The Abuse Potential of Novel Synthetic Phencyclidine Derivative 1-(1-(4-Fluorophenyl)Cyclohexyl)Piperidine (4'-F-PCP) in Rodents.

The dissociative anesthetic phencyclidine (PCP) and PCP derivatives, including 4'-F-PCP, are illegally sold and abused worldwide for recreational and non-medical uses. The psychopharmacological properties and abuse potential of 4'-F-PCP have not been fully characterized. In this study, we evaluated the psychomotor, rewarding, and reinforcing properties of 4'-F-PCP using the open-field test, conditioned place preference (CPP), and self-administration paradigms in rodents. Using Western immunoblotting, we also investigated the expression of dopamine (DA)-related proteins and DA-receptor-mediated downstream signaling cascades in the nucleus accumbens (NAc) of 4'-F-PCP-self-administering rats. Intraperitoneal administration of 10 mg/kg 4'-F-PCP significantly increased locomotor and rearing activities and increased CPP in mice. Intravenous administration of 1.0 mg/kg/infusion of 4'-F-PCP significantly enhanced self-administration during a 2 h session under fixed ratio schedules, showed a higher breakpoint during a 6 h session under progressive ratio schedules of reinforcement, and significantly altered the expression of DA transporter and DA D1 receptor in the NAc of rats self-administering 1.0 mg/kg 4'-F-PCP. Additionally, the expression of phosphorylated (p) ERK, pCREB, c-Fos, and FosB/ΔFosB in the NAc was significantly enhanced by 1.0 mg/kg 4'-F-PCP self-administration. Taken together, these findings suggest that 4'-F-PCP has a high potential for abuse, given its robust psychomotor, rewarding, and reinforcing properties via activation of DAergic neurotransmission and the downstream signaling pathways in the NAc.

Pseudo-Wellens' syndrome secondary to concurrent cannabis and phencyclidine intoxication.

Wellens' syndrome is an electrocardiographic pattern of T-wave changes associated with critical stenosis of the proximal left anterior descending artery, signifying imminent risk of an anterior-wall myocardial infarction. The Wellens' electrocardiographic pattern can also be noted in several cardiac and non-cardiac diseases. We chronicle here a unique case of a patient who presented with atypical left chest pain and dizziness for 6 hours. His pain started after he smoked phencyclidine-laced cannabis. Cardiac panel demonstrated normal troponin T levels. Electrocardiogram showed sinus rhythm with new deep biphasic T-wave inversions in anterolateral leads. Coronary angiography showed no pathological processes. Subsequently, ECG changes resolved coincidentally with the resolution of chest pain. He was eventually diagnosed with pseudo-Wellens' syndrome. This paper illustrates that physicians should be vigilant for Wellens' syndrome mimicked by acute phencyclidine and cannabis intoxication. Additionally, we present a review of various aetiologies of pseudo-Wellens' syndrome, especially in patients with substance abuse.

Quantitation of Cocaine and Metabolites, Phencyclidine, Butalbital and Phenobarbital in Meconium by Liquid Chromatography-Tandem Mass Spectrometry.

In this study, a quantitative polarity switching liquid chromatography coupled with a tandem mass spectrometer (LC-MS/MS) method was developed to detect and quantify cocaine and metabolites (cocaethylene, benzoylecgonine and meta-hydroxybenzoylecgonine), phencyclidine (PCP) and barbiturates (phenobarbital and butalbital) in meconium. Accuracy and precision samples at 0.0125% and 75% of the upper limit of quantitation (ULOQ) were analyzed in triplicate over 5 days with accuracy above 84% and average %CV values below 11%. Within-run (n = 15) and between-run (n = 15) %CV values were ≤5%. Analytical measurement ranges were reproducible and linear (R ≥ 0.995) for cocaine and metabolites (20-2,000 ng/g), PCP (10-1,000 ng/g) and barbiturates (50-5,000 ng/g). Accuracy of 100 ± 20% was observed at (the limits of detection) 10 ng/g for cocaine and metabolites, 2.5 ng/g for PCP and 25 ng/g for barbiturates. No carryover was observed at 2X ULOQ and no interfering substances were identified. Sample preparation recoveries were 53-83%. Fifty-one authentic patient samples previously characterized correlated with the newly developed test having R2 values ≥0.996. This combined method allows accurate quantitation of the targeted drugs in a complex matrix while decreasing sample preparation and analysis time with reduced sample volume. Clinical data and positivity rates were similar to previously published positivity rates. Validation data and positivity rate agreement signifies a reliable and robust assay.

