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The DOSE effect : optimize your brain and body by boosting your dopamine, oxytocin, serotonin, and endorphins
\"A neuroscientist's powerful framework for enhancing quality of life through the regulation of four key hormones: Dopamine, Oxytocin, Serotonin, and Endorphins (DOSE). You have everything you need to optimize your brain chemistry--this groundbreaking book shows you how\"-- Publisher description.
BOOK
Dreamlike effects of LSD on waking imagery in humans depend on serotonin 2A receptor activation
Rationale
Accumulating evidence indicates that the mixed serotonin and dopamine receptor agonist lysergic acid diethylamide (LSD) induces an altered state of consciousness that resembles dreaming.
Objectives
This study aimed to test the hypotheses that LSD produces dreamlike waking imagery and that this imagery depends on 5-HT2A receptor activation and is related to subjective drug effects.
Methods
Twenty-five healthy subjects performed an audiorecorded guided mental imagery task 7 h after drug administration during three drug conditions: placebo, LSD (100 mcg orally) and LSD together with the 5-HT2A receptor antagonist ketanserin (40 mg orally). Cognitive bizarreness of guided mental imagery reports was quantified as a standardised formal measure of dream mentation. State of consciousness was evaluated using the Altered State of Consciousness (5D-ASC) questionnaire.
Results
LSD, compared with placebo, significantly increased cognitive bizarreness (
p
< 0.001). The LSD-induced increase in cognitive bizarreness was positively correlated with the LSD-induced loss of self-boundaries and cognitive control (
p
< 0.05). Both LSD-induced increases in cognitive bizarreness and changes in state of consciousness were fully blocked by ketanserin.
Conclusions
LSD produced mental imagery similar to dreaming, primarily via activation of the 5-HT2A receptor and in relation to loss of self-boundaries and cognitive control. Future psychopharmacological studies should assess the differential contribution of the D2/D1 and 5-HT1A receptors to cognitive bizarreness.
Journal Article
Efficacy and safety of aticaprant, a kappa receptor antagonist, adjunctive to oral SSRI/SNRI antidepressant in major depressive disorder: results of a phase 2 randomized, double-blind, placebo-controlled study
This was a double-blind, randomized, phase 2 study of adults (18–64 years) with DSM−5 diagnosis of major depressive disorder (MDD), with moderate-to-severe episode severity (Montgomery–Åsberg Depression Rating Scale [MADRS] ≥25) despite an adequate course with ongoing antidepressant for ≥6 weeks to ≤12 months. Following a double-blind placebo lead-in period (up to 3 weeks), participants were randomized to receive once daily aticaprant 10 mg or continue placebo, added to their ongoing treatment, for 6 weeks. Of 184 participants enrolled, 169 were included in safety analyses (aticaprant n = 85, placebo n = 84) and 166 in full intent-to-treat (fITT) efficacy analyses; 121 placebo lead-in non-responders (<30% reduction in MADRS total score) in fITT were included in enriched ITT (eITT) analyses. Improvement (least squares mean difference [upper limit 1-sided 80% CI] versus placebo) in MADRS total score at week 6 for aticaprant was significant versus placebo (eITT: −2.1 [−1.09], 1-sided p = 0.044; effect size (ES) 0.23; fITT −3.1 [2.21], 1-sided p = 0.002; ES 0.36). The between-group difference was larger among participants with Snaith–Hamilton Pleasure Scale (SHAPS) score greater/equal to versus less than baseline median SHAPS. The most common treatment-emergent adverse events reported for aticaprant (versus placebo) were headache (11.8% versus 7.1%), diarrhea (8.2% versus 2.4%), nasopharyngitis (5.9% versus 2.4%), and pruritus (5.9% versus 0%). One participant (1.2%) in each arm discontinued treatment due to an adverse event. In this study of participants with MDD and inadequate response to SSRI/SNRI, adjunctive treatment with aticaprant significantly reduced depressive symptoms versus placebo, without resulting in significant safety signals, supporting further investigation in larger trials.
Journal Article
Structural pharmacology and therapeutic potential of 5-methoxytryptamines
Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders
1
–
3
. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT
2A
(ref.
4
). However, 5-HT
1A
also plays a part in the behavioural effects of tryptamine hallucinogens
5
, particularly 5-methoxy-
N,N
-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads
6
. Although 5-HT
1A
is a validated therapeutic target
7
,
8
, little is known about how psychedelics engage 5-HT
1A
and which effects are mediated by this receptor. Here we map the molecular underpinnings of 5-MeO-DMT pharmacology through five cryogenic electron microscopy (cryo-EM) structures of 5-HT
1A
, systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure–activity relationship analyses of 5-methoxytryptamines at both 5-HT
1A
and 5-HT
2A
enable the characterization of molecular determinants of 5-HT
1A
signalling potency, efficacy and selectivity. Moreover, we contrast the structural interactions and in vitro pharmacology of 5-MeO-DMT and analogues to the pan-serotonergic agonist LSD and clinically used 5-HT
1A
agonists. We show that a 5-HT
1A
-selective 5-MeO-DMT analogue is devoid of hallucinogenic-like effects while retaining anxiolytic-like and antidepressant-like activity in socially defeated animals. Our studies uncover molecular aspects of 5-HT
1A
-targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders.
