-
Expert Opinion on Drug Safety Jun 2022Racemic ketamine, a derivative of phencyclidine, has been used as a dissociative anesthetic since 1970. In 2000, the first randomized controlled trial showed a rapid... (Review)
Review
INTRODUCTION
Racemic ketamine, a derivative of phencyclidine, has been used as a dissociative anesthetic since 1970. In 2000, the first randomized controlled trial showed a rapid relief of depressive symptoms. Since then, intravenous ketamine and intranasal S-ketamine have been validated for the treatment of depression and suicidal ideation following dose-response and double-blind placebo-controlled clinical trials. In clinical practice, after dose titration and with repeated treatments, patients may experience approximately 2-3 weeks of symptomatic relief from depression.
AREAS COVERED
Areas covered in this narrative review include mechanism of action, dosing, safety, and tolerability. Some attention is paid to the possibility of R-ketamine as a future antidepressant.
EXPERT OPINION
We recommend further investigation into treatment dosing and frequency strategies as well as approaches that prolong the therapeutic effects. The current fixed dosing of esketamine for obese individuals may be insufficient. Additional investigation into co-administration with somatic and neuromodulation treatments needs investigation. Finally, continuing to monitor research subjects and patients long-term for the emergence of adverse effects on cognition or other organ systems is critical.
Topics: Administration, Intranasal; Antidepressive Agents; Depression; Depressive Disorder, Treatment-Resistant; Humans; Ketamine; Randomized Controlled Trials as Topic
PubMed: 35475388
DOI: 10.1080/14740338.2022.2069749 -
Psychopharmacology Aug 2020MK801, like other NMDA receptor open-channel blockers (e.g., ketamine and phencyclidine), increases the locomotor activity of rats and mice. Whether this behavioral...
RATIONALE
MK801, like other NMDA receptor open-channel blockers (e.g., ketamine and phencyclidine), increases the locomotor activity of rats and mice. Whether this behavioral effect ultimately relies on monoamine neurotransmission is of dispute.
OBJECTIVE
The purpose of this study was to determine whether these psychopharmacological effects and underlying neural mechanisms vary according to sex and age.
METHODS
Across four experiments, male and female preweanling and adolescent rats were pretreated with vehicle, the monoamine-depleting agent reserpine (1 or 5 mg/kg), the dopamine (DA) synthesis inhibitor ∝-methyl--p-tyrosine (AMPT), the serotonin (5-HT) synthesis inhibitor 4-chloro--phenylalanine methyl ester hydrochloride (PCPA), or both AMPT and PCPA. The locomotor activity of preweanling and adolescent rats was then measured after saline or MK801 (0.3 mg/kg) treatment.
RESULTS
As expected, MK801 increased the locomotor activity of all age groups and both sexes, but the stimulatory effects were significantly less pronounced in male adolescent rats. Preweanling rats and adolescent female rats were more sensitive to the effects of DA and 5-HT synthesis inhibitors, as AMPT and PCPA caused only small reductions in the MK801-induced locomotor activity of male adolescent rats. Co-administration of AMPT+PCPA or high-dose reserpine (5 mg/kg) treatment substantially reduced MK801-induced locomotor activity in both age groups and across both sexes.
CONCLUSIONS
These results, when combined with other recent studies, show that NMDA receptor open-channel blockers cause pronounced age-dependent behavioral effects that can vary according to sex. The neural changes underlying these sex and age differences appear to involve monoamine neurotransmission.
Topics: Adrenergic Uptake Inhibitors; Age Factors; Animals; Animals, Newborn; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Female; Locomotion; Male; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Antagonists; Sex Factors; Sexual Maturation
PubMed: 32445054
DOI: 10.1007/s00213-020-05547-3 -
JAMA Network Open Mar 2024Young children are ingesting illicit drugs at increased rates, but it is unknown what the associated child protection system (CPS) responses are when a child tests...
IMPORTANCE
Young children are ingesting illicit drugs at increased rates, but it is unknown what the associated child protection system (CPS) responses are when a child tests positive.
OBJECTIVE
To document the child protection system involvement and the characteristics of children who test positive for illicit substances.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cross-sectional study linked medical discharge and child protection system administrative data. The setting was Rady Children's Hospital San Diego, a free-standing pediatric hospital in California. Participants included all emergency department and inpatient medical encounters involving children aged 12 years or younger with a positive urine drug test between 2016 and 2021. Statistical analysis was performed from February 2023 to January 2024.
