Evaluation of potential punishing effects of 2,5-dimethoxy-4-methylamphetamine (DOM) in rhesus monkeys responding under a choice procedure.

OBJECTIVES: There has been substantial and growing interest in the therapeutic utility of drugs acting at serotonin 2A subtype (5-HT 2A ) receptors, increasing the need for characterization of potential beneficial and adverse effects of such compounds. Although numerous studies have evaluated the possible rewarding and reinforcing effects of 5-HT 2A receptor agonists, there have been relatively few studies on potential aversive effects. METHODS: The current study investigated punishing effects of 2,5-dimethoxy-4-methylamphetamine (DOM) in four rhesus monkeys responding under a choice procedure in which responding on one lever delivered a sucrose pellet alone and responding on the other lever delivered a sucrose pellet plus an intravenous infusion of a range of doses of fentanyl (0.1-3.2 µg/kg/infusion), histamine (3.2-100 µg/kg/infusion), or DOM (3.2-100 µg/kg/infusion). RESULTS: When fentanyl was available, responding for a pellet plus an infusion increased dose dependently in all subjects, indicating a positive reinforcing effect of fentanyl. When histamine was available, responding for a pellet plus an infusion decreased in three of four subjects, indicating a punishing effect of histamine. Whether available before or after histamine, DOM did not systematically alter choice across the range of doses tested. CONCLUSION: These results suggest that the 5-HT 2A receptor agonist DOM has neither positive reinforcing nor punishing effects under a choice procedure that is sensitive to both processes.

Effects of Ketanserin, M100907 and Olanzapine on hallucinogenic like action induced by 2,5-dimethoxy-4-methylamphetamine.

2,5-dimethoxy-4-methylamphetamine (DOM) is a kind of hallucinogen of phenylalkylamine. Psychedelic effects mainly include audiovisual synesthesia, complex imagery, disembodiment etc. that can impair control and cognition leading to adverse consequences such as suicide. By now, there are no specific drugs regarding the management of classic hallucinogen use clinically. We evaluated the effects of three 5-HT 2A receptor antagonists ketanseirn, M100907 and olanzapine on hallucination-like behavior in therapeutic and preventive administration with male C57BL/6J mice. Two models were used to evaluate the therapeutic potential of antagonists, one is head-twitch response (HTR) and the other is locomotion. Effects of ketanserin, M100907 and olanzapine on DOM-induced HTR were studied in preventive and therapeutic administration, respectively. In the preventive administration, the ID 50 values of ketanseirn, M100907 and olanzapine were 0.4 mg/kg, 0.005 mg/kg and 0.25 mg/kg. In the therapeutic administration, the ID 50 values of ketanseirn, M100907 and olanzapine were 0.04 mg/kg, 0.005 mg/kg and 0.03 mg/kg. Secondly, locomotor activity induced by DOM was performed to further evaluate the efficacy of three compounds. In locomotion, M100907(0.005 mg/kg) whenever in preventive or therapeutic administration, reduced the increase of movement distance induced by DOM. Although ketanserin (0.4 mg/kg) in the preventive administration also decreased the movement distance induced by DOM, it was alone administrated to influence the locomotor activity. Through HTR and locomotion, we compared the efficacy and latent side effects of ketanserin, M100907 and olanzapine against hallucinogenic like action induced by DOM. Our study provided additional experimental evidence on specific therapeutic drugs against hallucinogenic behavior induce by representative hallucinogen DOM.

Effects of 2,5-Dimethoxy-4-Methylamphetamine (DOM) and 2-Piperazin-1-yl-Quinoline (Quipazine) on Fentanyl Versus Food Choice in Rhesus Monkeys.

