Dissociative therapies are being increasingly explored for their psychiatric applications, although questions remain about how they work and how best to use them. In exploring these questions, this review highlights six key areas of clinical relevance: (1) The possible contributions of functional unblinding when interpreting efficacy data; (2) The degree to which the therapeutic effects of dissociative therapies can be distinguished from the transient forms of relief seen with recreational drug use; (3) Understanding the construct of dissociation as it is tasked with describing the function of dissociative drugs; (4) The investigation of subjective drug effects as predictors of therapeutic outcome; (5) Similarities and differences in the effects of dissociative and classic psychedelics; and (6) The anticipated need for judicious prescribing/deprescribing resources as dissociative therapies proliferate.

The recognition of glycine as an endogenous ligand at the allosteric activation site of the NMDA-type glutamatergic receptor led to the assumption that the excess glycine in nonketotic hyperglycinemia would result in overactivation of these receptors, and of the proposed use of inhibitors such as dextromethorphan or ketamine as a therapeutic agent. Years later it was recognized that these same receptors have an alternative endogenous activator d-serine, which is markedly decreased in nonketotic hyperglycinemia. This may result in underactivation of these NMDA-type glutamatergic receptors, challenging the earlier hypothesis. Clear clinical evidence of an added therapeutic benefit beyond the use of glycine reduction strategies from use of either dextromethorphan or ketamine in nonketotic hyperglycinemia has not been documented. The systematic use of these NMDA-type receptor antagonists in nonketotic hyperglycinemia should be reevaluated, particularly in light of emerging potential adverse effects.

For treatment of type 1 diabetes mellitus, a combination of immune-based interventions and medication to promote beta-cell survival and proliferation has been proposed. Dextromethorphan (DXM) is an N-methyl-D-aspartate receptor antagonist with a good safety profile, and to date, preclinical and clinical evidence for blood glucose-lowering and islet-cell-protective effects of DXM have only been provided for animals and individuals with type 2 diabetes mellitus. Here, we assessed the potential anti-diabetic effects of DXM in the non-obese diabetic mouse model of type 1 diabetes. More specifically, we showed that DXM treatment led to five-fold higher numbers of pancreatic islets and more than two-fold larger alpha- and beta-cell areas compared to untreated mice. Further, DXM treatment improved glucose homeostasis and reduced diabetes incidence by 50%. Our data highlight DXM as a novel candidate for adjunct treatment of preclinical or recent-onset type 1 diabetes.

Both guaifenesin and dextromethorphan are routinely available nonprescription medications that are also common drugs of abuse amongst young adults. We describe a presentation of guaifenesin and dextromethorphan misuse resulting in acute renal failure due to bilateral nephrolithiasis. The patient underwent placement of bilateral ureteral stents but again formed small renal stones bilaterally. While most renal calculi are not drug-induced, this case highlights the potential for nephrolithiasis after guaifenesin and dextromethorphan ingestion. It suggests that in this combination ingestion multiple mechanisms lead to a prolonged period of nephrolith formation.

Dextromethorphan (DXM) is a commonly used antitussive medication with positive effects in people with type 2 diabetes mellitus, since it increases glucose tolerance and protects pancreatic islets from cell death. However, its use as an antidiabetic medication is limited due to its central nervous side effects and potential use as a recreational drug. Therefore, we recently modified DXM chemically to reduce its blood-brain barrier (BBB) penetration and central side effects. However, our best compound interacted with the cardiac potassium channel hERG (human ether-à-go-go-related gene product) and the μ-opioid receptor (MOR). Thus, the goal of this study was to reduce the interaction of our compound with these targets, while maintaining its beneficial properties.

Receptor and channel binding assays were conducted to evaluate the drug safety of our DXM derivative. Pancreatic islets were used to investigate the effect of the compound on insulin secretion and islet cell survival. Via liquor collection from the brain and a behavioral assay, we analyzed the BBB permeability. By performing intraperitoneal and oral glucose tolerance tests as well as pharmacokinetic analyses, the antidiabetic potential and elimination half-life were investigated, respectively. To analyze the islet cell-protective effect, we used fluorescence microscopy as well as flow cytometric analyses.

Here, we report the design and synthesis of an optimized, orally available BBB-impermeable DXM derivative with lesser binding to hERG and MOR than previous ones. We also show that the new compound substantially enhances glucose-stimulated insulin secretion (GSIS) from mouse and human islets and glucose tolerance in mice as well as protects pancreatic islets from cell death induced by reactive oxygen species and that it amplifies the effects of tirzepatide on GSIS and islet cell viability.

We succeeded to design and synthesize a novel morphinan derivative that is BBB-impermeable, glucose-lowering and islet cell-protective and has good drug safety despite its morphinan and imidazole structures.

