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MDMA-like stimulus effects of hallucinogens in male Fawn-Hooded rats.

A two-lever, food-motivated, operant technique was employed to train the purportedly serotonergically dysfunctional Fawn-Hooded (FH) rat to discriminate 1.5 mg/kg MDMA. Once all 10 male subjects learned the MDMA-vehicle discrimination at criterion performance level, doses different than the training dose were used to generate a dose-response discrimination gradient. The ED50 value of MDMA was shown to be 0.136 mg/kg, not significantly different from that of previously trained Sprague-Dawley male rats. Thus, the Fawn-Hooded rat appears to not differ in its sensitivity to lower doses of MDMA. Testing for MDMA-like stimulus generalizations with other drugs indicated that the MDMA derivative MDE produced generalization at a dose of 2.25 mg/kg and allowed for an ED50 value of 0.496 mg/kg. Like MDE, the testing of alpha-ethyltryptamine was shown to produce MDMA-like responding. Lastly, a dose of 0.12 mg/kg LSD produced 90% MDMA-lever selection. In contrast to MDMA generalizations to these three drugs, testing of cocaine at doses of 2.5-10 mg/kg and mescaline at 8-14 mg/kg did not produce MDMA-like discriminative effects. The results of this testing in the presumably serotonergically dysfunctional Fawn-Hooded rat would indicate that this line not only can discriminate MDMA as well as heterogenous-bred lines, but also shows the same discriminative generalizations and nongeneralizations from MDMA to serotonergic and dopaminergic agents.

Animals↗

Serotonin model of schizophrenia: emerging role of glutamate mechanisms.

The serotonin (5-HT) hypothesis of schizophrenia arose from early studies on interactions between the hallucinogenic drug LSD (D-lysergic acid diethylamide) and 5-HT in peripheral systems. More recent studies have shown that the two major classes of psychedelic hallucinogens, the indoleamines (e.g., LSD) and phenethylamines (e.g. , mescaline), produce their central effects through a common action upon 5-HT(2) receptors. This review focuses on two brain regions, the locus coeruleus and the cerebral cortex, where the actions of indoleamine and the phenethylamine hallucinogens have been shown to be mediated by 5-HT(2A) receptors; in each case, the hallucinogens (via 5-HT(2A) receptors) have been found to enhance glutamatergic transmission. In the prefrontal cortex, 5-HT(2A)-receptors stimulation increases the release of glutamate, as indicated by a marked increase in the frequency of excitatory postsynaptic potentials/currents (EPSPs/EPSCs) in the apical dendritic region of layer V pyramidal cells; this effect is blocked by inhibitory group II/III metabotropic glutamate agonists acting presynaptically and by an AMPA/kainate glutamate antagonist, acting postsynaptically at non-NMDA glutamate receptors. A major alternative drug model of schizophrenia, previously believed to be entirely distinct from that of the psychedelic hallucinogens, is based on the psychotomimetic properties of antagonists of the NMDA subtype of glutamate receptor (e.g., phencylidine and ketamine). However, recently it has been found that many of the effects of the NMDA antagonists may also (1) involve 5-HT(2A) receptors and (2) be mediated through excess activity at non-NMDA (i.e., AMPA/kainate) glutamate receptors. Moreover, pharmacological manipulations of glutamate transmission (e. g., by inhibitory metabotropic glutamate agonists) provide unexpected parallels between the actions of these two classes of drugs. Given an emerging recognition of the importance of alterations in glutamatergic transmission in the actions of both psychedelic hallucinogens an NMDA antagonists, this review concludes with of implications for the pathophysiology and therapy of schizophrenia.

Animals↗

Reinforcing, subjective, and physiological effects of MDMA in humans: a comparison with d-amphetamine and mCPP.