There has been increasing interest in the potential therapeutic effects of drugs with agonist properties at serotonin 2A subtype (5-HT2A) receptors (e.g., psychedelics), including treatment of substance use disorders. Studying interactions between 5-HT2A receptor agonists and other drugs is important for understanding potential therapeutic effects as well as adverse interactions. Direct-acting 5-HT2A receptor agonists such as 2,5-dimethoxy-4-methylamphetamine (DOM) and 2-piperazin-1-yl-quinoline (quipazine) enhance some (e.g., antinociceptive) effects of opioids; however, it is unclear whether they alter the abuse-related effects of opioids. This study examined whether DOM and quipazine alter the reinforcing effects of fentanyl in rhesus monkeys (n = 6) responding under a food versus drug choice procedure. Responding on one lever delivered sucrose pellets and responding on the other lever delivered intravenous (i.v.) infusions. In one set of experiments, fentanyl (0.1-3.2 µg/kg/infusion) versus food choice sessions were preceded by noncontingent i.v. pretreatments with DOM (0032-0.32 mg/kg), quipazine (0.32-1.0 mg/kg), naltrexone (0.032 mg/kg), or heroin (0.1 mg/kg). In another set of experiments, fentanyl was available during choice sessions in combination with DOM (0.32-100 µg/kg/infusion) or quipazine (3.2-320 µg/kg/infusion) in varying dose ratios. Naltrexone decreased and heroin increased fentanyl choice, demonstrating sensitivity of responding to pharmacological manipulation. However, whether given as a pretreatment or made available in combination with fentanyl as a mixture, neither DOM nor quipazine significantly altered fentanyl choice. These results suggest that 5-HT2A receptor agonists do not enhance the reinforcing effects of opioids and, thus, will not likely enhance abuse potential. SIGNIFICANCE STATEMENT: Serotonin 2A subtype receptor agonists enhance some (e.g., antinociceptive) effects of opioids, suggesting they could be combined with opioids in some therapeutic contexts such as treating pain. However, it is unclear whether they also enhance adverse effects of opioids, including abuse. Results of this study indicate that serotonin 2A subtype receptor agonists do not reliably enhance opioid self-administration and, thus, are unlikely to enhance the abuse potential of opioids.

Mix of new substances psychoactive, NPS, found in blotters sold in two Colombian cities.

The new psychoactive substances (NPS) in Colombia are detected by national authorities, in blotters strip, in different circumstances and places: airports, music concerts, discos and parks. Blotters are marketed as LSD and cause several cases of intoxication and death in some consumers: due to acute intoxication or when mixed with other drugs and may have different effects on the central nervous system (CNS). This study was conducted to research into and identify the chemical composition of the drugs impregnated in the blotters sold in two Colombian cities. This research provides the analysis of 70 doses coming from forensic cases of the Colombian Attorney General's Office in Bogota and from the Laboratory of Narcotics of the Colombian National Institute of Legal Medicine and Forensic Sciences (North Headquarter) in Barranquilla. Mixtures of drugs, such as DOB, 25I-NBOMe, MDMA and 25I-NBOMe imine were found within the blotters through gas chromatography coupled to mass spectrometry (CGMS); these drugs are classified by international authorities as NPS belonging to the phenylethylamines group. The results clearly warn about a growing public health problem in the country.

Comparison of the behavioral responses induced by phenylalkylamine hallucinogens and their tetrahydrobenzodifuran ("FLY") and benzodifuran ("DragonFLY") analogs.

