Journal of Neuroscience
November 12, 2014
Michael H. Baumann, Ernesto Solis, Lucas R. Watterson et al.
157 citations
The abuse of synthetic psychoactive substances known as "designer drugs" or "new psychoactive substances" (NPS) is increasing rapidly. These drugs are manufactured as legal alternatives to traditional illicit drugs. Synthetic cathinones ("bath salts") and synthetic cannabinoids ("spice") have received substantial media attention. Low recreational doses can produce desirable effects, but high doses or chronic exposure often lead to dangerous medical consequences including psychosis, violent behaviors, tachycardia, hyperthermia, and death. Despite their popularity, there is a paucity of scientific data about these drugs. This review describes the mechanisms of action and neurobiological effects of synthetic cathinones and cannabinoids.
Behavioural Pharmacology
March 1, 2004
William E Fantegrossi, J H Woods, Gail Winger
99 citations
Hallucinogenic compounds such as DMT, mescaline, and psilocybin can produce weak and transient self-administration in rhesus monkeys previously trained to self-administer MDMA. No compound generated reliable responding, and no subject self-administered DOI at rates above those for saline. In some sessions, 3 out of 4 subjects responded at rates between 0.75 and 3.0 responses per second when DMT, mescaline, or psilocybin were available, earning a majority of infusions and appearing intoxicated. This pattern suggests these hallucinogens may have weak reinforcing effects or mixed reinforcing and aversive properties.
Behavioural Pharmacology
December 1, 2005
William E Fantegrossi, Kelly M Kugle, Leander J. Valdés et al.
80 citations
Salvinorin A, a natural compound from the Mexican mint Salvia divinorum, is the first known naturally occurring kappa-opioid receptor agonist with a novel chemical structure distinct from other opioids. In mice, salvinorin A caused rapid but short-lived sedation and motor incoordination, similar to the effects of the mu-agonist remifentanil and the synthetic kappa-agonist U69,593. Using selective antagonists, the motor effects of salvinorin A and U69,593 were shown to be mediated by kappa-opioid receptors, while remifentanil's effects involved mu-receptors. Salvinorin A and U69,593 differed in their susceptibility to antagonism by nor-binaltorphamine, suggesting salvinorin A may bind to the kappa-receptor differently than traditional kappa-agonists. This raises the possibility that developing other diterpene-based opioids could yield therapeutic compounds.
Psychopharmacology
September 1, 2005
William E Fantegrossi, Andrew W Harrington, Justin R Eckler et al.
72 citations
The hallucinogen 2C-T-7 produces head twitch responses in mice and serves as a discriminative stimulus in rats, effects that are blocked by a selective 5-HT2A antagonist. In drug discrimination tests, 2C-T-7 partially generalized (75%) to the LSD cue in rats and acted as a discriminative stimulus itself, with those interoceptive effects also attenuated by the 5-HT2A antagonist. Binding studies show 2C-T-7 has nanomolar affinity for 5-HT2A and 5-HT2C receptors and lower affinity for 5-HT1A receptors. The antagonism of its behavioral effects strongly suggests the 5-HT2A receptor is an important site of action for this compound.
The Journal of pharmacology and experimental therapeutics
December 1, 2014
Douglas A Smith, Jessica M Bailey, Diarria Williams et al.
31 citations
Tolerance developed to the head twitch response (HTR) elicited by daily administration of the phenethylamine-derived hallucinogens DOI and 2C-T-7 in mice, but not to the tryptamine-derived drugs DPT and DIPT. Tolerance to DOI was insurmountable by increasing dose, and cross-tolerance to 2C-T-7 and DPT was also insurmountable in DOI-tolerant mice. These results suggest that phenethylamine-derived 5-HT2A agonists may be limited for chronic therapeutic use by rapid tolerance development that persists even when switching to a different structural class. Tryptamine-derived hallucinogens may have a reduced tolerance potential and could be more suitable for long-term administration.