Detailed analyses of the serotonin receptor 5-HT
1A
and the psychedelic 5-methoxy-
N,N
-dimethyltryptamine reveal the differences in receptor structural pharmacology that mediate signalling specificity, efficacy and potency, findings that may facilitate the development of new neuropsychiatric therapeutics.
Journal Article
Structural insights into the lipid and ligand regulation of serotonin receptors
Serotonin, or 5-hydroxytryptamine (5-HT), is an important neurotransmitter
1
,
2
that activates the largest subtype family of G-protein-coupled receptors
3
. Drugs that target 5-HT
1A
, 5-HT
1D
, 5-HT
1E
and other 5-HT receptors are used to treat numerous disorders
4
. 5-HT receptors have high levels of basal activity and are subject to regulation by lipids, but the structural basis for the lipid regulation and basal activation of these receptors and the pan-agonism of 5-HT remains unclear. Here we report five structures of 5-HT receptor–G-protein complexes: 5-HT
1A
in the apo state, bound to 5-HT or bound to the antipsychotic drug aripiprazole; 5-HT
1D
bound to 5-HT; and 5-HT
1E
in complex with a 5-HT
1E
- and 5-HT
1F
-selective agonist, BRL-54443. Notably, the phospholipid phosphatidylinositol 4-phosphate is present at the G-protein–5-HT
1A
interface, and is able to increase 5-HT
1A
-mediated G-protein activity. The receptor transmembrane domain is surrounded by cholesterol molecules—particularly in the case of 5-HT
1A
, in which cholesterol molecules are directly involved in shaping the ligand-binding pocket that determines the specificity for aripiprazol. Within the ligand-binding pocket of apo-5-HT
1A
are structured water molecules that mimic 5-HT to activate the receptor. Together, our results address a long-standing question of how lipids and water molecules regulate G-protein-coupled receptors, reveal how 5-HT acts as a pan-agonist, and identify the determinants of drug recognition in 5-HT receptors.
Cryo-electron microscopy structures of three different serotonin receptors in complex with serotonin and other agonists provide insights into the role of lipids in regulating these receptors and the structural basis of ligand recognition.
Journal Article
Esketamine Nasal Spray versus Quetiapine for Treatment-Resistant Depression
In this randomized trial, esketamine nasal spray plus an SSRI or SNRI was superior to quetiapine plus an SSRI or SNRI with respect to remission at week 8 in patients with treatment-resistant depression.
Journal Article
Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects
Drugs may cause serotonin toxicity by a number of different mechanisms including inhibition of serotonin uptake and metabolism, increased serotonin synthesis and release, activation of serotonin receptors, and inhibition of cytochrome P450 oxidases. Some drug interactions involving opioids can increase intrasynaptic levels of serotonin, and opioid analgesic drugs are now recognized as being involved in some cases of serotonin toxicity especially if administered in conjunction with other serotonergic medications including monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants. In March 2016, the FDA issued a Drug Safety Communication concerning the association of the entire class of opioid pain medicines with serotonin toxicity. Reports of the involvement of individual opioids particularly tramadol, tapentadol, meperidine, methadone, oxycodone, fentanyl, and dextromethorphan are reviewed. While relevance to human serotonin toxicity of animal models, including many studies on rat brain synaptosomes, is questionable, important insights have recently been forthcoming from research utilizing 5-HT receptors, serotonin transporter (SERT), and knockout mice. In studies with human SERT-transfected human HEK293 cells, the synthetic opioids tramadol, meperidine, methadone, tapentadol, and dextromethorphan inhibited SERT, but fentanyl and a number of phenanthrenes including morphine and hydromorphone did not. Receptor ligand-binding assays revealed interaction of fentanyl with 5-HT1A receptors and interaction of meperidine, methadone, and fentanyl with 5-HT2A receptors. Although the opioids most often associated with serotonin toxicity in humans inhibit human SERT in vitro, fentanyl and oxycodone are not inhibitory even though their clinical involvement has been reported. This suggests some SERT-independent effects on the serotonin system in vivo. Heightened clinician awareness of the possibility of serotonin toxicity among patients taking opioids and serotonergic antidepressants is called for.