In recent years, rigid analogs of phenylalkylamine hallucinogens have appeared as recreational drugs. Examples include 2-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)ethan-1-amine (2C-B-FLY) and 1-(8-bromobenzo[1,2-b;4,5-b']difuran-4-yl)-2-aminopropane (Bromo-DragonFLY, DOB-DFLY). Although some rigid compounds such as DOB-DFLY reportedly have higher potency than their non-rigid counterparts, it is not clear whether the same is true for 2C-B-FLY and other tetrahydrobenzodifurans. In the present study, the head twitch response (HTR), a 5-HT2A receptor-mediated behavior induced by serotonergic hallucinogens, was used to assess the effects of 2,5-dimethoxy-4-bromoamphetamine (DOB) and its α-desmethyl homologue 2,5-dimethoxy-4-bromophenethylamine (2C-B), as well as their benzodifuranyl and tetrahydrobenzodifuranyl analogs, in C57BL/6J mice. DOB (ED50 = 0.75 µmol/kg) and 2C-B (ED50 = 2.43 µmol/kg) induced the HTR. The benzodifurans DOB-DFLY (ED50 = 0.20 µmol/kg) and 2C-B-DFLY (ED50 = 1.07 µmol/kg) had significantly higher potency than DOB and 2C-B, respectively. The tetrahydrobenzodifurans DOB-FLY (ED50 = 0.67 µmol/kg) and 2C-B-FLY (ED50 = 1.79 µmol/kg), by contrast, were approximately equipotent with their non-rigid counterparts. Three novel tetrahydrobenzodifurans (2C-I-FLY, 2C-E-FLY and 2C-EF-FLY) were also active in the HTR assay but had relatively low potency. In summary, the in vivo potency of 2,5-dimethoxyphenylalkylamines is enhanced when the 2- and 5-methoxy groups are incorporated into aromatic furan rings, whereas potency is not altered if the methoxy groups are incorporated into dihydrofuran rings. The potency relationships for these compounds in mice closely parallel the human hallucinogenic data. The high potency of DOB-DFLY is probably linked to the presence of two structural features (a benzodifuran nucleus and an α-methyl group) known to enhance the potency of phenylalkylamine hallucinogens.

Rewarding and reinforcing effects of 4-chloro-2,5-dimethoxyamphetamine and AH-7921 in rodents.

New psychoactive substances (NPSs), i.e., newly designed substances with chemical residues that are slightly different from those of known psychoactive substances, have been emerging since the late 2000s, and social problems related to the use of these substances are increasing globally. Two such NPSs are 4-chloro-2,5-dimethoxyamphetamine (DOC), a psychedelic substance that is structurally related to amphetamine, and AH-7921, an opioid analgesic that is used for recreational purposes and has a potency similar to that of morphine. Currently, scientific evidence for the dependence liability or toxicity of NPSs is lacking. Therefore, in this study, we performed animal behavioral tests to evaluate the dependence liability of DOC and AH-7921. The rewarding and reinforcing effects of DOC and AH-7921 were evaluated using the conditioned place preference (CPP) paradigm in mice and the self-administration (SA) procedure in rats. Both DOC and AH-7921 increased the preference for the drug-paired compartment in the CPP test at a dose of 0.3 mg/kg and increased the number of responses to the active lever in the SA test at 0.01 mg/(kg·infusion). Collectively, the data suggest that DOC and AH-7921 may have both rewarding and reinforcing effects. Further studies are needed to confirm the reinforcing effects in broader dose ranges with various schedules.

Locomotor and discriminative stimulus effects of four novel hallucinogens in rodents.

There has been increasing use of novel synthetic hallucinogenic compounds, 2-(4-bromo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25B-NBOMe), 2-(4-chloro-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25C-NBOMe), 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine hydrochloride (25I-NBOMe), and N,N-diallyl-5-methoxy tryptamine (5-MeO-DALT), which have been associated with severe toxicities. These four compounds were tested for discriminative stimulus effects similar to a prototypical hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) and the entactogen (±)-3,4-methylenedioxymethamphetamine (MDMA). Locomotor activity in mice was tested to obtain dose range and time-course information. 25B-NBOMe, 25C-NBOMe, and 25I-NBOMe decreased locomotor activity. 5-MeO-DALT dose dependently increased locomotor activity, with a peak at 10 mg/kg. A higher dose (25 mg/kg) suppressed activity. 25B-NBOMe fully substituted (≥80%) in both DOM-trained and MDMA-trained rats at 0.5 mg/kg. However, higher doses produced much lower levels of drug-appropriate responding in both DOM-trained and MDMA-trained rats. 25C-NBOMe fully substituted in DOM-trained rats, but produced only 67% drug-appropriate responding in MDMA-trained rats at doses that suppressed responding. 25I-NBOMe produced 74-78% drug-appropriate responding in DOM-trained and MDMA-trained rats at doses that suppressed responding. 5-MeO-DALT fully substituted for DOM, but produced few or no MDMA-like effects. All of the compounds, except 25I-NBOMe, fully substituted for DOM, whereas only 25B-NBOMe fully substituted for MDMA. However, the failure of 25I-NBOMe to fully substitute for either MDMA or DOM was more likely because of its substantial rate-depressant effects than weak discriminative stimulus effects. All of the compounds are likely to attract recreational users for their hallucinogenic properties, but probably of much less interest as substitutes for MDMA. Although no acute adverse effects were observed at the doses tested, the substantial toxicities reported in humans, coupled with the high likelihood for illicit use, suggests that these compounds have the same potential for abuse as other, currently scheduled compounds.

