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Psychol Res Behav Manag. 2013 Aug 27;6:65-74. doi: 10.2147/PRBM.S47526.
Influence of methylphenidate treatment assumptions on cognitive function in healthy young adults in a double-blind, placebo-controlled trial.
Mommaerts JL, Beerens G, Van den Block L, Soetens E, Schol S, Van De Vijver E, Devroey D.
Department of Family Medicine, Vrije Universiteit Brussel, Belgium.
Increasing numbers of students use stimulants such as methylphenidate (MPH) to improve their study capacity, making them prone to subsequent prolonged drug abuse. This study explored the cognitive effects of MPH in students who either assumed they received MPH or assumed they received a placebo.
[...]
RESULTS:

No significant differences were found between those subjects who received MPH and those who received a placebo. However, significant differences were found between subjects who assumed they had received MPH or had no opinion, and those who assumed they had received a placebo. At three minutes, one hour, and one day after memorizing ten lists of 20 words, those who assumed they had received MPH recalled 54%, 58%, and 54% of the words, respectively, whereas those who assumed they had received placebo only recalled 35%, 37%, and 34%.

CONCLUSION:

Healthy, partially sleep-deprived young students who assume they have received 20 mg of MPH experience a substantial placebo effect that improves consolidation of information into long-term memory. This is independent of any pharmacologic effects of MPH, which had no significant effects on verbal memory in this study. This information may be used to dissuade students from taking stimulants such as MPH during examination periods, thus avoiding subsequent abuse and addiction.
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So in laymans terms: Ritalin is just an active placebo. Not a smart drug.
 
Right, but this is a pretty restrictive operationalization of "cognitive enhancer", and the measure they chose, encoding of new long term memories, is something that classical stimulants seem to hinder. Then again, classical stimulants seem to show cognitive enhancement only with very specific measures (centering on vigilance and STM management), not translating well to everyday learning and cognitive processing.

ebola
 
ebola? said:
encoding of new long term memories, is something that classical stimulants seem to hinder
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I'm going to be fascinated to see what effects PRL-8-53 has on that, once it hits the RC noots market soon: en.wikipedia.org/wiki/PRL-8-53

Too bad it has barely been formally studied, but it certainly appears to have the most effect on people with somewhat naturally impaired memories.
 
sekio said:
Psychol Res Behav Manag. 2013 Aug 27;6:65-74. doi: 10.2147/PRBM.S47526.
Influence of methylphenidate treatment assumptions on cognitive function in healthy young adults in a double-blind, placebo-controlled trial.
Mommaerts JL, Beerens G, Van den Block L, Soetens E, Schol S, Van De Vijver E, Devroey D.
Department of Family Medicine, Vrije Universiteit Brussel, Belgium.


So in laymans terms: Ritalin is just an active placebo. Not a smart drug.
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I'm not saying the conclusion is wrong. But if you were going to write an academic article on the matter you'd need a lot more evidence. What I'm saying is that doesn't prove its more likely than not Ritalin is just an active placebo.
 
5-(2-Aminopropyl)indole (5-IT): a psychoactive substance used for recreational purposes is an inhibitor of human monoamine oxidase (MAO)

5-(2-Aminopropyl)indole (5-IT) is a psychoactive compound that has recently been associated with several fatal and non-fatal intoxications in a number of European countries. There are indications that acute effects may include symptoms of monoaminergic (e.g. serotonin) toxicity and one mechanism involved in the increase of serotonin levels includes the inhibition of monoamine oxidase. This study investigated the effect of 5-IT on human MAO-A and -B isozymes using kynuramine as the substrate. Substrate conversion to 4-hydroxyquinoline was monitored by high-performance liquid chromatography coupled to diode array detection. This method was employed to determine the extent of MAO inhibition (IC50 and Ki) and it was found that 5-IT was a selective, competitive and reversible inhibitor of MAO-A. 5-IT revealed a relatively potent ability to inhibit MAO-A (IC50 = 1.6 μM and Ki = 0.25 μM) while MAO-B inhibition was not observed (0–500 μM 5-IT). Under identical experimental conditions, other established inhibitors of MAO-A and antidepressants provided the following IC50 values: clorgyline 16 nM, harmaline 20 nM, toloxatone 6.7 μM and moclobemide >500 μM. These data indicated that 5-IT was less potent than clorgyline and harmaline but more potent than toloxatone and moclobemide under the in-vitro conditions studied. The inhibition of MAO-A suggests that 5-IT by itself or in combination with other substances may be able to potentiate serotonergic/monoaminergic effects and further studies are needed to clarify its relevance to the adverse effects reported for 5-IT.
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The does explain its lethality in higher doses. However, the typical dose of harmaline is 150mg, yet in this study harmaline is reported as ~100x more potent. So in theory, productive MAO inhibition is not going to really manifest until at least the 500mg mark. Am I missing something?
 