Potential benefit of lamotrigine in managing ketamine use disorder.

Ketamine is an anesthetic derivative of phencyclidine (PCP; 'Angel dust') with dissociative, analgesic and psychedelic properties. Ketamine has become a popular recreational drug of abuse in many parts of the world in recent years. The preclinical studies demonstrate the reinforcing effects of ketamine and long-term ketamine abuse induces a delayed and persistent upregulation of dopamine system. In humans, there have been concerns about its liability to development of addiction. The dilemma of mental professionals in managing the treatment-seeking ketamine abusers comes from a lack of effective pharmacotherapy. Limiting evidence showed that lamotrigine, which inhibits glutamate release, is effective to reduce cocaine craving. We propose that lamotrigine might be beneficial for managing ketamine use disorder clinically. We also reported one case of ketamine use disorder who experienced a great reduction in craving and ketamine use after taking lamotrigine. Although the mechanisms underlying neuroadaptation and reward related to ketamine are not entirely clear, future clinical trials are needed to advance our understanding of the benefit yielded by lamotrigine to treat ketamine use disorder.

Phencyclidine analog use in Sweden--intoxication cases involving 3-MeO-PCP and 4-MeO-PCP from the STRIDA project.

BACKGROUND: 3-Methoxy-phencyclidine (3-MeO-PCP) and 4-methoxy-phencyclidine (4-MeO-PCP) are analogs of and drug substitutes for the dissociative substance PCP ("Angel dust"), a recreational drug that was most popular in the 1970s. In Sweden, use of methoxylated PCP analogs was noted starting in mid-2013, according to statistics from the Poisons Information Centre. The objective of this case series was to present clinical and bioanalytical data from analytically confirmed non-fatal intoxications associated with 3-MeO-PCP and/or 4-MeO-PCP within the STRIDA project. STUDY DESIGN: Observational case series of consecutive patients with self-reported or suspected exposure to new psychoactive substances (NPS) and who require hospital care. PATIENTS AND METHODS: Blood and urine samples were collected from intoxicated patients presenting at emergency departments (ED) or intensive care units (ICU) all over Sweden. NPS analysis was performed by multicomponent liquid chromatographic-tandem mass spectrometric (LC-MS/MS) and LC-high-resolution MS (LC-HRMS) methods. Data on clinical features were collected during Poisons Information Centre consultations and retrieved from medical records. RESULTS: The Poisons Information Centre registered its first call related to methoxylated PCP analogs in July 2013, while analytically confirmed cases first appeared in October 2013. From July 2013 to March 2015, 1243 cases of suspected NPS intoxication originating from ED or ICU were enrolled in the STRIDA project. During the 21-month period, 56 (4.5%) patients tested positive for 3-MeO-PCP and 11 (0.9%) for 4-MeO-PCP; 8 of these cases involved both substances. The 59 patients were aged 14-55 (median: 26) years and 51 (86%) were men. Co-exposure to other NPSs and/or classical drugs of abuse was common with only 7 cases (12%) indicated to be 3-MeO-PCP single-substance intoxications; prominent clinical signs seen in the latter cases were hypertension (systolic blood pressure ≥ 140 mmHg; 7 cases), tachycardia (≥ 100/min; 5 cases), and altered mental status (4 cases) including confusion, disorientation, dissociation, and/or hallucinations. Mixed-drug users displayed not only the same clinical features, but also more sympathomimetic effects including agitation (38%) and dilated pupils (33%). Patients testing positive for 3-/4-MeO-PCP were typically under medical care for 1-2 days (85%), and 37% of all cases were graded as severe intoxications (Poisoning Severity Score 3). Besides standard supportive therapy, 49% of the patients were treated with benzodiazepines and/or propofol. CONCLUSION: Laboratory analysis constitutes an important basis for the assessment of NPS hazard and availability. The adverse effects noted in cases of acute intoxications involving 3- and/or 4-MeO-PCP resembled those of other dissociatives such as PCP, ketamine, and methoxetamine. However, similar to intoxications involving other NPS, poly-substance use was found to be common.