Abuse potential of methylenedioxymethamphetamine (MDMA) and its derivatives in zebrafish: role of serotonin 5HT2-type receptors.

RATIONALE: The synthetic phenethylamines are recreational drugs known to produce psychostimulant effects. However, their abuse potential has not been widely studied. OBJECTIVES: Here, we investigated the rewarding and the hallucinatory effects of 2,5-dimetoxy-4-bromo-amphetamine hydrobromide (DOB) and para-methoxyamphetamine (PMA) in comparison with the classical 3,4-methylenedioxymethamphetamine (MDMA). In addition, the role of serotonin 5-HT2-like receptor on the abovementioned effects was evaluated. METHODS: Zebrafish were intramuscularly (i.m.) treated with a wide range of doses of DOB (0.1-20 mg/kg), PMA (0.0005-2 mg/kg), or MDMA (0.5-160 mg/kg). Animals were submitted to a conditioned place preference (CPP) task, to investigation of the rewarding properties, and to the evaluation of hallucinatory behavior in terms of appearance of a trance-like behavior. The serotonin 5-HT2 subtype receptor antagonist ritanserin (0.025-2.5 mg/kg) in association with the maximal effective dose of MDMA, DOB, and PMA was given i.m., and the effect on CPP or hallucinatory behavior was evaluated. RESULTS: MDMA and its derivatives exhibited CPP in a biphasic fashion, being PMA the most potent. This effect was accompanied, for DOB (2 mg/kg) and PMA (0.1 mg/kg), by a trance-like hallucinatory behavior. MDMA at a high dose as 160 mg/kg did not induce any hallucinatory behavior. Ritanserin significantly blocked the rewarding and hallucinatory effects suggesting the involvement of serotonin 5HT2 subtype receptor. CONCLUSION: Collectively, these findings demonstrate for the first time that the rewarding properties of DOB and PMA are accompanied by hallucinatory behavior through a serotonergic system and reinforce zebrafish as an emerging experimental model for screening new hallucinogens.

Locomotor, discriminative stimulus, and place conditioning effects of MDAI in rodents.

5,6-Methylenedioxy-2-aminoindane (MDAI) has become a common substitute for (±)-3,4-methylenedioxymethamphetamine (MDMA) in Ecstasy. MDAI is known to produce MDMA-like discriminative stimulus effects, but it is not known whether MDAI has psychostimulant or hallucinogen-like effects. MDAI was tested for locomotor stimulant effects in mice and subsequently for discriminative stimulus effects in rats trained to discriminate cocaine (10 mg/kg, intraperitoneally), methamphetamine (1 mg/kg, intraperitoneally), ±MDMA (1.5 mg/kg, intraperitoneally), or (-)-2,5-dimethoxy-4-methylamphetamine hydrochloride (0.5 mg/kg, intraperitoneally) from saline. The ability of MDAI to produce conditioned place preference was also tested in mice. MDAI (3 to 30 mg/kg) depressed locomotor activity from 10 to 60 min. A rebound stimulant effect was observed at 1 to 3.5 h following 30 mg/kg. Lethality occurred in 8/8 mice following 100 mg/kg MDAI. Similarly, MDMA depressed locomotor activity immediately following the administration of 0.25 mg/kg and stimulant effects were observed 50-70 min following the administration of 0.5 and 1 mg/kg. MDAI fully substituted for the discriminative stimulus effects of MDMA (2.5 mg/kg), (-)-2,5-dimethoxy-4-methylamphetamine hydrochloride (5 mg/kg), and cocaine (7.5 mg/kg), but produced only 73% methamphetamine-appropriate responding at a dose that suppressed responding (7.5 mg/kg). MDAI produced tremors at 10 mg/kg in one methamphetamine-trained rat. MDAI produced conditioned place preference from 0.3 to 10 mg/kg. The effects of MDAI on locomotor activity and drug discrimination were similar to those produced by MDMA, having both psychostimulant-like and hallucinogen-like effects; thus, MDAI may have similar abuse potential as MDMA.