EXPOSURE
Drug type, including amphetamines, barbiturates, benzodiazepines, cannabis, cocaine, fentanyl, opiates, and phencyclidine.
MAIN MEASURES AND OUTCOMES
CPS responses associated with the medical encounter including reports, substantiations, case openings, and out-of-home placements.
RESULTS
A total of 511 emergency department and inpatient medical encounters involving children had a positive drug test (262 [51.3%] were female; 309 [60.5%] were age 6 years or younger; fewer than 10 [<3.0%] were American Indian or Alaska Native; 252 [49.3%] were Hispanic [any race], 20 [3.9%] were non-Hispanic Asian, 56 [11.0%] were non-Hispanic Black, 143 [28.0%] were non-Hispanic White, 36 [7.0%] had other or unknown race and ethnicity; 233 [43.6%] had a CPS report prior to the medical encounter). Following the positive screen, 244 (47.7%) were reported to child protection, and 61 (11.9%) were placed out-of-home within 30 days. Mean (SD) quarterly counts of encounters with positive drug tests doubled after the COVID-19 pandemic onset (32.9 [9.8]) compared with prior to the pandemic onset (16.5 [4.7]); for encounters positive for cannabis, mean (SD) quarterly counts were 3 times as high after the pandemic onset than prior (16.6 [4.7] vs 5.7 [2.9]). Encounters for children under age 1 were significantly more likely to have associated child protection reports (relative risk [RR], 2.91 [95% CI, 2.21-3.83]) and child protection case openings (RR, 1.71 [95% CI, 1.07-2.72]) than encounters involving older children.
CONCLUSIONS AND RELEVANCE
In this cross-sectional study of emergency department and inpatient medical encounters, less than half of children with positive urine drug screens were reported to CPS; out-of-home placements were uncommon. With increased encounters for positive drug tests, it is unclear what services these children and families are receiving.
Topics: Child; Humans; Female; Adolescent; Child, Preschool; Male; Cross-Sectional Studies; Pandemics; Retrospective Studies; Urine; Urinalysis; Cannabinoid Receptor Agonists; Cannabis; Hallucinogens
PubMed: 38512254
DOI: 10.1001/jamanetworkopen.2024.3133 -
British Journal of Pharmacology Jan 2023Improvement of cognitive deficits in schizophrenia remains an unmet need owing to the lack of new therapies and drugs. Recent studies have reported that fingolimod, an...
BACKGROUND AND PURPOSE
Improvement of cognitive deficits in schizophrenia remains an unmet need owing to the lack of new therapies and drugs. Recent studies have reported that fingolimod, an immunomodulatory drug for treating multiple sclerosis, demonstrates anti-inflammatory and neuroprotective effects in several neurological disease models. This suggests its usefulness for ameliorating cognitive dysfunction in schizophrenia. Herein, we assessed the efficacy profile and mechanism of fingolimod in a rat model of phencyclidine (PCP)-induced schizophrenia.
EXPERIMENTAL APPROACH
Male Sprague-Dawley rats were treated with PCP for 14 days. The therapeutic effect of fingolimod on cognitive function was assessed using the Morris water maze and fear conditioning tests. Hippocampal neurogenesis and the expression of astrocytes and microglia were evaluated using immunostaining. Cytokine expression was quantified using multiplexed flow cytometry. Brain-derived neurotrophic factor expression and phosphorylation of extracellular signal-regulated kinase were determined using western blot analysis.
KEY RESULTS
Fingolimod attenuated cognitive deficits and restored hippocampal neurogenesis in a dose-dependent manner in PCP-treated rats. Fingolimod treatment exerted anti-inflammatory effects by inhibiting microglial activation and IL-6 and IL-1β pro-inflammatory cytokine expression. The underlying mechanism involves the upregulation of brain-derived neurotrophic factor protein expression and activation of the ERK signalling pathway.
CONCLUSION AND IMPLICATIONS
This is the first preclinical assessment of the effects of fingolimod on cognitive function in a model for schizophrenia. Our results suggest the immune system plays an crucial role in cognitive alterations in schizophrenia and highlight the potential of immunomodulatory strategies to improve cognitive deficits in schizophrenia.