Phencyclidine Intoxication Case Series Study.

BACKGROUND: Phencyclidine (PCP) is a synthetic compound derived from piperidine and used as an anesthetic and hallucinogenic. Little has been recently published regarding the clinical presentation of PCP intoxication. PCP use as a recreational drug is resurging. OBJECTIVE: Our objective was to describe clinical findings in patients presenting to the emergency department (ED) under the influence of PCP. METHODS: This was a case series study conducted at a tertiary care center with an annual census of 100,000 patients/year. Emergency physicians, residents, physician assistants, and research assistants identified patients with possible PCP intoxication. Self-reported PCP use, report by bystanders or Emergency Medical Services (EMS) staff, was used in this process. A structured data collection form was completed, documenting both clinical and behavioral events observed by the treating team during the ED visit. RESULTS: We collected data on 219 patients; 184 were analyzed; two patients were excluded secondary to incomplete data. The mean age of patients was 32.5 years (±7 years) with 65.2 % being males. PCP use was self-reported by 60.3 % of patients. Of the 184 patients, 153 (83.1 %) received a urine drug screen (UDS); 152 (98.7 %) were positive for PCP. On arrival, 78.3 % of patients were awake and alert, and 51.6 % were oriented to self, time/date, and place. Mean physiological parameters were the following: heart rate 101.1 bpm (±24.3), RR 18.9 bpm (±3.4), BP 146.3 (±19.4)/86.3 (±14.0) mmHg, 36.9° C (±0.5), and pulse oximetry 98.2 % (±1.9). Clinical findings were the following: retrograde amnesia in 46 (25 %), horizontal nystagmus in 118 (64.1 %), vertical nystagmus in 90 (48.9 %), hypertension in 87 (47.3 %), and agitation in 71 (38.6 %). Concomitant use of at least one other substance was reported by 99 (53.8 %) patients. The mean length of stay in the ED for all subjects was 261.1 (±172.8) minutes. Final disposition for 152 (82.6 %) patients was to home. Of the 184 patients, 14 (7.6 %) required admission; 12 were referred to Crisis Response Center. CONCLUSION: Patients with PCP intoxication tended to be young males. The prevalent clinical signs and symptoms were the following: retrograde amnesia, nystagmus, hypertension, and psychomotor agitation. Co-use of other substances was the norm. Most patients presenting to the ED with PCP intoxication do well and can be discharged home after a period of observation.

Generation Z: Adolescent Xenobiotic Abuse in the 21st Century.

NMDA receptor antagonists include the prescription medication ketamine, the illicit xenobiotics PCP, MXE, and other novel PCP analogs, and the OTC medication DXM. The NMDA receptor antagonist most commonly abused by adolescents in the United States is DXM. These xenobiotics cause dissociative effects by non-competitively inhibiting the action of glutamate at the NMDA receptor. Additionally, these agents modulate the actions of monoamine neurotransmitters, agonize opioid receptors, and inhibit nitric oxide synthase. Patients typically present with sympathomimetic and neuropsychiatric clinical manifestations after abuse of NMDA receptor antagonists. Treatment is generally symptomatic and supportive. Interventions include benzodiazepines, propofol, fluids, antiemetics, aggressive cooling, and respiratory support.