Directly Observable Behavioral Effects of Lorcaserin in Rats.

(1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (lorcaserin) is approved by the United States Food and Drug Administration for treating obesity, and its therapeutic effects are thought to result from agonist activity at serotonin (5-HT)2C receptors. Lorcaserin has affinity for other 5-HT receptor subtypes, although its activity at those subtypes is not fully described. The current study compared the behavioral effects of lorcaserin (0.0032-32.0 mg/kg) to the effects of other 5-HT receptor selective agonists in rats (n = 8). The 5-HT2C receptor selective agonist 1-(3-chlorophenyl)piperazine (mCPP, 0.032-1.0 mg/kg) and lorcaserin induced yawning which was attenuated by the 5-HT2C receptor selective antagonist 6-chloro-5-methyl-N-(6-[(2-methylpyridin-3-yl)oxy]pydidin-3-yl)indoline-1-carboxamide (1.0 mg/kg). The 5-HT2A receptor selective agonist 2,5-dimethoxy-4-methylamphetamine (0.1-3.2 mg/kg) induced head twitching, which was attenuated by the 5-HT2A receptor selective antagonist R-(+)-2,3-dimethoxyphenyl-1-[2-(4-piperidine)-methanol] (MDL 100907, 0.01 mg/kg), lorcaserin (3.2 mg/kg), and mCPP (3.2 mg/kg). In rats pretreated with MDL 100907 (1.0 mg/kg), lorcaserin also induced head twitching. At larger doses, lorcaserin produced forepaw treading, which was attenuated by the 5-HT1A receptor selective antagonist N-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-N-(2-pyridyl)cyclohexanecarboxamide (0.178 mg/kg). While the behavioral effects of lorcaserin in rats are consistent with it having agonist activity at 5-HT2C receptors, these data suggest that at larger doses it also has agonist activity at 5-HT2A and possibly 5-HT1A receptors. Mounting evidence suggests that 5-HT2C receptor agonists might be effective for treating drug abuse. A more complete description of the activity of lorcaserin at 5-HT receptor subtypes will facilitate a better understanding of the mechanisms that mediate its therapeutic effects.

Pharmacological modulation of abnormal involuntary DOI-induced head twitch response movements in male DBA/2J mice: II. Effects of D3 dopamine receptor selective compounds.

