal data and the high level of interest in this treatment must not obscure objective assessments of any potential and realized short- and long-term adverse effects of cannabis, particularly with respect to age of onset and chronicity of exposure. This critical review focuses on evidence-based research designed to assess both therapeutic benefits and harmful effects of cannabis exposure and is combined with an illustration of the neuropathologic findings in a fatal case of cannabis-induced psychosis. The literature and reported case provide strong evidence that chronic cannabis abuse causes cognitive impairment and damages the brain, particularly white matter, where cannabinoid 1 receptors abound. Contrary to popular perception, there are few objective data supporting preferential use of cannabis over conventional therapy for restoration of central nervous system structure and function in disease states such as multiple sclerosis, epilepsy, or schizophrenia. Additional research is needed to determine if subsets of individuals with various neurological and psychiatric diseases derive therapeutic benefits from cannabis.

Synthetic Cannabinoids-Further Evidence Supporting the Relationship Between Cannabinoids and Psychosis.

Consumption of synthetic mind-altering compounds, also known as "new psychoactive substances," is increasing globally at an alarming rate. Synthetic cannabinoids (SCs) are among the most commonly used new psychoactive substances. They are usually purchased as marijuana-like drugs, marketed as herbal blends and perceived as risk-free by inexperienced users. Yet, contrary to Δ(9)-tetrahydrocannabinol, SCs may lead to severe health consequences, including anxiety, tachycardia, hallucinations, violent behavior, and psychosis. This review focuses on the latest (2010-2015) evidence of psychotic symptoms induced by ingestion of products containing SCs. Reports suggesting that SCs may either exacerbate previously stable psychotic symptoms (in vulnerable individuals) or trigger new-onset psychosis (in individuals with no previous history of psychosis) are reviewed. Pharmacology and toxicology of these compounds are discussed, with particular reference to their psychoactive effects.

Ketamine Suppresses the Ventral Striatal Response to Reward Anticipation: A Cross-Species Translational Neuroimaging Study.

Convergent evidence implicates regional neural responses to reward anticipation in the pathogenesis of several psychiatric disorders, such as schizophrenia, where blunted ventral striatal responses to positive reward are observed in patients and at-risk populations. In vivo oxygen amperometry measurements in the ventral striatum in awake, behaving rats reveal reward-related tissue oxygen changes that closely parallel blood oxygen level dependent (BOLD) signal changes observed in human functional magnetic resonance imaging (fMRI), suggesting that a cross-species approach targeting this mechanism might be feasible in psychopharmacology. The present study explored modulatory effects of acute, subanaesthetic doses of ketamine-a pharmacological model widely used in psychopharmacological research, both preclinically and clinically-on ventral striatum activity during performance of a reward anticipation task in both species, using fMRI in humans and in vivo oxygen amperometry in rats. In a region-of-interest analysis conducted following a cross-over placebo and ketamine study in human subjects, an attenuated ventral striatal response during reward anticipation was observed following ketamine relative to placebo during performance of a monetary incentive delay task. In rats, a comparable attenuation of ventral striatal signal was found after ketamine challenge, relative to vehicle, in response to a conditioned stimulus that predicted delivery of reward. This study provides the first data in both species demonstrating an attenuating effect of acute ketamine on reward-related ventral striatal (O2) and fMRI signals. These findings may help elucidate a deeper mechanistic understanding of the potential role of ketamine as a model for psychosis, show that cross-species pharmacological experiments targeting reward signaling are feasible, and suggest this phenotype as a promising translational biomarker for the development of novel compounds, assessment of disease status, and treatment efficacy.

Selective augmentation of striatal functional connectivity following NMDA receptor antagonism: implications for psychosis.

The psychotomimetic effect of the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine is thought to arise from a functional modulation of the brain's fronto-striato-thalamic (FST) circuits. Animal models suggest a pronounced effect on ventral 'limbic' FST systems, although recent work in patients with psychosis and high-risk individuals suggests specific alterations of dorsal 'associative' FST circuits. Here, we used functional magnetic resonance imaging to investigate the effects of a subanesthetic dose of ketamine on measures of functional connectivity as indexed by the temporal coherence of spontaneous neural activity in both dorsal and ventral FST circuits, as well as their symptom correlates. We adopted a placebo-controlled, double-blind, randomized, repeated-measures design in which 19 healthy participants received either an intravenous saline infusion or a racemic mixture of ketamine (100 ng/ml) separated by at least 1 week. Compared with placebo, ketamine increased functional connectivity between the dorsal caudate and both the thalamus and midbrain bilaterally. Ketamine additionally increased functional connectivity of the ventral striatum/nucleus accumbens and ventromedial prefrontal cortex. Both connectivity increases significantly correlated with the psychosis-like and dissociative symptoms under ketamine. Importantly, dorsal caudate connectivity with the ventrolateral thalamus and subthalamic nucleus showed inverse correlation with ketamine-induced symptomatology, pointing to a possible resilience role to disturbances in FST circuits. Although consistent with the role of FST in mediating psychosis, these findings contrast with previous research in clinical samples by suggesting that acute NMDAR antagonism may lead to psychosis-like experiences via a mechanism that is distinct from that implicated in frank psychotic illness.