Paliperidone for the treatment of ketamine-induced psychosis: a case report.

Ketamine is an anaesthetic and analgesic drug synthesized in the 1960s from phencyclidine. The recreational use of ketamine increased among the dance culture of techno and house music, in particular in clubs, discotheques, and rave parties. The psychotropic effects of ketamine are now well known and they range from dissociation to positive, negative, and cognitive schizophrenia-like symptoms. We report a case of a chronic oral consumption of ketamine which induced agitation, behavioral abnormalities, and loss of contact with reality in a poly-drug abuser; these symptoms persisted more than two weeks after the drug consumption had stopped. Antipsychotic treatment with paliperidone led to a successful management of the psychosis, getting a complete resolution of the clinical picture. Paliperidone has proven to be very effective in the treatment of ketamine-induced disorders. Moreover, the pharmacological action and metabolism of paliperidone are poorly dependent from the activity of liver enzymes, so that it seems to be one of the best second generation antipsychotics for the treatment of smokers and alcohol abusers.

Novel psychoactive substance intoxication resulting in attempted murder.

A man in his twenties who had no previous history of violence, snorted large quantities of two substances he identified as 3-methoxyphencyclidine (3-MeO-PCP), and methylenedioxypyrovalerone (MDPV); both are recognised as novel psychoactive substances, or commonly described in the media as "legal highs". He also inhaled butane gas. He experienced vivid hallucinations and developed bizarre ideas. During this state of mind he stabbed his father multiple times and was arrested and charged with attempted murder. He had a previous history of drug induced psychosis and although he had some slight residual symptoms before he consumed the substances, these were not considered relevant to his criminal liability at the time of the offence. The hallucinations caused by the use of these substances took six weeks to completely recede. He was convicted of attempted murder and sentenced to four years in prison.

The evolving high: new designer drugs of abuse.

Over the past decade, emerging drugs of abuse and synthetic derivatives of more traditional agents have flooded the market. While Europe was the first to experience a surge in the use of drugs such as synthetic cathinones and cannabinoids, poison centers throughout the United States have seen a dramatic rise in calls related to these new designer drugs of abuse. In the majority of cases, care is largely supportive but significant medical and traumatic complications may occur. Providers must be aware of the ever-changing trends in abuse, so that they may optimally care for poisoned patients.

Accidental cell phone ingestion with pharyngeal impaction.

BACKGROUND: 35 year old intoxicated male ingested an unusual, large foreign object (cell phone). OBJECTIVE: To report the ingestion of an unusual large foreign object with hypopharyngeal impaction, complications, and treatment. DISCUSSION: Foreign body ingestion in the adult population is more prevalent in those who engage in drug or alcohol abuse. Impaction and perforation of the upper aerodigestive tract can lead to significant and potentially fatal complications including parapharyngeal/retropharyngeal abscess, mediastinitis, and aortoesophageal fistula. The treatment of foreign object ingestion is dependent on the type of foreign object ingested, its location, and potential for perforation. Endoscopic removal under general anesthesia is the treatment method recommended for foreign bodies impacted at the cricopharyngeus or esophagus. CONCLUSIONS: We report the only case of the accidental ingestion of an entire cell phone with casing. A plain film x-ray of the neck can be used in the assessment of the location of radiopaque foreign objects and in diagnosing potential complication.

The ultimate intra-/extra-dimensional attentional set-shifting task for mice.