We recently reported on the characterization of the hallucinogen 2,5-dimethoxy-4-methylamphetamine's (DOI) ability to elicit a head twitch response (HTR) in DBA/2J mice and the ability of D2 vs. D3 dopamine receptor selective compounds to modulate that response. For these studies, the ability of D3 vs. D2 dopamine receptor selective compounds to attenuate the DOI-dependent HTR was examined. WC 10, a D3 dopamine receptor weak partial agonist with 40-fold binding selectivity for D3 vs. D2 dopamine receptors, produced a dose-dependent decrease in the DOI-induced HTR (IC50 = 3.7 mg/kg). WC 44, a D3 receptor selective full agonist, also inhibited the DOI-induced HTR (IC50 = 5.1 mg/kg). The effect of two D3 receptor selective partial agonists, LAX-4-136 and WW-III-55, were also evaluated. These analogs exhibit 150-fold and 800-fold D3 vs. D2 binding selectivity, respectively. Both compounds inhibited the HTR with similar potency but with different maximum efficacies. At 10 mg/kg WW-III-55 inhibited the HTR by 95%, while LAX-4-136 administration resulted in a 50% reduction. In addition, DOI (5 mg/kg) was administered at various times after LAX-4-136 or WW-III-55 administration to compare the duration of action. The homopiperazine analog LAX-4-136 exhibited greater stability. An assessment of our test compounds on motor performance and coordination was performed using a rotarod test. None of the D3 dopamine receptor selective compounds significantly altered latency to fall, suggesting that these compounds a) did not attenuate the DOI-dependent HTR due to sedative or adverse motor effects and b) may have antipsychotic/antihallucinogenic activity.

Tolerance to LSD and DOB induced shaking behaviour: differential adaptations of frontocortical 5-HT(2A) and glutamate receptor binding sites.

Serotonergic hallucinogens, such as lysergic acid diethylamide (LSD) and dimethoxy-bromoamphetamine (DOB), provoke stereotype-like shaking behaviour in rodents, which is hypothesised to engage frontocortical glutamate receptor activation secondary to serotonin2A (5-HT2A) related glutamate release. Challenging this hypothesis, we here investigate whether tolerance to LSD and DOB correlates with frontocortical adaptations of 5-HT2A and/or overall-glutamate binding sites. LSD and DOB (0.025 and 0.25 mg/kg, i.p.) induce a ketanserin-sensitive (0.5 mg/kg, i.p., 30-min pretreatment) increase in shaking behaviour (including head twitches and wet dog shakes), which with repeated application (7× in 4 ds) is undermined by tolerance. Tolerance to DOB, as indexed by DOB-sensitive [(3)H]spiroperidol and DOB induced [(35)S]GTP-gamma-S binding, is accompanied by a frontocortical decrease in 5-HT2A binding sites and 5-HT2 signalling, respectively; glutamate-sensitive [(3)H]glutamate binding sites, in contrast, remain unchanged. As to LSD, 5-HT2 signalling and 5-HT2A binding, respectively, are not or only marginally affected, yet [(3)H]glutamate binding is significantly decreased. Correlation analysis interrelates tolerance to DOB to the reduced 5-HT2A (r=.80) as well as the unchanged [(3)H]glutamate binding sites (r=.84); tolerance to LSD, as opposed, shares variance with the reduction in [(3)H]glutamate binding sites only (r=.86). Given that DOB and LSD both induce tolerance, one correlating with 5-HT2A, the other with glutamate receptor adaptations, it might be inferred that tolerance can arise at either level. That is, if a hallucinogen (like LSD in our study) fails to induce 5-HT2A (down-)regulation, glutamate receptors (activated postsynaptic to 5-HT2A related glutamate release) might instead adapt and thus prevent further overstimulation of the cortex.

Identification and quantitation of 4-bromo-2,5-dimethoxyamphetamine in seized blotters.

Blotters are usually impregnated with hallucinogens such as lysergic acid diethylamide (LSD); only rarely other psychoactive substances are detected. In this work we identified 4-bromo-2,5-dimethoxyamphetamine (DOB) and 2,5-dimethoxyamphetamine (DMA) in illicit blotters seized in Italy. This report describes a rapid method for the simultaneous identification and quantitation of DOB and its precursor (DMA) by liquid chromatography tandem mass spectrometry (LC-MS-MS), using 2,3-dimethoxyphenethylamine-d3 as internal standard. Regression equations were linear over the tested concentration range with good correlation coefficients. The achieved levels of sensitivity may be suitable to confirm the possible presence of DOB and DMA also in low concentration or in traces in seized material for forensic analysis. The developed method showed good reproducibility and sensitivity, and could be used for similar routine analysis. To our knowledge, this is the first report describing the detection of DOB and DMA from blotters.