Cannabis, psychosis and the thalamus: a theoretical review.

The role of cannabis in the etiology of schizophrenia has been documented as possibly the strongest environmental risk factor. However, the pathomechanism whereby cannabis use increases this risk has not yet been identified. We argue that this pathomechanism may involve direct effects of exogenous cannabinoids on T-type calcium channels in the thalamus. These channels are crucial for amplification of corticothalamic inputs, as well as for the ability of the thalamus to generate neuronal burst firing. Cortically induced thalamic burst firing has been found to be important in trans-thalamic cortico-cortical interactions. Therefore, any potential interference with the burst firing mode in the thalamus could lead to an impairment in these interactions, which in turn causes a relative disconnection between cortical areas. This in turn could result in reduced ability to recognize re-afferent sensory inputs and psychosis. We also argue that the effects of Δ(9)THC are more detrimental compared with the effects of cannabidiol, as the former may increase the excitability of thalamic neurons by its direct effect on T-type calcium channels.

Functional connectivity measures after psilocybin inform a novel hypothesis of early psychosis.

Psilocybin is a classic psychedelic and a candidate drug model of psychosis. This study measured the effects of psilocybin on resting-state network and thalamocortical functional connectivity (FC) using functional magnetic resonance imaging (fMRI). Fifteen healthy volunteers received intravenous infusions of psilocybin and placebo in 2 task-free resting-state scans. Primary analyses focused on changes in FC between the default-mode- (DMN) and task-positive network (TPN). Spontaneous activity in the DMN is orthogonal to spontaneous activity in the TPN, and it is well known that these networks support very different functions (ie, the DMN supports introspection, whereas the TPN supports externally focused attention). Here, independent components and seed-based FC analyses revealed increased DMN-TPN FC and so decreased DMN-TPN orthogonality after psilocybin. Increased DMN-TPN FC has been found in psychosis and meditatory states, which share some phenomenological similarities with the psychedelic state. Increased DMN-TPN FC has also been observed in sedation, as has decreased thalamocortical FC, but here we found preserved thalamocortical FC after psilocybin. Thus, we propose that thalamocortical FC may be related to arousal, whereas DMN-TPN FC is related to the separateness of internally and externally focused states. We suggest that this orthogonality is compromised in early psychosis, explaining similarities between its phenomenology and that of the psychedelic state and supporting the utility of psilocybin as a model of early psychosis.

Antipsychotic property of aqueous and ethanolic extracts of Lonchocarpus cyanescens (Schumach and Thonn.) Benth. (Fabaceae) in rodents.

Lonchocarpus cyanescens (LC) is a medicinal plant commonly used in combination with other recipes in the treatment of psychotic disorders in traditional medicine. This study was designed to examine whether the aqueous and ethanolic extracts of LC possess antipsychotic property in rats. The antipsychotic effects of the extracts were assessed using the amphetamine animal model of psychosis in rats. The effect of the extracts on spontaneous motor activity was also studied in the open field test in mice. The extrapyramidal side effect of catalepsy was tested based on the ability of the extracts to alter the duration of akinesia in mice placed on a vertical wrapped string. Aqueous and ethanolic extracts of LC (25-400 mg/kg, i.p.) significantly (p < 0.05) suppressed stereotyped behaviour induced by amphetamine (10.0 mg/kg, i.p.) in rats, which suggest antipsychotic activity. The extracts (25-400 mg/kg, i.p.) further produced a significant (p < 0.05) reduction in spontaneous motor activity of the animals in the open field test. However, in contrast to chlorpromazine, a typical antipsychotic, the extracts did not induce cataleptic behaviour in the animals. Preliminary phytochemical screening showed the presence of alkaloids, anthraquinones, cardiac glycosides, cyanogenetic glycosides, flavonoids, saponins, steroids and tannins in the leaves of LC. The presence of these secondary metabolites was confirmed by thin-layer chromatography. Taken together, these findings suggest that the extracts possess phytochemically active constituents with antipsychotic property. Thus, this investigation provides evidence that may justify the ethnomedicinal applications of Lonchocarpus cyanescens as the major constituent of the recipe used for the management of psychosis in Nigeria.