Topics: Animals; Rats; Male; Phencyclidine; Schizophrenia; Fingolimod Hydrochloride; Brain-Derived Neurotrophic Factor; Rats, Sprague-Dawley; Cognitive Dysfunction; Cytokines; Disease Models, Animal
PubMed: 36106568
DOI: 10.1111/bph.15954 -
Genes, Brain, and Behavior Apr 2022Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual...
Genetic studies implicate disruption to the DLG2 gene in copy number variants as increasing risk for schizophrenia, autism spectrum disorders and intellectual disability. To investigate psychiatric endophenotypes associated with DLG2 haploinsufficiency (and concomitant PSD-93 protein reduction) a novel clinically relevant Dlg2 rat was assessed for abnormalities in anxiety, sensorimotor gating, hedonic reactions, social behaviour, and locomotor response to the N-Methyl-D-aspartic acid receptor antagonist phencyclidine. Dlg gene and protein expression were also investigated to assess model validity. Reductions in PSD-93 messenger RNA and protein were observed in the absence of compensation by other related genes or proteins. Behaviourally Dlg2 rats show a potentiated locomotor response to phencyclidine, as is typical of psychotic disorder models, in the absence of deficits in the other behavioural phenotypes assessed here. This shows that the behavioural effects of Dlg2 haploinsufficiency may specifically relate to psychosis vulnerability but are subtle, and partially dissimilar to behavioural deficits previously reported in Dlg2 mouse models demonstrating issues surrounding the comparison of models with different aetiology and species. Intact performance on many of the behavioural domains assessed here, such as anxiety and reward processing, will remove these as confounds when continuing investigation into this model using more complex cognitive tasks.
Topics: Animals; Disease Models, Animal; Guanylate Kinases; Haploinsufficiency; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Mice; Phencyclidine; Rats; Schizophrenia; Social Behavior; Tumor Suppressor Proteins
PubMed: 35075790
DOI: 10.1111/gbb.12797 -
Drug and Alcohol Dependence Nov 2021Despite increasing prevalence of nonmedical ketamine use globally, data on ketamine use disorders, which are classified in the DSM-5 under criteria for phencyclidine,...
BACKGROUND
Despite increasing prevalence of nonmedical ketamine use globally, data on ketamine use disorders, which are classified in the DSM-5 under criteria for phencyclidine, are limited. This study assessed the reliability and applicability of DSM-based diagnostic criteria for ketamine use disorder.
METHODS
Participants who used ecstasy were recruited through the Tri-City Study of Club Drug Use, Abuse, and Dependence in St. Louis, Miami, and Sydney. Those who reported using ketamine (lifetime use >5 times) were included in these analyses (n = 205). Participants were interviewed using the computerized Substance Abuse Module for Club Drugs (CD-SAM) at baseline and 7 days later for the reliability of diagnoses and individual diagnostic criteria.
RESULTS
Overall, 29.3% met DSM-5 adopted criteria for ketamine use disorder at Time 1. Moderate to excellent test-retest reliability was observed consistently across study sites for any ketamine use disorder (κ = 0.57, Y = 0.61) and severe ketamine use disorder (κ = 0.62, Y = 0.79). Continued use of ketamine despite knowledge of physical or psychological problems was the most frequently endorsed individual criterion (59.0%), followed by reported withdrawal (30.2%) and physically hazardous use (29.8%). All individual criteria had acceptable reliability estimates (κ ≥ 0.41).
CONCLUSIONS
Diagnoses of ketamine use disorder can be reliably evaluated using this fully structured diagnostic instrument's questions and algorithm. Ketamine-related withdrawal among people who use ketamine should be re-evaluated. Considering that after-effects of this dissociative anesthetic can last for many hours, it is important to explore a different timeframe for possible withdrawal effects.
Topics: Cross-Cultural Comparison; Diagnostic and Statistical Manual of Mental Disorders; Humans; Ketamine; Reproducibility of Results; Substance-Related Disorders
PubMed: 34592704
DOI: 10.1016/j.drugalcdep.2021.109056 -
Archives of Toxicology May 2021Methods to assess neuronal receptor functions are needed in toxicology and for drug development. Human-based test systems that allow studies on glutamate signalling are...
