Addiction Biology
October 1, 2002
Torsten Passie, Juergen Seifert, Udo Schneider et al.
465 citations
Psilocybin, the main psychoactive alkaloid in certain mushrooms found worldwide, is increasingly abused as a hallucinogenic drug. Although it was used experimentally in medicine during the 1960s, pharmacological information about it remained scarce until recently. This review compiles all available pharmacological data on psilocybin, addressing the ongoing abuse potential and the need for comprehensive knowledge.
Addiction Biology
June 14, 2013
Sarah Bradbury, Judith Bird, Joyce Colussi‐mas et al.
59 citations
About half of rats fail to acquire MDMA self-administration, and the difference is not due to how the drug is metabolized. MDMA triggers greater release of serotonin than dopamine in the brain. Rats that did acquire self-administration showed lower serotonin overflow than those that did not. Destroying serotonin neurons with a toxin made more rats acquire MDMA self-administration and speeded acquisition of cocaine self-administration. These findings suggest that serotonin limits initial sensitivity to MDMA's rewarding effects and delays reliable self-administration.
Addiction Biology
December 22, 2019
Natasha L. Mason, Eef L. Theunissen, Nadia R. P. W. Hutten et al.
58 citations
Regular cannabis users develop tolerance to the drug's impairing and rewarding effects, but the underlying brain changes are unclear. In a double-blind, placebo-controlled study, 12 occasional and 12 chronic cannabis users received acute doses of cannabis (300 μg/kg delta-9-tetrahydrocannabinol) or placebo. In occasional users, cannabis decreased functional connectivity and increased striatal glutamate levels in reward circuitry, linked to greater subjective high and worse attention performance. Chronic users showed none of these changes, indicating reduced responsiveness of reward circuitry to cannabis intoxication, suggesting a pharmacodynamic mechanism for tolerance development.
Addiction Biology
March 3, 2016
Laura Blanco‐Hinojo, Jesus Pujol, Ben J. Harrison et al.
52 citations
Chronic cannabis use is associated with reduced motivation, and this study examined how it affects functional connectivity between the basal ganglia and brain regions involved in internal (frontal cortex) and external (sensory cortices) motivation signals. Resting-state fMRI in 28 chronic cannabis users and 29 controls showed that cannabis exposure attenuated the positive correlation between the striatum and limbic frontal-basal ganglia circuits, and attenuated the negative correlation between the striatum and the fusiform gyrus, which is important for recognizing significant visual features. These connectivity alterations were linked to lower arousal in response to affective pictures. Changes tended to normalize after one month of abstinence, indicating that cannabis impairs fine-tuning of the motivation system, but this effect is reversible.
Addiction Biology
March 1, 2014
Xaver Koenig, Michael Kovar, Stefan Boehm et al.
50 citations
Therapeutic concentrations of ibogaine, an alkaloid from the African shrub Tabernanthe iboga used in alternative medicine for its anti-addictive properties, reduce currents through human ether-a-go-go-related gene potassium channels. This provides a mechanism by which ibogaine may generate life-threatening cardiac arrhythmias, consistent with anecdotal evidence that it can disturb heart rhythm.
Addiction Biology
August 31, 2022
Elena Giné, Javier Calleja‐conde, José Á. Morales-García et al.
49 citations
Classic psychedelics like LSD, psilocybin, ayahuasca, and mescaline act mainly on 5-HT2A receptors and are being studied as treatments for psychiatric disorders, including alcohol use problems. This systematic review analyzed 27 studies (20 human, 7 preclinical) published between 2000 and 2021. Human studies generally suggest that classic psychedelics could help reduce alcohol consumption, but many have methodological limitations such as small sample sizes or lack of control groups. Preclinical studies are scarce and show conflicting results. Psilocybin shows the most consistent data as a potential candidate for treating alcohol use disorders. More rigorous studies are needed to understand the underlying mechanisms.
Addiction Biology
October 1, 2010
Sebastien Carnicella, Dao‐yao He, Quinn V Yowell et al.
49 citations
Noribogaine, a metabolite of ibogaine, increases GDNF expression in cell cultures and reduces alcohol self-administration when infused into the ventral tegmental area (VTA) of rats, whereas 18-MC, a synthetic ibogaine derivative, does not affect GDNF expression or alcohol responding in the VTA. These findings indicate that noribogaine and 18-MC act through different mechanisms and brain sites to reduce alcohol consumption, and that noribogaine may share ibogaine's anti-addictive properties without some of its side effects.