Experimental and Clinical Psychopharmacology
February 1, 2008
William E Fantegrossi
30 citations
The chiral nature of the MDMA molecule produces two enantiomers, each biologically active. Reviewing the author's research and other publications, no differences between racemic MDMA and its enantiomers in maintaining behavior were noted. Blocking the 5-HT2A receptor shifted the dose-effect function rightward for S(+)-MDMA but insurmountably reduced the reinforcing effects of R(-)-MDMA. Long-term self-administration can lead to chronic tolerance, with S(+)-MDMA somewhat less susceptible than the racemate or R(-)-enantiomer. PET neuroimaging showed negligible dopamine transporter occupancy after R(-)-MDMA but reasonable interaction after S(+)-MDMA. Non-human primate studies caution that results with enantiomers may not inform about the racemate and vice versa.
Psychedelic medicine (New Rochelle, N.Y.)
September 1, 2023
Harpreet Kaur, Sedat Karabulut, James W Gauld et al.
10 citations
Autism spectrum disorder (ASD) involves social communication deficits and repetitive behaviors, with no approved drugs for its core symptoms. Existing medications like aripiprazole and risperidone treat irritability but can cause side effects such as weight gain and sedation. Drugs with pro-social effects, including MDMA and its analogue MBDB, may help address social anxiety and avoidance in ASD. This review examines the pharmacology of methylenedioxy amphetamine analogues (MDXX drugs), focusing on their binding sites, metabolism, and structure-activity relationships. It emphasizes how individual stereoisomers and their racemic mixtures shape drug effects. The authors propose that MDXX compounds offer a promising chemical space for developing safer, more effective treatments for ASD.
Journal of psychopharmacology (Oxford, England)
January 1, 2026
Jack E Henningfield, Sandra D Comer, Matthew L Banks et al.
5 citations
A panel of abuse potential experts convened to discuss challenges in assessing the abuse potential of novel drugs, especially psychedelics and cannabinoids. The U.S. Controlled Substances Act scheduling process, intended to balance public safety with medicinal access, can be overly restrictive when abuse potential is overestimated, as postmarketing evaluations have suggested for some substances. Existing methods recommended by the FDA are generally reliable for many drug categories but require modifications—such as behavioral economic assessments and broader outcome measures in human abuse potential studies—to accurately characterize newer agents. The commentary emphasizes the need for updated approaches to ensure valid scheduling decisions that protect public health without hindering access to beneficial medicines.
Psychedelic Medicine
March 28, 2026
Levi Neal, Hannah E. Shaw, Brenda M. Gannon et al.
A single dose of the psychedelics LSD or DOI did not reduce opioid consumption or withdrawal signs in mice that had become dependent on fentanyl analogs. Mice drinking water avoided the bitter taste of quinine, but mice consuming fentanyl solutions continued drinking despite the adulteration, a behavior unchanged by psychedelic treatment. Fifteen days later, neither LSD nor DOI altered naloxone-precipitated jumping or restlessness, but both drugs lessened withdrawal-associated heightened sensitivity to heat. These results do not support a single psychedelic exposure as a treatment for opioid use disorder, though they suggest possible persistent effects on pain perception during withdrawal.
The FASEB Journal
March 1, 2008
Kevin Sean Murnane, Leonard L. Howell, William E Fantegrossi
MDMA has both stimulant and hallucinogen-like effects, and its two isomers, R(−)-MDMA and S(+)-MDMA, produce different behavioral effects: R(−)-MDMA is hallucinogen-like, while S(+)-MDMA is stimulant-like. In this study, mice were trained to discriminate each isomer from a vehicle in a two-lever operant task. Drugs with hallucinogen-like effects (2C-T-7, DPT) and stimulant-like effects (amphetamine, cocaine) were substituted for the training isomer. Results showed efficacy differences within chemical classes and potency differences within behavioral classes, clarifying the complex discriminative stimulus properties of MDMA isomers.