3,4-methylenedioxymethamphetamine (MDMA) is a widely used drug of abuse chemically related to both the amphetamines and mescaline. Laboratory animal studies have shown that MDMA is a potent re-uptake inhibitor and releaser of dopamine and serotonin. Although the subjective and physiological effects of MDMA have been compared to d-amphetamine in humans, no direct comparison with a serotonin releasing agent has been reported and reinforcing effects have not been evaluated. In this paper we report a direct comparison of the reinforcing, subjective, and physiological effects of MDMA (1 and 2 mg/kg) to d-amphetamine (10 and 20 mg), to metachlorophenylpiperazine (mCPP--a serotonin releasing agent (0.5 and 0.75 mg/kg)), and to placebo using a within-subject design in 12 volunteers with moderate MDMA experience. Both the high dose of d-amphetamine and MDMA showed significant reinforcing effects as indicated by high cross-over values on the multiple choice procedure compared to all other treatments. All three drugs showed dose-dependent changes in subjective effects whereas physiological effects were most pronounced for MDMA with almost no changes seen with mCPP. The subjective effects of MDMA were similar both to those of mCPP and d-amphetamine, suggesting that both dopamine and serotonin systems are involved in mediating these effects. In contrast, only the dopaminergic agents, d-amphetamine and MDMA, had reinforcing effects.

Adolescent↗

The effects and consequences of selected club drugs.

Ecstasy (MDMA), gamma-hydroxybutyrate (GHB), ketamine, and methamphetamine are 4 examples of club drugs that are increasing in popularity. Although the pharmacological classifications of these drugs vary, MDMA has structural similarities to both amphetamine and the hallucinogen mescaline. Ketamine and GHB are anesthetic agents and methamphetamine is a long-acting psychostimulant. Medical visits for club drug-related toxicity have sharply increased across the country. This article provides a brief review of the literature on club drugs.

Central Nervous System Stimulants↗

Serotonin and hallucinogens.

This brief review traces the serotonin (5-HT) hypothesis of the action of hallucinogenic drugs from the early 1950s to the present day. There is now converging evidence from biochemical, electrophysiological, and behavioral studies that the two major classes of psychedelic hallucinogens, the indoleamines (e.g., LSD) and the phenethylamines (e.g., mescaline), have a common site of action as partial agonists at 5-HT2A and other 5-HT2 receptors in the central nervous system. The noradrenergic locus coeruleus and the cerebral cortex are among the regions where hallucinogens have prominent effects through their actions upon a 5-HT2A receptors. Recently, we have observed a novel effect of hallucinogens--a 5-HT2A receptor-mediated enhancement of nonsynchronous, late components of glutamatergic excitatory postsynaptic potentials at apical dendrites of layer V cortical pyramidal cells. We propose that an effect of hallucinogens upon glutamatergic transmission in the cerebral cortex may be responsible for the higher-level cognitive, perceptual, and affective distortions produced by these drugs.

Animals↗

Structure-activity studies on hallucinogenic amphetamines using molecular connectivity.

A series of ring-substituted hallucinogenic amphetamines has been analyzed using molecular connectivity. A correlating equation has been found between potency and connectivity terms. The equation permits an interpretation of SAR. The equation is capable of predicting potency for amphetamines not in the list and mescalines and tryptamines.

Amphetamines↗

Psychotomimetic phenylisopropylamines. 5. 4-Alkyl-2,5-dimethoxyphenylisopropylamines.

A homologous series of 4-alkyl-2,5-dimethoxyphenylisopropylamines (alkyl = H through n-C5H11 and t-C4H9) was synthesized and compared with mescaline as serotonin agonists in a sheep umbilical preparation. The three-carbon homolog 6d was found to be the most potent of the straight-chain series in accordance with its observed psychotomimetic effectiveness in man.

Animals↗

Psychedelic-induced hypomania and mania: a systematic review and meta-analysis.