BACKGROUND: Alterations in executive control and cognitive flexibility, such as attentional set-shifting abilities, are core features of several neuropsychiatric diseases. The most widely used neuropsychological tests for the evaluation of attentional set shifting in humans are the Wisconsin Card Sorting Test and the Cambridge Neuropsychological Test Automated Battery Intra-/Extra-Dimensional set-shift task (ID/ED). These tasks have proven clinical relevance and have been successfully adapted for monkeys. However, similar tasks currently available for rodents are limited, mainly because of their manual-based testing procedures. The current limitations of rodent attentional set-shifting tasks are hampering translational advances in psychiatric medicine. METHODS: To closely mimic the Cambridge Neuropsychological Test Automated Battery ID/ED task in primates, we present the development of a novel operant-based two-chamber ID/ED "Operon" task for mice. RESULTS: We show the ability of this novel task to measure attentional set shifting in mice and the effects of genetic and pharmacologic manipulations of dopamine and glutamate. In genetically modified mice with reduced catechol-O-methyltransferase activity there was selective improvement on extradimensional shift abilities and impairment of serial reversal learning. Chronic administration of phencyclidine produced a selective impairment of extradimensional shift while producing a generalized decrease in latency to respond. CONCLUSIONS: We demonstrate that this novel ID/ED Operon task may be an effective preclinical tool for drug testing and large genetic screening relevant to the study of executive dysfunctions and cognitive symptoms of psychiatric disorders. These findings may help elucidate the biological validity of similar findings in humans.

Clozapine ameliorates epigenetic and behavioral abnormalities induced by phencyclidine through activation of dopamine D1 receptor.

Accumulating evidence suggests that dysregulation of histone modification is involved in the pathogenesis and/or pathophysiology of psychiatric disorders. However, the abnormalities in histone modification in the animal model of schizophrenia and the efficacy of antipsychotics for such abnormalities remain unclear. Here, we investigated the involvement of histone modification in phencyclidine-induced behavioral abnormalities and the effects of antipsychotics on these abnormalities. After repeated phencyclidine (10 mg/kg) treatment for 14 consecutive days, mice were treated with antipsychotics (clozapine or haloperidol) or the histone deacetylase inhibitor sodium butyrate for 7 d. Repeated phencyclidine treatments induced memory impairment and social deficit in the mice. The acetylation of histone H3 at lysine 9 residues decreased in the prefrontal cortex with phencyclidine treatment, whereas the expression level of histone deacetylase 5 increased. In addition, the phosphorylation of Ca²âº/calmodulin-dependent protein kinase II in the nucleus decreased in the prefrontal cortex of phencyclidine-treated mice. These behavioral and epigenetic changes in phencyclidine-treated mice were attenuated by clozapine and sodium butyrate but not by haloperidol. The dopamine D1 receptor antagonist SCH-23390 blocked the ameliorating effects of clozapine but not of sodium butyrate. Furthermore, clozapine and sodium butyrate attenuated the decrease in expression level of GABAergic system-related genes in the prefrontal cortex of phencyclidine-treated mice. These findings suggest that the antipsychotic effect of clozapine develops, at least in part, through epigenetic modification by activation of the dopamine D1 receptor in the prefrontal cortex.

Psychiatric intensive care of dementia praecox.

33 year old British male's first presentation to mental health services was prompted by florid paranoid psychosis and volatile aggression. The patient developed agitated catatonia which eventually improved after 12 courses of ECT. The ongoing psychopharmacological management includes a second generation antipsychotic, a mood stabilizer antiepileptic and an anxiolytic. All investigations including blood tests, CSF analysis, urine and hair drug screen, CT and MRI scans with multidisciplinary medical consultations excluded any underlying pathology. The working diagnosis is an enduring paranoid psychosis with prominent signs of cognitive decline, all of which conclude to Kraepelin's Dementia Praecox.

The association between phencyclidine use and partner violence: an initial examination.

The association between phencyclidine (PCP) use and violent behavior is unclear. The current investigation evaluated the association between PCP addiction and intimate partner violence, a specific violent behavior, using the substance abuse evaluations of 109 PCP, 81 cannabis, and 97 polysubstance (alcohol and cannabis) abusing offenders. Relative to both comparison groups, PCP users were more likely to receive inpatient referrals, have a significant legal history, and have perpetrated past-year general and intimate partner violence. Data suggest that PCP use may be associated with greater violence perpetration than cannabis use alone or in conjunction with problematic alcohol use.