Depression is a well-known serious mental illness, and the onset of treatment using traditional antidepressants is frequently delayed by several weeks. Moreover, numerous patients with depression fail to respond to therapy. One major breakthrough in antidepressant therapy is that subanesthetic ketamine doses can rapidly alleviate depressive symptoms within hours of administering a single dose,...
NeuropharmacologyOctober 1, 2022Atsushi Suzuki, Hiroe Hara, H. Kimura
Ketamine exerts rapid and long-lasting antidepressant effects in patients with treatment-resistant depression. However, its clinical use is limited by its undesirable psychotomimetic side effects. Accumulating evidence from preclinical studies has shown that the antidepressant effects of ketamine are dependent on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) activation,...
Psychedelic therapy is perhaps the most exciting new development in psychiatry. Not only does it offer a radical new approach to treatment where mainstream approaches have proven ineffective, but the growing evidence for transdiagnostic efficacy is eliciting a re-think of current diagnostic and symptom-specific approaches to psychiatry. This excitement has led to a massive investment in this...
Psychiatric and existential distress commonly occur in advanced cancer and other serious, life-threatening or end-of-life medical illnesses and are associated with poor medical and psychiatric outcomes. Currently available treatment modalities in this patient population, including medication and psychotherapy, are limited in effectiveness, especially regarding existential distress. The lack of...
Classic psychedelics and related substances have shown promising initial research results. However, they raise a number of relatively novel ethical and policy challenges in light of their psychoactive properties, their emergence from the unregulated "underground" settings in which they have been used, their rapid commercialization, and the means and speed with which they are moving from...
The discovery of the robust antidepressant actions of ketamine is regarded as one of the greatest advancements in depression treatment in the past 60 years. Recent findings have provided strong evidence for the presence of bidirectional communication networks between the gastrointestinal tract and the brain in depression. Moreover, increasing evidence supports the antidepressant role of...
Psychedelics have seen a resurgence of interest from both the scientific and lay community in recent years. Psychedelics are known for their ability to produce profound perceptual alterations, ego dissolution, and separation from reality in humans. Virtually all research into psychedelics and their mechanism of action has focused on examining effects in the brain, and on consciousness....
New medicines containing classic hallucinogenic and entactogenic psychedelic substance are under development for various psychiatric and neurological disorders. Many of these, including psilocybin, lysergic acid diethylamide (LSD), and 3,4-methylenedioxymethamphetamine (MDMA) are Schedule I controlled substances of the United States Controlled Substances Act (US CSA), and similarly controlled...
The N-methyl-d-aspartate receptor (NMDAR) antagonist (R,S)-ketamine causes rapid onset and sustained antidepressant actions in treatment-resistant patients with major depressive disorder (MDD) and other psychiatric disorders, such as bipolar disorder and post-traumatic stress disorder. (R,S)-ketamine is a racemic mixture consisting of (R)-ketamine (or arketamine) and (S)-ketamine (or...
There is mounting evidence suggesting psychedelic and entactogen medicines (namely psilocybin and 3,4-methylenedioxymethamphetamine [MDMA]), in conjunction with proper psychosocial support, hold the potential to provide safe, rapid acting, and robust clinical improvements with durable effects. In the US, both psilocybin and MDMA have been granted Breakthrough Therapy designations by the US Food...
Non-competitive NMDA receptor (NMDA-R) antagonists like ketamine, phencyclidine (PCP) and MK-801 are routinely used as pharmacological models of schizophrenia. However, the NMDA-R subtypes, neuronal types (e.g., GABA vs. glutamatergic neurons) and brain regions involved in psychotomimetic actions are not fully understood. PCP activates thalamo-cortical circuits after NMDA-R blockade in...
The effects of psychedelic drugs in headache and chronic pain disorders have been reported for several decades, and now controlled studies are emerging. The existing evidence supports a lasting therapeutic benefit after limited dosing, a unique feature of the drug class that distinguishes it from conventional treatment. This commentary summarizes these reports of preventive effects of...
Psilocybin-facilitated psychotherapy shows potential transdiagnostic efficacy for a range of mental health conditions. Though vulnerable populations bear disproportionate mental health burden, they have been largely neglected in the clinical psilocybin literature. However, if the field is to best respond to the diverse needs of individuals from vulnerable populations, care must be taken to...
NeuropharmacologyMarch 1, 2022Nastaran Golitabari, Forouzan Mohammadian, Ali-Akbar Salari et al.