Methods to assess neuronal receptor functions are needed in toxicology and for drug development. Human-based test systems that allow studies on glutamate signalling are still scarce. To address this issue, we developed and characterized pluripotent stem cell (PSC)-based neural cultures capable of forming a functional network. Starting from a stably proliferating neuroepithelial stem cell (NESC) population, we generate "mixed cortical cultures" (MCC) within 24 days. Characterization by immunocytochemistry, gene expression profiling and functional tests (multi-electrode arrays) showed that MCC contain various functional neurotransmitter receptors, and in particular, the N-methyl-D-aspartate subtype of ionotropic glutamate receptors (NMDA-R). As this important receptor is found neither on conventional neural cell lines nor on most stem cell-derived neurons, we focused here on the characterization of rapid glutamate-triggered Ca signalling. Changes of the intracellular free calcium ion concentration ([Ca]) were measured by fluorescent imaging as the main endpoint, and a method to evaluate and quantify signals in hundreds of cells at the same time was developed. We observed responses to glutamate in the low µM range. MCC responded to kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and a subpopulation of 50% had functional NMDA-R. The receptor was modulated by Mg, Zn and Pb in the expected ways, and various toxicologically relevant agonists (quinolinic acid, ibotenic acid, domoic acid) triggered [Ca] responses in MCC. Antagonists, such as phencyclidine, ketamine and dextromethorphan, were also readily identified. Thus, the MCC developed here may fill an important gap in the panel of test systems available to characterize the effects of chemicals on neurotransmitter receptors.
Topics: Animals; Calcium; Cells, Cultured; Excitatory Amino Acid Agonists; Glutamic Acid; Humans; Kainic Acid; N-Methylaspartate; Neural Stem Cells; Neurons; Receptors, AMPA; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
PubMed: 33713149
DOI: 10.1007/s00204-021-03024-0 -
International Journal of Environmental... May 2022Psychedelics represent a unique subset of psychoactive substances that can induce an aberrant state of consciousness principally via the neuronal 5-HT2A receptor. There...
BACKGROUND
Psychedelics represent a unique subset of psychoactive substances that can induce an aberrant state of consciousness principally via the neuronal 5-HT2A receptor. There is limited knowledge concerning the interest in these chemicals in Poland and how they changed during the pandemic. Nonetheless, these interests can be surveyed indirectly via the web.
OBJECTIVES
We aim to conduct a spatial-temporal mapping of online information-seeking behavior concerning cannabis and the most popular psychedelics before and during the pandemic.
METHODS
We retrieved online information search data via Google Trends concerning twenty of the most popular psychedelics from 1 January 2017 to 1 January 2022 in Poland. We conducted Holt-Winters exponential smoothing for time series analysis to infer potential seasonality. We utilized hierarchical clustering analysis based on Ward's method to find similarities of psychedelics' interest within Poland's voivodships before and during the pandemic.
RESULTS
Twelve (60%) psychedelics had significant seasonality; we proved that psilocybin and ayahuasca had annual seasonality (-value = 0.0120 and = 0.0003, respectively), and four substances-LSD, AL-LAD, DXM, and DOB-exhibited a half-yearly seasonality, while six psychedelics had a quarterly seasonal pattern, including cannabis, dronabinol, ergine, NBOMe, phencyclidine, and salvinorin A. Further, the pandemic influenced a significant positive change in the trends for three substances, including psilocybin, ergine, and DXM.
CONCLUSIONS
Different seasonal patterns exist for psychedelics, and some might correlate with school breaks or holidays in Poland. The pandemic induced some changes in the temporal and spatial trends. The spatial-temporal trends could be valuable information to health authorities and policymakers responsible for monitoring and preventing addictions.
Topics: COVID-19; Cannabis; Hallucinogens; Humans; Lysergic Acid Diethylamide; Pandemics; Poland; Psilocybin
PubMed: 35682204
DOI: 10.3390/ijerph19116619 -
The International Journal of... Dec 2022The role of glutamatergic receptors in major depressive disorder continues to be of great interest for therapeutic development. Recent studies suggest that both negative...
BACKGROUND
The role of glutamatergic receptors in major depressive disorder continues to be of great interest for therapeutic development. Recent studies suggest that both negative and positive modulation of N-methyl-D-aspartate receptors (NMDAR) can produce rapid antidepressant effects. Here we report that zelquistinel, a novel NMDAR allosteric modulator, exhibits high oral bioavailability and dose-proportional exposures in plasma and the central nervous system and produces rapid and sustained antidepressant-like effects in rodents by enhancing activity-dependent, long-term synaptic plasticity.