Corticosteroid induced psychosis in the pain management setting.

BACKGROUND: Synthetic corticosteroids are commonly utilized in interventional pain management procedures. These substances have potential side-effects including psychological adverse events. OBJECTIVE: We describe a case of substance-induced psychotic disorder resulting from corticosteroids administration. DESIGN: Case Report. METHODS: We describe a 67-year-old male that, six months prior to being consulted at our center, received a cervical epidural, 4 level medial branch blocks, 4 trigger point injections and a tendon injection in the shoulder all including corticosteroids all in one treatment session. RESULTS: Approximately 7 days following the multiple injections, the patient developed psychotic episodes including racing thoughts, anger, agitation, pressured hyperverbal speech and paranoia. The symptoms spontaneously resolved in approximately 7-10 days. DISCUSSION: Although well known as a potential complication, corticosteroid induced psychosis secondary to interventional pain procedures have never been reported. We further discuss this potential side effect of utilizing corticosteroids and emphasize the need for guidelines regarding steroid utilization.

Attentional deficits in cocaine-dependent patients: converging behavioral and electrophysiological evidence.

Although there are several reports of patients with cocaine dependence displaying cognitive deficits, the nature of their information processing deficits is not well characterized. In the present study, the attentional performance of cocaine-dependent patients (n=14) was examined and compared with that of healthy control individuals (n=15). Attention was assessed using an auditory oddball event-related task as well as the Continuous Performance Test (CPT, Identical Pairs version). The cocaine-dependent group displayed P300 amplitude reduction compared to controls. The group difference in P300 response latency did not reach significance. On the CPT, the cocaine-dependent patients displayed significantly poorer discriminability and greater errors of commission than the controls. There was a positive correlation between performance on the oddball event-related task and performance on the CPT. This investigation provides converging behavioral and electrophysiological evidence of attentional deficits in cocaine-dependent patients.

Acute effects of Delta9-tetrahydrocannabinol and standardized cannabis extract on the auditory evoked mismatch negativity.

Reduced amplitudes of auditory evoked mismatch negativity (MMN) have often been found in schizophrenic patients, indicating deficient auditory information processing and working memory. Cannabis-induced psychotic states may resemble schizophrenia. Currently, there are discussions focusing on the close relationship between cannabis, the endocannabinoid and dopaminergic system, and the onset of schizophrenic psychosis. This study investigated the effects of cannabis on MMN amplitude in 22 healthy volunteers (age 28+/-6 years, 11 male) by comparing Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and standardized cannabis extract containing Delta(9)-THC and cannabidiol (CBD) in a prospective, double-blind, placebo-controlled cross-over design. The MMNs resulting from 1000 auditory stimuli were recorded by 32 channel EEG. The standard stimuli were 1000 Hz, 80 dB SPL, and 100 ms duration. The deviant stimuli differed in frequency (1500 Hz). Significantly greater MMN amplitude values at central electrodes were found under cannabis extract, but not under Delta(9)-THC. There were no significant differences between MMN amplitudes at frontal electrodes. MMN amplitudes at central electrodes were significantly correlated with 11-OH-THC concentration, the most important psychoactive metabolite of Delta(9)-THC. Since the main difference between Delta(9)-THC and standardized cannabis extract is CBD, which seems to have neuroprotective and anti-psychotic properties, it can be speculated whether the greater MMN amplitude that may imply higher cortical activation and cognitive performance is related to the positive effects of CBD. This effect may be relevant for auditory cortex activity in particular because only MMN amplitudes at the central, but not at the frontal electrodes were enhanced under cannabis.

P3a of event-related potential in chronic methamphetamine dependence.

To investigate the psychophysiological features of methamphetamine (MAP) dependence, we recorded auditory event-related potentials (ERPs) in 15 patients with MAP dependence and in 15 age-matched normal controls. ERPs were recorded during a standard oddball task and a read task similar to those employed by Squires et al. (Squires NK, Squires KC, Hillyard SA [1975] Two varieties of long-latency positive waves evoked by unpredictable auditory stimuli in man. Electroenceph Clin Neurophysiol 38:387-401). The patients with MAP dependence showed reduced P3a amplitude and area in the read task and delayed P3b latency with normal P3b amplitude and area in the oddball task. These results suggest that central noradrenergic dysregulation may persist after the remission of acute psychotic symptoms in MAP psychosis and that chronic MAP dependence would produce impairment of the frontal cortex.

The effects of cocaine, amphetamine, and the dopamine D1 receptor agonist SKF 38393 on fear extinction as measured with potentiated startle: implications for psychomotor stimulant psychosis.