Addiction Biology
October 2, 2007
Firas Kobeissy, Jennifer A. Jeung, Matthew Warren et al.
47 citations
Acute administration of MDMA (ecstasy) and methamphetamine to adult male rats altered serum levels of appetite-regulating hormones in a dose- and time-dependent manner. MDMA caused transient decreases in leptin and growth hormone and increases in ghrelin, with levels returning to baseline after 24 hours. Both MDMA and methamphetamine produced a steady decrease in neuropeptide-Y. These hormone changes may help explain the reduced eating observed in humans who abuse these drugs.
Addiction Biology
December 22, 2021
Thomas R. Arkell, Richard C. Kevin, Frederick Vinckenbosch et al.
45 citations
Males and females show few differences in their acute responses to a moderate dose of vaporized cannabis containing 13.75 mg THC, with or without 13.75 mg CBD. After controlling for body mass index and plasma THC concentrations, males performed better on a divided attention task and had higher peak plasma levels of a THC metabolite (11-COOH-THC), but no sex differences appeared in subjective drug effects, cardiovascular measures, or plasma concentrations of THC, CBD, or other metabolites. The findings suggest an absence of systematic sex differences at this dose, though differences might emerge with higher THC doses or other routes of administration.
Addiction Biology
October 1, 2010
Vicente Hernández‐rabaza, Graciela Navarro‐mora, Clara Velázquez-sánchez et al.
40 citations
Adolescent rats repeatedly exposed to alcohol and MDMA (ecstasy) together showed lasting memory deficits, while either drug alone did not. The combination also reduced mature granule neurons in the dentate gyrus and increased reactive microglia, but did not affect the survival of new neurons or the structure of immature neurons. Memory impairment was linked to the loss of granule cells, not to changes in adult neurogenesis. The findings underscore the heightened risk of combining alcohol and MDMA during adolescence.
Addiction Biology
January 5, 2016
Alexander F. Hoffman, Matthew D. Lycas, Jakub Kaczmarzyk et al.
39 citations
Synthetic cannabinoids found in 'Spice' products are potent activators of CB1 receptors in the mouse hippocampus, disrupting synaptic transmission and long-term potentiation (LTP). JWH-018 was the most potent inhibitor of hippocampal synaptic transmission (EC50 ~15 nM), followed by AM2201 (EC50 ~60 nM), while XLR-11 (EC50 ~900 nM) and Δ9-THC (EC50 ~700 nM) were much less potent. All effects were reversed by CB1 receptor antagonists, and AM2201 had no effect in mice lacking CB1 receptors. Exposure to any of these cannabinoids significantly impaired LTP, suggesting that synthetic cannabinoids can cause profound cognitive and behavioral deficits.
Addiction Biology
July 11, 2012
Judith Bird, Susan Schenk
39 citations
Impulsivity, but not novelty-seeking, predicts how strongly rats seek MDMA after withdrawal. Before self-administration, rats were tested for impulsivity (premature responding on a five-choice task) and novelty-seeking (locomotor activity in a novel environment). Impulsivity was positively correlated with the magnitude of drug-seeking triggered by MDMA, while novelty-seeking showed no significant link to either acquisition or drug-seeking. MDMA self-administration also caused transient deficits in attention and increased premature responses. The findings suggest impulsivity may be a risk factor for compulsive drug-seeking after MDMA withdrawal.
Addiction Biology
November 11, 2010
Jillian H. Broadbear, Brendan J. Tunstall, Katherine Beringer
38 citations
MDMA produces prosocial mood changes by enhancing serotonin transmission, which can stimulate oxytocin release. In a drug discrimination experiment with 24 male and female rats, an oxytocin analog partially mimicked MDMA's effects, while an oxytocin receptor blocker selectively reduced responses to MDMA but not to amphetamine. Imipramine had no effect. Oxytocin receptor activation appears to be a key cue distinguishing MDMA from amphetamine.
Addiction Biology
September 28, 2011
Jennifer Do, Susan Schenk
37 citations
MDMA use is rising worldwide, and high doses reduce serotonin (5HT) markers in the brain. This study examined whether self-administered MDMA causes lasting serotonin deficits in rats. Rats self-administered MDMA infusions until reaching total doses of either 165 or 315 mg/kg. Serotonin levels in the frontal cortex, striatum, and hippocampus were measured 2 or 10 weeks later. The lower dose did not significantly reduce serotonin in any brain region. The higher dose decreased serotonin by 30–35% in all three regions at 2 weeks, but levels recovered by 10 weeks. These dose- and time-dependent deficits suggest similar effects may occur in humans who use MDMA.