A fatal intoxication of 2,5-dimethoxy-4-chloroamphetamine: a case report.

Designer drugs appear to be increasing in popularity because of the ease of obtaining these constituents, the lack of ability to identify the substance(s) in routine drug screening, the appeal of the drug(s) being 'safe' due to them being marketed as a 'legal high' and possibly due to stronger restrictions that are being placed on prescription drugs. As components of designer drugs are identified and regulated by the DEA, new constituents, or analogs, of these designer drugs are being manufactured to circumvent legislation. 2,5-Dimethoxy-4-chloroamphetamine (DOC) is a substituted alpha-methylated phenethylamine and acts as a selective serotonin receptor partial agonist. There is limited literature on this particular compound and no literature that attributes death to use of this drug alone. We present a case of a 37-year-old male found at home lying face down next to a book titled 'Psychedelic Chemistry' by Michael Valentine Smith and in the early stages of decomposition. The decedent was a known methamphetamine abuser. A peripheral blood sample collected at autopsy was sent to toxicology for routine analysis. Results yielded negative for the drugs of abuse classes on the enzyme-linked immunosorbent assay screen but was positive for DOC during routine GC-MS analysis. A urine sample collected at autopsy was subjected to a routine urine liquid/liquid analysis via GC-MS, and the specimen was positive for DOC. Quantification analyses showed DOC concentration levels to be 377 ng/mL in iliac blood; 3,193 ng/mL in urine; 3,143 ng/g in liver and 683 ng/g in brain. DOC was not detected in the gastric contents. Caffeine was the only other compound detected in blood and urine. Due to the lack of literature, we believe that this is the first case where death can be attributed to DOC alone.

Restricted access to standard or high fat chow alters sensitivity of rats to the 5-HT(2A/2C) receptor agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane.

Feeding conditions can impact sensitivity to drugs acting on dopamine receptors; less is known about the impact of feeding conditions on the effects of drugs acting on serotonin (5-HT) receptors. This study examined the effects of feeding conditions on sensitivity to the direct-acting 5-HT(2A/2C) receptor agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM; 0.1-3.2 mg/kg) and the direct-acting dopamine D3/D2 receptor agonist quinpirole (0.0032-0.32 mg/kg). Male Sprague-Dawley rats had free access (11 weeks), followed by restricted access (6 weeks), to high fat (34.3%, n=8) or standard (5.7% fat; n=7) chow. Rats eating high fat chow became insulin resistant and gained more weight than rats eating standard chow. Free access to high fat chow did not alter sensitivity to DOM-induced head twitch but increased sensitivity to quinpirole-induced yawning. Restricting access to high fat or standard chow shifted the DOM-induced head twitch dose-response curve to the right and shifted the quinpirole-induced yawning dose-response curve downward in both groups of rats. Some drugs of abuse and many therapeutic drugs act on 5-HT and dopamine systems; these results show that feeding conditions impact sensitivity to drugs acting on these systems, thereby possibly affecting vulnerability to abuse, as well as the therapeutic effectiveness of drugs.

Effects of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) and quipazine on heroin self-administration in rhesus monkeys.