METHODS
NMDAR-mediated functional activity was measured in cultured rat brain cortical neurons (calcium imaging), hNR2A or B subtype-expressing HEK cells, and synaptic plasticity in rat hippocampal and medial prefrontal cortex slices in vitro. Pharmacokinetics were evaluated in rats following oral administration. Antidepressant-like effects were assessed in the rat forced swim test and the chronic social deficit mouse model. Target engagement and the safety/tolerability profile was assessed using phencyclidine-induced hyperlocomotion and rotarod rodent models.
RESULTS
Following a single oral dose, zelquistinel (0.1-100 µg/kg) produced rapid and sustained antidepressant-like effects in the rodent depression models. Brain/ cerebrospinal fluid concentrations associated with zelquistinel antidepressant-like activity also increased NMDAR function and rapidly and persistently enhanced activity-dependent synaptic plasticity (long-term potentiation), suggesting that zelquistinel produces antidepressant-like effects by enhancing NMDAR function and synaptic plasticity. Furthermore, Zelquistinel inhibited phencyclidine (an NMDAR antagonist)-induced hyperlocomotion and did not impact rotarod performance.
CONCLUSIONS
Zelquistinel produces rapid and sustained antidepressant effects by positively modulating the NMDARs, thereby enhancing long-term potentiation of synaptic transmission.
Topics: Animals; Rats; Mice; Receptors, N-Methyl-D-Aspartate; Depressive Disorder, Major; Rats, Sprague-Dawley; Antidepressive Agents; Long-Term Potentiation; Phencyclidine
PubMed: 35882204
DOI: 10.1093/ijnp/pyac043 -
Medicine Dec 20193-Methoxyphencyclidine (3-MeO-PCP) is a new psychoactive substance derived from phencyclidine. Although it can lead to severe intoxications, the main manifestations and... (Review)
Review
RATIONALE
3-Methoxyphencyclidine (3-MeO-PCP) is a new psychoactive substance derived from phencyclidine. Although it can lead to severe intoxications, the main manifestations and optimal management have not been well characterized. Here, we report 2 cases of 3-MeO-PCP intoxication in the same patient, and summarize the manifestations of this intoxication reported in literature.
PATIENT CONCERNS
A 17-year-old male purchased a bag of 3-MeO-PCP on the Internet but took an oral dose (200 mg) that corresponds to the less active isomer 4-MeO-PCP. He developed high blood pressure (158/131 mm Hg), tachycardia (100 bpm), and neurological manifestations (confusion, hypertonia, nystagmus, and then agitation). A maculopapular rash appeared, although this may have been related to the administration of midazolam. Hyperlactatemia (2.6 mmol/L) was the main laboratory finding. Seven days later, he returned to the emergency department after sniffing 50 mg of 3-MeO-PCP. High blood pressure, tachycardia, and neurological manifestations (psychomotor impairment and dysarthria) were present but less severe than after the first intoxication.
DIAGNOSIS
In the first intoxication, the blood and urine 3-MeO-PCP concentrations were, respectively, 71.1 ng/mL and 706.9 ng/mL. Conventional toxicity tests were all negative. In the second intoxication, biological samples were not available.
INTERVENTIONS
In the first intoxication, treatment consisted of intravenous hydration and midazolam. The patient was transferred to an intensive care unit for monitoring. After the second intoxication, he was monitored for 12 hours.
OUTCOMES
The patient's condition improved quickly in both cases.
LESSONS
These cases provide additional information on the manifestations of 3-MeO-PCP intoxication. These manifestations are mainly cardiovascular (high blood pressure, tachycardia) and neurological. The fact that second (50 mg) intoxication was less severe than the first (200 mg) is suggestive of a dose-effect relationship for 3-MeO-PCP. The first case also emphasizes the risk of dosing errors caused by the similarity between the names "3-MeO-PCP" and "4-MeO-PCP."
Topics: Adolescent; Designer Drugs; Humans; Hypertension; Male; Phencyclidine; Substance-Related Disorders; Tachycardia
PubMed: 31876705
DOI: 10.1097/MD.0000000000018295