Addiction Biology
September 8, 2009
Manuel Daza‐losada, Marta Rodríguez‐arias, María A. Aguilar et al.
37 citations
Adolescent mice exposed to MDMA, cocaine, or both drugs showed lasting changes into adulthood in their response to MDMA. Only those pre-treated with MDMA alone developed a conditioned place preference for a low dose of MDMA. All groups developed preference for a higher dose, but extinction took longer in mice pre-treated with cocaine (46 sessions) or MDMA alone (28 sessions). Preference was reinstated with progressively lower priming doses in mice pre-treated with MDMA or cocaine alone. Early exposure to MDMA or cocaine induces long-lasting changes that modify adult responses to MDMA.
Addiction Biology
November 22, 2021
Dusan Hirjak, Mike M. Schmitgen, Florian Werler et al.
33 citations
Heavy cannabis use (HCU) is linked to changes in both brain structure and function, even in individuals without a cannabis-use disorder or other major mental illnesses. This study used multimodal MRI to examine grey matter volume and intrinsic neural activity in 24 heavy users and 16 controls. Two distinct brain component patterns differed between groups: one involving the cerebellum, temporal, and thalamic regions (structural), and another involving frontal and parietal regions (functional). These patterns correlated with specific cannabis-use behaviors. Additionally, the structural changes were associated with the serotonergic system, while functional changes were linked to serotonergic, dopaminergic, and μ-opioid receptor systems, offering new insights into the neural mechanisms of heavy cannabis use.
Addiction Biology
January 19, 2012
Xavier Viñals, Rafaël Maldonado, Patricia Robledo
32 citations
Repeated high doses of MDMA (30 mg/kg) given to mice impaired working memory and cognitive flexibility, with deficits in recalling learned alternation behavior persisting five days after the last dose. The high dose also increased perseveration errors in an attentional set-shifting task, indicating reduced cognitive flexibility. These behavioral effects were not due to anhedonia, as saccharin preference remained unchanged. Although baseline dopamine levels in the striatum were unaffected, an acute MDMA challenge failed to increase dopamine outflow in mice that had received the high dose, suggesting reduced dopamine transporter function. Dopamine outflow recovered seven days later. The findings suggest that neurotoxic MDMA doses cause lasting impairments in recall and cognitive flexibility in mice.
Addiction Biology
February 3, 2021
Bree A. Humburg, Chloe J. Jordan, Hai‐Ying Zhang et al.
30 citations
Most cannabinoids reduce rather than enhance reward-seeking behavior in mice, according to an optogenetic self-stimulation procedure. Cocaine dose-dependently increased responding, shifting stimulation–response curves upward. In contrast, Δ9-tetrahydrocannabinol (THC), WIN55,212-2, and ACEA dose-dependently decreased responding and shifted curves downward; cannabidiol had no effect. Among newer synthetic cannabinoids, XLR-11 produced a cocaine-like increase, AM-2201 produced a THC-like reduction, and 5F-AMB had no effect. CB1 receptors were expressed mainly in VTA GABA and glutamate neurons, while CB2 receptors were expressed mainly in VTA dopamine neurons. These findings suggest most cannabinoids are reward attenuating or aversive in mice.
Addiction Biology
May 1, 2019
Shaul Schreiber, Miaad Bader, Tatiana Lenchinski et al.
30 citations
Three synthetic cannabinoids (AB-FUBINACA, AB-CHMINACA, PB-22) and Δ9-THC all caused hypothermia and reduced anxiety, spatial memory, and exploratory behavior in adult ICR mice. Only Δ9-THC produced clear pain relief. Unlike Δ9-THC, all synthetic cannabinoids decreased locomotor activity. AB-FUBINACA and Δ9-THC impaired balance and grip strength. PB-22 increased depression-like behavior, while AB-FUBINACA reduced it. The findings indicate varied effects among synthetic cannabinoids and Δ9-THC.
Addiction Biology
July 1, 1998
Alan O'Donohoe, Karen O’flynn, Kevin Shields et al.