RATIONALE: The serotonin (5-HT) system is involved in pain modulation, and 5-HT receptor agonists can enhance antinociceptive effects of mu opioid receptor agonists. Less is known about the actions of 5-HT receptor agonists on other effects of opioids. OBJECTIVE: This study examined the effects of non-contingent and contingent administration of the 5-HT(2A) receptor agonists DOM and quipazine on i.v. heroin self-administration in rhesus monkeys. RESULTS: Heroin (0.0001-0.1 mg/kg/infusion) generated an inverted U-shaped dose-response function. Non-contingent administration of DOM (0.1-0.32 mg/kg) flattened the dose-response function in three monkeys and eliminated heroin self-administration in a fourth monkey. Contingent DOM (0.0032-0.032 mg/kg/infusion) alone did not maintain responding above that maintained by saline, and, when added to self-administered heroin, monkeys responded less than for the same unit doses of heroin alone. Non-contingent (0.32-3.2 mg/kg) and contingent (0.0032-0.56 mg/kg/infusion) administration of quipazine flattened the dose-response function in two monkeys, increasing responding maintained by small unit doses of heroin and saline, but failed to enhance responding for heroin in two other monkeys. CONCLUSION: This study shows that DOM does not enhance, and might attenuate, the positive reinforcing effects of the mu opioid receptor agonist heroin. Quipazine increased responding for saline and small doses of heroin; those effects were modest and observed in only two subjects. Taken together, these data suggest that 5-HT(2A) receptor agonists do not significantly enhance the reinforcing effectiveness of mu opioid receptor agonists and support the view that administering 5-HT drugs in combination with opioids to treat pain might not enhance abuse liability.

Discriminative stimulus effects of N,N-diisopropyltryptamine.

RATIONALE: Serotonergic hallucinogens such as (+)-lysergic acid diethylamide (LSD) and dimethyltryptamine (DMT) produce distinctive visual effects, whereas the synthetic hallucinogen N,N-diisopropyltryptamine (DiPT) is known for its production of auditory distortions. OBJECTIVE: This study compares the discriminative stimulus effects of DiPT to those of visual hallucinogens. METHODS: Adult male rats were trained to discriminate DiPT (5 mg/kg, 15 min) from saline under a FR10 schedule. A dose-effect and time course of DiPT's discriminative stimulus effects were established. DMT, (-)-2,5-dimethoxy-4-methylamphetamine (DOM), LSD, (±)-methylenedioxymethamphetamine (MDMA), and (+)-methamphetamine were tested for cross-substitution in DiPT-trained animals. RESULTS: Rats learned to discriminate DiPT from saline in an average of 60 training sessions (30 drug and 30 saline). DiPT (0.5-5 mg/kg) produced dose-dependent increases in drug-appropriate responding (DAR) to 99 % (ED(50) = 2.47 mg/kg). Onset of the discriminative stimulus effects was within 5 min, and the effects dissipated within 4 h. Full substitution for the discriminative stimulus effects of DiPT occurred with LSD, DOM, and MDMA. DMT only partially substituted for DiPT (65 % DAR), whereas (+)-methamphetamine failed to substitute for DiPT (29 % DAR). CONCLUSIONS: The discriminative stimulus effects of DiPT were similar those of a number of synthetic hallucinogens, only partially similar to those of DMT, but not similar to (+)-methamphetamine. The putative DiPT-induced auditory distortions do not lead to discriminative stimulus effects distinguishable from other hallucinogens.

GC-MS and GC-IRD studies on brominated dimethoxyamphetamines: regioisomers related to 4-Br-2,5-DMA (DOB).

A series of regioisomeric bromodimethoxyamphetamines have mass spectra essentially equivalent to the controlled drug substance 4-Br-2,5-dimethoxyamphetamine (4-Br-2,5-DMA; DOB); all have molecular weight of 274 and major fragment ions in their electron ionization mass spectra at m/z 44 and m/z 230/232. The trifluoroacetyl, pentafluoropropionyl and heptafluorobutryl derivatives of the primary regioisomeric amines were prepared and evaluated in gas chromatography-mass spectrometry (GC-MS) studies. The mass spectra for these derivatives did not show unique fragment ions for specific identification of individual isomers. However, the mass spectra do serve to divide the compounds into three groups, depending on their base peak. Gas chromatography with infrared detection (GC-IRD) provides direct confirmatory data for the identification of the designer drug 4-bromo-2,5-dimethoxyamphetamine from the other regioisomers involved in the study. The perfluoroacylated derivatives of the six regioisomeric bromodimethoxyamphetamines were successfully resolved on non-polar stationary phases such as a 100% dimethylpolysiloxane stationary phase (Rtx-1) and 50% phenyl - 50% methyl polysiloxane (Rxi-50).