Serotonergic psychedelics are increasingly investigated as treatments for affective disorders. Concerns persist regarding their potential to induce hypomania or mania, particularly in individuals with bipolar spectrum vulnerability. Whether these substances precipitate transient mood switches or contribute to persistent bipolar illness or diagnostic transition remains unclear. We conducted a systematic review of human studies examining manic or hypomanic symptoms following exposure to serotonergic psychedelics (psilocybin, LSD, mescaline, DMT/ayahuasca) or MDMA (CRD420251160656). Databases and trial registries were searched through January 26, 2026. Eligible designs included randomized and non-randomized clinical studies, registry-based cohorts, cross-sectional surveys, and longitudinal observational studies. Outcomes included dysphoria/euphoria, manic or hypomanic symptoms and transition to bipolar disorder. Risk of bias was assessed using ROBINS-I, ROB2 or NIH tools. Twenty-three studies met inclusion criteria, four contributing to meta-analysis. Rates of psychedelic-associated dysphoria/euphoria, hypomania or mania ranged from 5.8% in controlled trials of psilocybin-assisted psychotherapy for major depressive disorders to 30% in naturalistic studies of individuals with bipolar disorder. When present, manic symptoms were typically acute and self-limited. Observational studies identified higher risks among individuals with bipolar I disorder, familial vulnerability, polysubstance use, and unsupervised or illegal use. Registry-based cohorts examining diagnostic transitions showed a prevalence of subsequent transition to bipolar disorder of 4% (95% CI 2-8%; N = 7478; I² = 32.1%), with little evidence for a hallucinogen-specific signal. Overall, serotonergic psychedelics appear to pose a low but clinically meaningful relative risk of transient mood-related symptoms in susceptible individuals while remaining relatively safe in controlled clinical settings. Long-term outcomes and repeated exposure remain insufficiently studied, underscoring the need for rigorous longitudinal research.

Humans↗

Doxepin as a blocker of central serotonin receptors.

The antidepressant drug-Doxepin (DX) was examined in order to investigate its central antiserotonin activity. The drug antagonized the behavioral syndrome elecited by L-5-hydroxytryptophan in rats and mice, but did not affect the pinna reflex. In the flexor reflex preparation, DX acted like other sero-tonin receptor blockers: By itself, it had no influence on the flexor reflex but it prevented the potentiation induced by serotonergic agents (fenfluramine, LDS, mescaline). The hyperthermia provoked by serotonergic agent (fenfluramine, LSD)in rabbits was antagonized by DX. DX abolished the syndrome induced by oxotremorine. The results obtained indicate that DX blocks central 5-HT receptors, like the two other antidepressants, mianserin and danitracen.

5-Hydroxytryptophan↗

Psychedelic and entactogenic drugs in the treatment of depression.

CNS deficiency of 5-hydroxytryptamine (serotonin) has been implicated as a biochemical basis in some forms of depression. Existing drug modalities for treating depression include some with serotonergic effects. Studies suggest that psychedelic drugs are also serotonergic. This may indicate a role for psychedelics in the treatment of depression. Such treatment has already been attempted using psychedelic drugs in both the indoleamine and phenylalkylamine categories. Encouraging results seem to recommend further research, with special emphasis on drugs in the phenylisopropylamine subgroup of phenylalkylamines that are only peripherally psychedelic. Certain of these, called entactogens or empathogens, cause substantially less distortion of normative consciousness than classic psychedelics, such as LSD or mescaline. They could therefore be more easily assimilated into existing psychotherapy approaches, where their function would be to enhance the normal psychotherapeutic process rather than serving a maintenance role as chemotherapeutic agents. Their usefulness in such an application would be mainly at the start of psychotherapy in order to (1) reduce the client's "fear response" that often inhibits ability to deal with repressed traumatic material; (2) facilitate the client's interpersonal communications with the therapist, spouse or significant others; and (3) accelerate formation of a therapeutic alliance between client and therapist.

3,4-Methylenedioxyamphetamine↗

Cross-reactivity of amphetamine analogues with Roche Abuscreen radioimmunoassay reagents.