Dextromethorphan (DXM) was introduced in 1958 as the first non-opioid cough suppressant and is indicated for multiple psychiatric disorders. It has been the most used over-the-counter cough suppressant since its emergence. However, individuals quickly noticed an intoxicating and psychedelic effect if they ingested large doses. DXM's antagonism at N-methyl-d-aspartate receptors (NMDAr) is thought to underly its efficacy in treating acute cough, but supratherapeutic doses mimic the activity of dissociative hallucinogens, such as phencyclidine and ketamine. In this Review we will discuss DXM's synthesis, manufacturing information, drug metabolism, pharmacology, adverse effects, recreational use, abuse potential, and its history and importance in therapy to present DXM as a true classic in chemical neuroscience.

Dextromethorphan is a prevalent antitussive agent that can be easily obtained as an over-the-counter medication. There has been a growing number of reported cases of toxicity in recent years. Generally, there are numerous instances of mild symptoms, with only a limited number of reports of severe cases necessitating intensive care. We presented the case of a female who ingested 111 tablets of dextromethorphan, leading to shock and convulsions and requiring intensive care that ultimately saved her life.

A 19-year-old female was admitted to our hospital via ambulance, having overdosed on 111 tablets of dextromethorphan (15 mg) obtained through an online importer in a suicide attempt. The patient had a history of drug abuse and multiple self-inflicted injuries. At the time of admission, she exhibited symptoms of shock and altered consciousness. However, upon arrival at the hospital, the patient experienced recurrent generalized clonic convulsions and status epilepticus, necessitating tracheal intubation. The convulsions were determined to have been caused by decreased cerebral perfusion pressure secondary to shock, and noradrenaline was administered as a vasopressor. Gastric lavage and activated charcoal were also administered after intubation. Through systemic management in the intensive care unit, the patient's condition stabilized, and the need for vasopressors ceased. The patient regained consciousness and was extubated. The patient was subsequently transferred to a psychiatric facility, as suicidal ideation persisted.

We report the first case of shock caused by an overdose of dextromethorphan.

Psychosis is known as a broad term of symptoms that cause serious disorganization of behavior, thinking, and perception of reality. One of the medicines that recently gained much attention in terms of its psychotic potential is dextromethorphan (DXM). DXM, a widely used antitussive drug, is a commonly abused drug because of its euphoric, hallucinogenic, and dissociative properties. To date, DXM is a legally marketed cough suppressant that is neither a controlled substance nor a regulated chemical under the Controlled Substances Act. The management of DXM-related psychosis is dependent on the type of psychotic symptoms. Atypical neuroleptics (i.e., olanzapine, risperidone, quetiapine) and typical haloperidol have been used in symptomatic treatment due to their efficacy, especially in positive symptoms (hallucinations and delusions). These agents are also recognized as the preferred option in the symptomatic treatment of DXM-related psychosis due to their better efficacy and safety profile than typical haloperidol in the short-term course. The focus of the present review concerns the current stage of knowledge about DXM psychotic potency as well as the management of DXM-related psychoses with a special emphasis on atypical antipsychotic drugs (i.e., olanzapine, risperidone, quetiapine, and haloperidol).

Dextromethorphan (DXM) acts as cough suppressant via its central action. Cell-protective effects of this drug have been reported in peripheral tissues, making DXM potentially useful for treatment of several common human diseases, such as type 2 diabetes mellitus (T2DM). Pancreatic islets are among the peripheral tissues that positively respond to DXM, and anti-diabetic effects of DXM were observed in two placebo-controlled, randomized clinical trials in humans with T2DM. Since these effects were associated with central side effects, we here developed chemical derivatives of DXM that pass the blood-brain barrier to a significantly lower extent than the original drug. We show that basic nitrogen-containing residues block central adverse events of DXM without reducing its anti-diabetic effects, including the protection of human pancreatic islets from cell death. These results show how to chemically modify DXM, and possibly other morphinans, as to exclude central side effects, while targeting peripheral tissues, such as pancreatic islets.

Opioids were the most common drug class resulting in overdose deaths in the United States in 2019. Widespread clinical use of prescription opioids for moderate to severe pain contributed to the ongoing opioid epidemic with the subsequent emergence of fentanyl-laced heroin. More potent analogues of fentanyl and structurally diverse opioid receptor agonists such as AH-7921 and MT-45 are fueling an increasingly diverse illicit opioid supply. Overdose from synthetic opioids with high binding affinities may not respond to a typical naloxone dose, thereby rendering autoinjectors less effective, requiring higher antagonist doses or resulting in a confusing clinical picture for health care providers. Nonscheduled opioid drugs such as loperamide and dextromethorphan are associated with dependence and risk of overdose as easier access makes them attractive to opioid users. Despite a common opioid-mediated pathway, several opioids present with unique pharmacodynamic properties leading to acute toxicity and dependence development. Pharmacokinetic considerations involve half-life of the parent opioid and its metabolites as well as resulting toxicity, as is established for tramadol, codeine, and oxycodone. Pharmacokinetic considerations, toxicities, and treatment approaches for notable opioids are reviewed.