There is compelling evidence that neonatal blockade of NMDA receptors by phencyclidine (PCP) is associated with cognitive impairment in adulthood but little is known about the effects of early life PCP treatment on synaptic function later in life. Here, we sought to determine whether early life exposure to PCP alters the electrophysiologic function of hippocampal CA1 neurons in adult rats. To...
The newfound antidepressant efficacy of ketamine has provided opportunities for the development of new-generation, rapid-acting, glutamate-based antidepressants. We previously identified that methoxetamine (MXE), a ketamine analog, and an N-Methyl-d-aspartate (NMDA) receptor antagonist, produced rapid and sustained antidepressant effects in mice. MXE (R, S (±)-MXE) is a racemic mixture...
Dimethyltryptamine (DMT), an endogenous ligand of sigma-1 receptors (Sig-1Rs), acts against systemic hypoxia, but whether DMT may prevent cerebral ischemic injury is unexplored. Here global forebrain ischemia was created in anesthetized rats and aggravated with the induction of spreading depolarizations (SDs) and subsequent short hypoxia before reperfusion. Drugs (DMT, the selective Sig-1R...
NeuropharmacologyJune 19, 2021Ariandra Sartim, Jade Marques, Kennia Silveira et al.
BACKGROUND AND PURPOSE Although useful as a rapid-acting antidepressant drug, ketamine is known to induce psychotomimetic effects, which may interfere with its therapeutic use. Cannabidiol (CBD) is a non-psychostimulant compound from Cannabis sativa, which has shown promising antidepressant effects without inducing hyperlocomotion. AMPA receptor activation is involved in the antidepressant...
NeuropharmacologyFebruary 16, 2021C. Abuin-Martínez, Rebeca Vidal, Maria D Gutierrez-Lopez et al.
3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative that has been shown to produce serotonergic damage in the brains of primates, including humans, and of rats. Tryptophan, the precursor of serotonin, is primarily degraded through the kynurenine (KYN) pathway, producing among others KYN, the main metabolite of this route. KYN has been reported as an endogenous agonist of the...
Serotonergic hallucinogens such as lysergic acid diethylamide (LSD) induce head twitches in rodents via 5-HT2A receptor activation. The goal of the present investigation was to determine whether a correlation exists between the potency of hallucinogens in the mouse head-twitch response (HTR) paradigm and their reported potencies in other species, specifically rats and humans. Dose-response...
Traditional monoaminergic treatments of depression frequently exhibit suboptimal tolerability and effectiveness. The 'short' (s) allele variant of 5-HTTLPR is known to compromise transcriptional efficacy of the serotonin transporter (5-HTT) and can reduce treatment response to traditional antidepressants (e.g. selective serotonin reuptake inhibitors or SSRIs). This study sought to establish the...
The serotonin transporter (SERT) belongs to the monoamine transporter family, which also includes the dopamine and norepinephrine transporters. SERT is essential for regulating serotonergic signaling by the reuptake of serotonin from the synaptic cleft back into the presynaptic neuron. Dysregulation of SERT has been implicated in several major psychiatric disorders such as major depressive...
The ergoline d-lysergic acid diethylamide (LSD) is one of the most potent psychedelic drugs. 1-Acetyl-LSD (ALD-52), a derivative of LSD containing an acetyl group on the indole nitrogen, also produces psychedelic effects in humans and has about the same potency as LSD. Recently, several other 1-acyl-substitued LSD derivatives, including 1-propanoyl-LSD (1P-LSD) and 1-butanoyl-LSD (1B-LSD), have...
Recent studies have shown that ketamine, an open channel blocker of the N-methyl-d-aspartate receptor (NMDAR), is effective for patients with treatment-resistant depression. In this study, we aimed to elucidate the potential link between antidepressant-like effects of a single ketamine administration and dorsoventral differentiation in adult hippocampal neurogenesis. Immunohistochemical...
Subanesthetic rather than anesthetic doses are thought to bring the rapid antidepressant effects of the NMDAR (N-methyl-d-aspartate receptor) antagonist ketamine. Among molecular mechanisms, activation of BDNF receptor TrkB along with the inhibition of GSK3β (glycogen synthase kinase 3β) are considered as critical molecular level determinants for ketamine's antidepressant effects....
The recreational drug 3,4-methylenedioxymethamphetamine (MDMA) has well documented prosocial effects and is currently under clinical investigation as a treatment for patients with PTSD, autism, and other conditions. Early clinical trials have found that MDMA-assisted therapy may have robust long-lasting therapeutic effects, yet the mechanism by which acute treatments produce these long-term...