Cross-reactivity of amphetamine analogues with the Abuscreen amphetamine radioimmunoassay reagents was determined for both the standard and high specificity antibody systems. Compounds tested included 2-methoxyamphetamine, 4-hydroxymethamphetamine, 2,5-dimethoxyamphetamine (DMA), 4-bromo-2,5-dimethoxyamphetamine (DOB), 4-bromo-2,5-dimethoxy-beta-phenethylamine (BDMPEA), 3,4,5-trimethoxyamphetamine (TMA), 3,4-methylenedioxyamphetamine (MDA), N,N-dimethyl-3,4-methylenedioxyamphetamine and N-hydroxy-3,4-methylenedioxyamphetamine (N-OH MDA), 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyethylamphetamine (MDEA), 2,5-dimethoxy-4-ethylamphetamine, 2,5-dimethoxy-4-methylamphetamine (DOM), and 3,4,5-trimethoxyphenethylamine (mescaline). Blank negative reference material was spiked with 1,000 to 100,000 ng/mL of the amphetamine analogue and used as sample in the assays. MDA was the only analogue that showed cross reactivity equal to or greater than that of amphetamine. None of the other analogue compounds demonstrated a positive result at even the highest concentration; however several showed depressed counts at various concentration levels.

3,4-Methylenedioxyamphetamine↗

GC-MS identification of sympathomimetic amine drugs in urine: rapid methodology applicable for emergency clinical toxicology.

A method was developed that permitted rapid identification in urine of the following sympathomimetic amines: amphetamine, benzphetamine, cathinone, desmethylsegiline, diethylpropion, ephedrine, fenfluramine, mazindol, methylenedioxyamphetamine, methylenedioxyethylamphetamine, methylenedioxymethamphetamine, mescaline, methamphetamine, methcathinone, methylaminorex, methylphenidate, pemoline, phendimetrazine, phenylepherine, phentermine, phenylpropanolamine, pseudoephedrine, and selegiline. In addition, two alpha-phenylethylamine-like monoamine oxidase inhibitors, phenelizine and tranylcypromine, were studied. Those sympathomimetic amines containing a primary or secondary amine, a hydrazine, and/or hydroxyl (except mazindol) functional groups were derivatized effectively using an on-column derivatization technique that used a reagent consisting of 10% fluoroanhydride in hexane, whereas the other sympathomimetic amines, including mazindol, were analyzed underivatized. Three different fluoroanhydrides, trifluoroacetic (TFAA), pentafluoropropionic (PFPA), and heptafluorobutyric (HFBA), and three different injection-port temperatures (160, 200, and 260 degrees C) were investigated. Both TFAA and PFPA gave sympathomimetic amine derivatives with essentially identical retention times, whereas HFBA gave longer retention times and better separation of individual compounds. The base fragmentation ion was noted to increase 50 amu (CF2) for each derivatized sympathomimetic amine as the length of the carbon-fluorine chain increased. Fragmentation ion abundance was maximized at an injection-port temperature of 260 degrees C, and this enhanced sensitivity coupled with the better chromatographic resolution of the individual sympathomimetic amines prompted the selection of HFBA as the derivatizing agent of choice. Assignments were made for the fragmentation ions produced by each derivatized drug. The developed method was adapted to analyze urine specimens that might be encountered in emergency toxicology testing. For identification of sympathomimetic amines requiring derivatization, 0.1 mL of the patient specimen had amphetamine-d5 and methamphetamine-d5 added as internal standard followed by adjustment of pH to 9.3 with borate buffer, extraction with 9:1 chloroform/isopropanol, centrifugation and separation of the organic phase, addition of 10% methanolic HCI and evaporation under nitrogen, reconstitution with HFBA reagent, and on-column derivatization during gas chromatographic-mass spectrometric (GC-MS) analysis. For those sympathomimetic amines not requiring derivatization, 1.0 mL of urine specimen had diazepam-d5 added as internal standard followed by the same extraction procedure and reconstitution accomplished with ethyl acetate. Because precolumn derivatization was eliminated and only 8 min was required for GC-MS analysis, complete analysis time was approximately 30 min, making the method suitable for clinical emergency toxicology purposes.