Hallucinogens constitute a unique class of substances that cause changes in the user's thoughts, perceptions, and mood through various mechanisms of action. Although the serotonergic hallucinogens such as lysergic acid diethylamide, psilocybin, and N,N-dimethyltryptamine have been termed the classical hallucinogens, many hallucinogens elicit their actions through other mechanisms such as N-methyl-D-aspartate receptor antagonism, opioid receptor agonism, or inhibition of the reuptake of monoamines including serotonin, norepinephrine, and dopamine. The aim of this article is to compare the pharmacologic similarities and differences among substances within the hallucinogen class and their impact on physical and psychiatric effects. Potential toxicities, including life-threatening and long-term effects, will be reviewed.

Adolescence is a period of profound developmental changes, which run the gamut from behavioral and neural to physiological and hormonal. It is also a time at which there is an increased propensity to engage in risk-taking and impulsive behaviors like drug use. This review examines the human and preclinical literature on adolescent drug use and its consequences, with a focus on dissociatives (PCP, ketamine, DXM), classic psychedelics (LSD, psilocybin), and MDMA. It is the case for all the substances reviewed here that very little is known about their effects in adolescent populations. An emerging aspect of the literature is that dissociatives and MDMA produce mixed reinforcing and aversive effects and that the balance between reinforcement and aversion may differ between adolescents and adults, with consequences for drug use and addiction. However, many studies have failed to directly compare adults and adolescents, which precludes definitive conclusions about these consequences. Other important areas that are largely unexplored are sex differences during adolescence and the long-term consequences of adolescent use of these substances. We provide suggestions for future work to address the gaps we identified in the literature. Given the widespread use of these drugs among adolescent users, and the potential for therapeutic use, this work will be crucial to understanding abuse potential and consequences of use in this developmental stage.

Dextromethorphan hydrobromide is widely available as an over-the-counter cough suppressant. A semi-synthetic opioid displaying N-methyl-D-aspartate receptor antagonism, it is commonly abused for recreational purposes. Spuriously elevated serum chloride concentrations are a well-described phenomenon in the setting of dextromethorphan hydrobromide toxicity, but evidence to suggest the development of tolerance is limited to case reports.

A 32-year-old male known to chronically ingest dextromethorphan hydrobromide for recreational purposes presented to regional hospitals on 179 occasions over 110 months and was treated for dextromethorphan toxicity on 163/174 (93.7%) of these visits. He reported a subjective need to increase his dosing over time to achieve the same degree of intoxication. Measured serum chloride over this period (n = 217) ranged from 98 to 138 mEq/L (median 115 mEq/L, IQR 110-123 mEq/L). Measured concentrations over the 110-month period progressively rose, with a fitted plot of 111.15 + 0.00232x describing the rise in measured chloride. Though not formally assessed, anion gaps tended to become progressively more negative over the observed period.

We report a patient with persistent dextromethorphan hydrobromide abuse at escalating doses whose mean serum chloride concentration increased, on average, by 0.00232 mEq/L every day over a 110-month period. This case demonstrates progressive spurious hyperchloremia secondary to bromide interference in hospital-based chloride assays, supporting the patient's reported need to dose escalate to the same desired effect. Although this artefactual laboratory finding is a well-documented result of bromide ingestion, it may be useful in identifying patterns of dextromethorphan hydrobromide use that suggest tolerance.

Patients can use numerous drugs that exist outside of existing regulatory statutes in order to get "legal highs." Legal psychoactive substances represent a challenge to the emergency medicine physician due to the sheer number of available agents, their multiple toxidromes and presentations, their escaping traditional methods of analysis, and the reluctance of patients to divulge their use of these agents. This paper endeavors to cover a wide variety of "legal highs," or uncontrolled psychoactive substances that may have abuse potential and may result in serious toxicity. These agents include not only some novel psychoactive substances aka "designer drugs," but also a wide variety of over-the-counter medications, herbal supplements, and even a household culinary spice. The care of patients in the emergency department who have used "legal high" substances is challenging. Patients may misunderstand the substance they have been exposed to, there are rarely any readily available laboratory confirmatory tests for these substances, and the exact substances being abused may change on a near-daily basis. This review will attempt to group legal agents into expected toxidromes and discuss associated common clinical manifestations and management. A focus on aggressive symptom-based supportive care as well as management of end-organ dysfunction is the mainstay of treatment for these patients in the emergency department.