Using Pavlovian conditioned increases in the amplitude of the acoustic startle reflex as a behavioral indicator of fear motivation, the authors previously showed a resistance to extinction after repeated associations of cocaine with the fear-evoking conditioned stimulus (CS). In Experiment 1, acute administration of cocaine, amphetamine, and the dopamine (DA) D1 receptor agonist SKF 38393 produced a similar fear enhancement. In Experiment 2, a noncontingent injection of cocaine and SKF 38393 provoked a CS potentiation of acoustic startle in fear-extinguished laboratory rats. Potential behavioral, neurochemical, and neuroendocrine explanations for the effects of psychomotor stimulants on conditional fear were discussed. It was suggested that DA agonist drugs increase fear expression possibly by activating mesoamygdaloid associative neurocircuitry involved in excitatory conditioned fear reactions.

Stimulant-induced psychosis, the dopamine theory of schizophrenia, and the habenula.

While one of the original underpinnings of the dopamine theory of schizophrenia was the paranoid psychosis which often develops during the binges or speed runs of chronic amphetamine addicts (and, more recently, in cocaine addicts), neurochemical studies of such drug abusers or from animals given continuous stimulants in an effort to model stimulant psychoses have not played a major role in the further evolution of this theory. One clear persisting alteration produced by continuous amphetamine is a neurotoxicity to dopaminergic innervations in caudate. Yet continuous cocaine administration apparently does not induce a similar neurotoxicity and this makes this effect a poor candidate for an underpinning of stimulant psychoses. However, it has recently been found that both continuous amphetamine and cocaine induce a strong pattern of degeneration which is highly confined to the lateral habenula and its principal output pathway, fasciculus retroflexus. This finding has led to a reconsideration of the role of these structures in psychoses. The habenula, as the chief relay nucleus of the descending dorsal diencephalic system (consisting of stria medullaris, habenula and fasciculus retroflexus), is an important link between limbic and striatal forebrain and lower diencephalic and mesencephalic centers. Studies of glucose utilization have consistently shown the habenula to be highly sensitive to dopamine agonists and antagonists. Lesions of habenula produce a wide variety of behavioral alterations. The dorsal diencephalic system has major and predominantly inhibitory connections onto dopamine-containing cells and it mediates part of the negative feedback from dopamine receptors onto dopamine cell bodies. It represents one of the major inputs in brain to the raphe nuclei and has anatomical and functional connections to modulate important functions such as sensory gating through thalamus, pain gating through central gray and raphe and motor stereotypies and reward mechanisms through substantia nigra and the ventral tegmental area. It is argued that alterations in these pathways are ideal candidates for producing the behaviors which occur during psychosis and that future considerations of the circuitry underlying psychoses need to include this highly important but relatively neglected system.

Psychotic illness following 'mabi bark tea' consumption.

A first episode of psychosis occurred in a young woman of West Indian parentage and one of identical twins following a brief period of high consumption of a drink made from Colubrina plant extract (mabi bark). The course of the psychosis is described and possible underlying mechanisms and the relationship to amphetamine psychosis are discussed.

[The psychopathology of early and chronic psychotic symptoms in young drug-users]. / Zur Psychopathologie beginnender und chronischer psychotischer Zustandsbilder bei jugendlichen Drogenkonsumenten

Among the psychotic symptoms in juvenile drug-consumers one can find autonomous, i.e. drug-independent developments, whose connection with the drug-abuse is to be assessed in differing ways. A beginning psychosis can be modified in its actual symptoms by drug-consumption. On the other hand one must consider the manifestation of a latent psychosis or purely symptomatic psychosis, which, in its symptoms, can hardly be distinguished from schizophrenia. Finally drug-induced personality-changes can develop together with secondary psychotic symptoms. Psychotic symptoms are determined and influenced in a varying degree by drugs. Both after short drug-consumption and after a longer drug-anamnesis with polytoxicomanic symptoms psychotic syndromes can be discovered. Even the initial psychotic symptoms can hint at an adverse development and a bad prognosis. Sometimes the drug-experiences conceal the autonomous development of the psychosis, which, as a rule, shows predominantly schizophrenic symptoms. In addition to a quick change of the actual symptoms, acute states of confusion and depressive-suicidal syndromes, flash-back and horror-trip phenomena, closely connected with the psychotic experience, and a schizophrenic colouring of affective psychoses can be found as frequently drug-induced modifications of the psychotic symptoms. Furthermore one finds an increase of symptoms and of the psychotic episodes in the case of psychoses of the schizophrenic variety which have already begun. Grave personality changes with psychotic symptoms after chronic drug-abuse can cause differential-diagnostic difficulties.