29 citations
MDMA (ecstasy) is metabolized by the cytochrome P450 enzyme debrisoquine hydroxylase, coded by the CYP2D6 gene. Between 3 and 10% of the Caucasian population carry mutations that make them poor metabolizers, potentially increasing their risk of adverse reactions. This study examined seven individuals who had severe toxicity or died from MDMA. None were homozygous for the CYP2D6 mutation. The authors suggest three explanations: non-dose-related toxicity may stem from contaminants or environmental factors; the genotyping may have missed rare mutations; or the sample was too small to detect a statistically significant effect.
Addiction Biology
October 13, 2011
Bruno Ribeiro Do Couto, Manuel Daza‐losada, Marta Rodrı́guez-arias et al.
26 citations
Adolescent mice pre-exposed to ethanol, MDMA, or both showed increased rewarding effects from a low dose of MDMA in a conditioned place preference model. Pre-exposure did not alter acquisition of place preference induced by a higher MDMA dose, but the preference was more persistent in mice pre-exposed to MDMA or ethanol plus the higher MDMA dose. After extinction, reinstatement occurred with lower priming doses in pre-exposed groups. Pre-treatment also caused long-term changes in brain monoamine levels, including dopamine turnover and serotonin metabolites, depending on the dose used. The findings suggest that adolescent exposure to ethanol and MDMA may enhance the addictive properties of MDMA.
Addiction Biology
September 1, 2006
David H Overstreet, Amir H Rezvani, Michael Cowen et al.
19 citations
The Fawn-Hooded rat (FH/Wjd) is an inbred strain that naturally consumes high amounts of alcohol (over 5 g/kg/day) with a preference above 65%. Unlike selectively bred alcohol-preferring strains, this strain was chosen due to a serotonin platelet abnormality, but breeding experiments showed that the high alcohol intake is unrelated to that serotonin defect. Many compounds tested in these rats reduce alcohol intake, including amperozide, MTEP, ibogaine, St. John's wort, and kudzu extract. However, tolerance can develop to some drugs like opiate antagonists, possibly due to up-regulation of opioid receptors. This tolerance also appears in selectively bred alcohol-preferring rats, raising questions about its role in relapse among people treated with naltrexone. The broad range of effective compounds suggests diverse targets for developing new alcoholism treatments.
Addiction Biology
May 1, 2022
Feng Li, Han Du, Bo Wu et al.
16 citations
The drug 2-fluorodeschloroketamine (2-FDCK), a ketamine substitute used by drug abusers, shows abuse potential comparable to ketamine. In mice, 2-FDCK at 3 mg/kg induced conditioned place preference, similar to ketamine. Acute injections at 30 mg/kg increased locomotor activity, and repeated treatments led to locomotor sensitization after withdrawal. 2-FDCK supported self-administration at 0.5 mg/kg/infusion, matching ketamine, with peak seeking at 1 mg/kg. In drug discrimination tests, 2-FDCK dose-dependently substituted for ketamine with comparable potency. These findings indicate that 2-FDCK has an abuse potential similar to ketamine.
Addiction Biology
January 1, 2010
Nora Von Ameln, Andreas Von Ameln‐mayerhofer
14 citations
Repeated treatment of adolescent rats with the drug MDMA (Ecstasy) or its S-enantiomer caused immediate massive hyperactivity and, after a short habituation period, led to behavioral sensitization—a heightened response to the drug over time. The R-enantiomer did not cause hyperactivity and even reduced movement with repeated doses, but when given together with the S-enantiomer it increased hyperactivity and made the sensitization state-dependent. Rats pretreated with R-MDMA showed a sensitized response in adulthood when later given the racemic mixture. These results indicate that even without substantial neurotoxicity, both MDMA enantiomers can cause long-term changes in brain circuitry and behavior when given repeatedly during adolescence.
Addiction Biology
May 7, 2020
Nikola Pinterová, Rachel R. Horsley, Hynek Danda et al.
13 citations
Naphyrone, a synthetic cathinone similar to pyrovalerone, potently blocks monoamine transporters and produces stimulant and entactogen-like effects. In male Wistar rats, a single subcutaneous dose of 1 mg/kg reached peak concentrations in blood and tissues within 30 minutes, with prolonged elevation in the brain relative to serum. A higher dose of 20 mg/kg caused modest increases in body temperature and lasting hyperactivity in an open field test, while transiently improving sensorimotor gating as measured by prepulse inhibition. No acute toxicity was observed. The drug crosses the blood-brain barrier rapidly and is eliminated slowly, with effects matching its pharmacokinetics. Harm-reduction guidance should follow that for other stimulants and cathinones.