Journal Article
Structure-activity relationships of serotonergic 5-MeO-DMT derivatives: insights into psychoactive and thermoregulatory properties
Recent studies have sparked renewed interest in the therapeutic potential of psychedelics for treating depression and other mental health conditions. Simultaneously, the novel psychoactive substances (NPS) phenomenon, with a huge number of NPS emerging constantly, has changed remarkably the illicit drug market, being their scientific evaluation an urgent need. Thus, this study aims to elucidate the impact of amino-terminal modifications to the 5-MeO-DMT molecule on its interactions with serotonin receptors and transporters, as well as its psychoactive and thermoregulatory properties. Our findings demonstrated, using radioligand binding methodologies, that all examined 5-MeO-tryptamines exhibited selectivity for 5-HT1AR over 5-HT2AR. In fact, computational docking analyses predicted a better interaction in the 5-HT1AR binding pocket compared to 5-HT2AR. Our investigation also proved the interaction of these compounds with SERT, revealing that the molecular size of the amino group significantly influenced their affinity. Subsequent experiments involving serotonin uptake, electrophysiology, and superfusion release assays confirmed 5-MeO-pyr-T as the most potent partial 5-HT releaser tested. All tested tryptamines elicited, to some degree, the head twitch response (HTR) in mice, indicative of a potential hallucinogenic effect and mainly mediated by 5-HT2AR activation. However, 5-HT1AR was also shown to be implicated in the hallucinogenic effect, and its activation attenuated the HTR. In fact, tryptamines that produced a higher hypothermic response, mediated by 5-HT1AR, tended to exhibit a lower hallucinogenic effect, highlighting the opposite role of both 5-HT receptors. Moreover, although some 5-MeO-tryptamines elicited very low HTR, they still act as potent 5-HT2AR agonists. In summary, this research offers a comprehensive understanding of the psychopharmacological profile of various amino-substituted 5-MeO-tryptamines, keeping structural aspects in focus and accumulating valuable data in the frame of NPS. Moreover, the unique characteristics of some 5-MeO-tryptamines render them intriguing molecules as mixed-action drugs and provide insight within the search of non-hallucinogenic but 5-HT2AR ligands as therapeutical agents.
Journal Article
LSD-induced increases in social adaptation to opinions similar to one’s own are associated with stimulation of serotonin receptors
Adapting one’s attitudes and behaviors to group norms is essential for successful social interaction and, thus, participation in society. Yet, despite its importance for societal and individual functioning, the underlying neuropharmacology is poorly understood. We therefore investigated its neurochemical and neural correlates in a pharmacological functional magnetic resonance imaging study. Lysergic acid diethylamide (LSD) has been shown to alter social processing and therefore provides the unique opportunity to investigate the role of the 5-HT
2A
receptor in social influence processing. Twenty-four healthy human volunteers received either (1) placebo + placebo, (2) placebo + LSD (100 µg), or (3) the 5-HT
2A
receptor antagonist ketanserin (40 mg) + LSD (100 µg) at three different occasions in a double-blind, randomized, counterbalanced, cross-over design. LSD increases social adaptation but only if the opinions of others are similar to the individual’s own. These increases were associated with increased activity in the medial prefrontal cortex while participants received social feedback. Furthermore, pretreatment with the 5-HT
2A
antagonist ketanserin fully blocked LSD-induced changes during feedback processing, indicating a key role of the 5-HT
2A
system in social feedback processing. Our results highlight the crucial role of the 5-HT-system in social influence and, thus, provide important insight into the neuropharmacological basis of social cognition and behavior.
Journal Article
Serotonin transporter–ibogaine complexes illuminate mechanisms of inhibition and transport
The serotonin transporter (SERT) regulates neurotransmitter homeostasis through the sodium- and chloride-dependent recycling of serotonin into presynaptic neurons
1
–
3
. Major depression and anxiety disorders are treated using selective serotonin reuptake inhibitors—small molecules that competitively block substrate binding and thereby prolong neurotransmitter action
2
,
4
. The dopamine and noradrenaline transporters, together with SERT, are members of the neurotransmitter sodium symporter (NSS) family. The transport activities of NSSs can be inhibited or modulated by cocaine and amphetamines
2
,
3
, and genetic variants of NSSs are associated with several neuropsychiatric disorders including attention deficit hyperactivity disorder, autism and bipolar disorder
2
,
5
. Studies of bacterial NSS homologues—including LeuT—have shown how their transmembrane helices (TMs) undergo conformational changes during the transport cycle, exposing a central binding site to either side of the membrane
1
,
6
–
12
. However, the conformational changes associated with transport in NSSs remain unknown. To elucidate structure-based mechanisms for transport in SERT we investigated its complexes with ibogaine, a hallucinogenic natural product with psychoactive and anti-addictive properties
13
,
14
. Notably, ibogaine is a non-competitive inhibitor of transport but displays competitive binding towards selective serotonin reuptake inhibitors
15
,
16
. Here we report cryo-electron microscopy structures of SERT–ibogaine complexes captured in outward-open, occluded and inward-open conformations. Ibogaine binds to the central binding site, and closure of the extracellular gate largely involves movements of TMs 1b and 6a. Opening of the intracellular gate involves a hinge-like movement of TM1a and the partial unwinding of TM5, which together create a permeation pathway that enables substrate and ion diffusion to the cytoplasm. These structures define the structural rearrangements that occur from the outward-open to inward-open conformations, and provide insight into the mechanism of neurotransmitter transport and ibogaine inhibition.
Cryo-electron microscopy reveals three conformations of the serotonin transporter in complex with ibogaine, detailing the structural rearrangements that occur between the different stages of its transport cycle.
Journal Article