Emergency Service, Hospital↗

Hyperthermia associated with drug intoxication.

Hyperthermia (temperature of at least 40.5 degrees C for at least one hour) associated with drug intoxication was identified in 12 patients over a 5-yr period. Intoxication was due to anticholinergic drugs (tricyclic antidepressants, antipsychotics, antihistamines), CNS stimulants (phencyclidine, cocaine, 3,4-methylene dioxyamphetamine, mescaline, lysergic acid diethylamide), salicylates, or combinations of these. Hyperthermia was present in four patients on admission, but its onset was delayed up to 12 h in the remainder. Outcome of hyperthermic patients was poor: five died and four had severe permanent neurologic sequelae. Clinical signs common to patients who developed hyperthermia were increased muscular activity and absence of sweating. Five patients suffered seizures, and four did not respond to anticonvulsant medication until body temperature was lowered. Cooling did not appear to favorably affect the outcome after body temperature had remained above 40.5 degrees C for a prolonged period. Prevention of death or neurologic sequelae from drug-induced hyperthermia depends upon the recognition of risk factors and the prompt treatment of hyperthermia.

Adolescent↗

Risk assessment of ritual use of oral dimethyltryptamine (DMT) and harmala alkaloids.

AIM: To extend previous reviews by assessing the acute systemic toxicity and psychological hazards of a dimethyltryptamine and beta-carboline brew (ayahuasca/hoasca) used in religious ceremonies. METHOD: A systematic literature search, supplemented by interviews with ceremony participants. RESULTS: No laboratory animal models were located that tested the acute toxicity or the abuse potential of ayahuasca. Separate animal studies of the median lethal dose of dimethyltryptamine (DMT) and of several harmala alkaloids indicated that a lethal dose of these substances in humans is probably greater than 20 times the typical ceremonial dose. Adverse health effects may occur from casual use of ayahuasca, particularly when serotonergic substances are used in conjunction. DMT is capable of inducing aversive psychological reactions or transient psychotic episodes that resolve spontaneously in a few hours. There was no evidence that ayahuasca has substantial or persistent abuse potential. Long-term psychological benefits have been documented when ayahuasca is used in a well-established social context. CONCLUSION: A decoction of DMT and harmala alkaloids used in religious ceremonies has a safety margin comparable to codeine, mescaline or methadone. The dependence potential of oral DMT and the risk of sustained psychological disturbance are minimal.

Alkaloids↗

The action of 5-hydroxytryptamine and some of its antagonists on the umbilical vessels of the human placenta.

The vasoconstrictor action of 5-hydroxytryptamine (5-HT) in the human placental preparation is about 10 times stronger than that of adrenaline and is antagonized by anti-adrenaline compounds like phentolamine. Both 5-HT and adrenaline are antagonized by yohimbine and chlorpromazine. Specific and strong anti-5-HT action is demonstrated for lysergic acid diethylamide (LSD) and tryptamine. Both LSD and tryptamine in larger doses have a vasoconstrictor action. Mescaline has no certain modifying effect on the action of 5-HT, but itself causes vasoconstriction in large doses. The antihistamine drug phenbenzamine in histamine blocking doses abolishes the action of 5-HT in half the preparations tested. The ganglionic blocking agent trimetaphan in large doses antagonizes the action of 5-HT added subsequently, and also, to a lesser degree, the effect of adrenaline. Hexamethonium and tetraethylammonium bromides are ineffective in this preparation. No certain modifying action of reserpine on subsequently added 5-HT could be demonstrated, and the same was true for heparin even in very high concentrations.

Antihypertensive Agents↗

The responses of the Venus heart to catechol amines and high concentration of 5-hydroxytryptamine.

The catechol amines excite the isolated heart of Venus mercenaria in a characteristic manner. This response was not obtained with phenethylamine, tyramine, ephedrine, or mescaline, nor with histamine, nor with the basic n-alkylamines. 5-Hydroxytryptamine had a distinctive effect at high concentrations (above 3x10(-6) M) different from that at lower doses. The response to high concentrations was dominated by an increase in muscle tone. Hearts exposed to high concentrations of 5-hydroxytryptamine and other tryptamine analogues for long periods became tachyphylactic to low doses of these substances. However, high doses of 5-hydroxytryptamine (about 2x10(-5) M) still excited the tachyphylactic heart, but the response was then like that to the catechol amines. When high bath temperatures rendered the heart insensitive to 5-hydroxytryptamine, high concentrations of this compound again had the catechol amine effect. The possibility of a physiological role for the catechol amines or high 5-hydroxytryptamine concentrations is discussed.

Amines↗

SOME ACTIONS OF CENTRALLY ACTIVE AND OTHER DRUGS ON THE TRANSMISSION OF SINGLE NERVE IMPULSES THROUGH THE ISOLATED SUPERIOR CERVICAL GANGLION PREPARATION OF THE RABBIT.

The effect of some centrally-active and other drugs on the transmission of single nerve impulses through the isolated superior cervical ganglion preparation of the rabbit has been studied by recording both preganglionic and postganglionic action potentials. Block of conduction in the axon could be distinguished from block of the synaptic mechanism. The drugs did not appear to exert any one characteristic form of blocking action. A continuous spectrum of drug action linked an agent such as meprobamate which acted predominantly on the synapse to benactyzine which acted mainly by blocking axonal conduction. The drugs have been divided into three groups. Group I: hexamethonium, meprobamate, paraldehyde, amylobarbitone, methylpentynol and azacyclonal; these acted relatively selectively at the ganglion. Group II: N714C (the cis-isomer of chlorprothixene), prochlorperazine, methylpentynol carbamate, pipradrol, promethazine, perphenazine and procaine; the action of these drugs on the ganglion could be accounted for entirely in terms of their axonal depressant action. Group III: chlorprothixene, promazine, N720 (dihydrochlorprothixene), chlorpromazine, hydroxyzine and benactyzine; these drugs also blocked axonal conduction but in addition they appeared to exert a "facilitating" action at the ganglionic synapse. The actions of adrenaline, adrenochrome, iproniazid, ergotoxine, mescaline and lysergic acid diethylamide on transmission were also studied. The implications of the modifications of ganglionic transmission produced by these drugs is discussed.

Action Potentials↗

Shape change of blood platelets--a model for cerebral 5-hydroxytryptamine receptors?

1. In blood platelets of rabbits isolated by a stractan gradient and incubated in a protein-poor medium, tryptamine, 5-hydroxytryptamine (5-HT) and derivatives, quipazine and mescaline caused a shape change. This shape change was inhibited by low concentrations of methysergide. 2. The most potent antagonists of the 5-HT-induced shape change included ergoline derivatives and neuroleptic drugs, which showed high stereoselectivity. 3. (+)-Lysergic acid diethylamide ((+)-LSD), psilocine and some N',N'-dimethylated tryptamines acted as mixed agonist-antagonists. 4. The compounds found to be agonists or mixed agonist-antagonists on platelets have previously been shown to act also as 5-HT agonists in the central nervous system (CNS). 5. With regard to 5-HT antagonists, the 5-HT receptors of platelets reacted differently from those described earlier in brain areas with dense 5-hydroxytryptaminergic innervation, but showed similarities to 5-HT receptors investigated previously in spinal cord, cerebral cortex and possibly reticular formation. 6. It is concluded that platelets may be considered with caution as models for some, but not for all, 5-HT receptors in the CNS.

Adenosine Diphosphate↗