It looks like those who took it to binge levels were in for a world of hurt/death. Too bad. :( Goes to show that maybe people need to approach very new compounds with Shulginesque dosing schedules until more research comes out.

ebola
 
Pharmacokinetic and pharmacodynamic effects of methylphenidate and MDMA administered alone or in combination
Cédric M. Hysek, Linda D. Simmler, Nathalie Schillinger, Nicole Meyer, Yasmin Schmid, Massimiliano Donzelli, Eric Grouzmann and Matthias E. Liechti
The International Journal of Neuropsychopharmacology
DOI: http://dx.doi.org/10.1017/S1461145713001132 (About DOI), Published online: 08 October 2013
Methylphenidate and 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’) are widely misused psychoactive drugs. Methylphenidate increases brain dopamine and norepinephrine levels by blocking the presynaptic reuptake transporters. MDMA releases serotonin, dopamine and norepinephrine through the same transporters. Pharmacodynamic interactions of methylphenidate and MDMA are likely. This study compared the pharmacodynamic and pharmacokinetic effects of methylphenidate and MDMA administered alone or in combination in healthy subjects using a double-blind, placebo-controlled, crossover design. Methylphenidate did not enhance the psychotropic effects of MDMA, although it produced psychostimulant effects on its own. The haemodynamic and adverse effects of co-administration of methylphenidate and MDMA were significantly higher compared with MDMA or methylphenidate alone. Methylphenidate did not change the pharmacokinetics of MDMA and vice versa. [...] In conclusion, the combined use of methylphenidate and MDMA does not produce more psychoactive effects compared with either drug alone, but potentially enhances cardiovascular and adverse effects. The findings may be of clinical importance for assessing the risks of combined psychostimulant misuse.
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Yay for human studies on psychoactives!
 
Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects
Molecular Psychiatry advance online publication 15 October 2013; doi: 10.1038/mp.2013.130
G Sanacora, M A Smith, S Pathak, H-L Su, P H Boeijinga, D J McCarthy and M C Quirk
Ketamine, an N-methyl-D-aspartate receptor (NMDAR) channel blocker, has been found to induce rapid and robust antidepressant-like effects in rodent models and in treatment-refractory depressed patients. However, the marked acute psychological side effects of ketamine complicate the interpretation of both preclinical and clinical data. Moreover, the lack of controlled data demonstrating the ability of ketamine to sustain the antidepressant response with repeated administration leaves the potential clinical utility of this class of drugs in question. Using quantitative electroencephalography (qEEG) to objectively align doses of a low-trapping NMDA channel blocker, AZD6765 (lanicemine), to that of ketamine, we demonstrate the potential for NMDA channel blockers to produce antidepressant efficacy without psychotomimetic and dissociative side effects. Furthermore, using placebo-controlled data, we show that the antidepressant response to NMDA channel blockers can be maintained with repeated and intermittent drug administration. Together, these data provide a path for the development of novel glutamatergic-based therapeutics for treatment-refractory mood disorders.
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Well I'll be damned. The rumors are true. Or at least, they appear to be.

The HIV Antiretroviral Drug Efavirenz has LSD-Like Properties
Neuropsychopharmacology (2013) 38, 2373–2384; doi:10.1038/npp.2013.135; published online 3 July 2013

Anecdotal reports have surfaced concerning misuse of the HIV antiretroviral medication efavirenz ((4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one) by HIV patients and non-infected teens who crush the pills and smoke the powder for its psychoactive effects. Molecular profiling of the receptor pharmacology of efavirenz pinpointed interactions with multiple established sites of action for other known drugs of abuse including catecholamine and indolamine transporters, and GABAA and 5-HT2A receptors. In rodents, interaction with the 5-HT2A receptor, a primary site of action of lysergic acid diethylamine (LSD), appears to dominate efavirenz’s behavioral profile. Both LSD and efavirenz reduce ambulation in a novel open-field environment. Efavirenz occasions drug-lever responding in rats discriminating LSD from saline, and this effect is abolished by selective blockade of the 5-HT2A receptor. Similar to LSD, efavirenz induces head-twitch responses in wild-type, but not in 5-HT2A-knockout, mice. Despite having GABAA-potentiating effects (like benzodiazepines and barbiturates), and interactions with dopamine transporter, serotonin transporter, and vesicular monoamine transporter 2 (like cocaine and methamphetamine), efavirenz fails to maintain responding in rats that self-administer cocaine, and it fails to produce a conditioned place preference. Although its molecular pharmacology is multifarious, efavirenz’s prevailing behavioral effect in rodents is consistent with LSD-like activity mediated via the 5-HT2A receptor. This finding correlates, in part, with the subjective experiences in humans who abuse efavirenz and with specific dose-dependent adverse neuropsychiatric events, such as hallucinations and night terrors, reported by HIV patients taking it as a medication.
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Is there anything else with a similar SAR? Lorcaserin came to mind but I just checked and it's very different. RH-34 was my second thought but that's also quite dissimilar.

150px-Efavirenz_skeletal.svg.png

Efavirenz
200px-Lorcaserin.svg.png

Lorcaserin
220px-RH-34_structure.png

RH-34
 
Reverend Random said:
Apparently, NMDA-agonists also show anti-depressant properties, similar to ketamine's NMDA antagonism. News article here, abstract here.
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It sounds like they're using a glycine transporter inhibitor rather than a direct NMDA agonist. I think a direct NMDA agonist would be fairly neurotoxic. Very exciting never the less.

Inhibition of Glycine Transporter-I as a Novel Mechanism for the Treatment of Depression
Background
Antidepressants, aiming at monoaminergic neurotransmission, exhibit delayed onset of action, limited efficacy, and poor compliance. Glutamatergic neurotransmission is involved in depression. However, it is unclear whether enhancement of the N-methyl-D-aspartate (NMDA) subtype glutamate receptor can be a treatment for depression.

Methods
We studied sarcosine, a glycine transporter-I inhibitor that potentiates NMDA function, in animal models and in depressed patients. We investigated its effects in forced swim test, tail suspension test, elevated plus maze test, novelty-suppressed feeding test, and chronic unpredictable stress test in rats and conducted a 6-week randomized, double-blinded, citalopram-controlled trial in 40 patients with major depressive disorder. Clinical efficacy and side effects were assessed biweekly, with the main outcomes of Hamilton Depression Rating Scale, Global Assessment of Function, and remission rate. The time course of response and dropout rates was also compared.

Results
Sarcosine decreased immobility in the forced swim test and tail suspension test, reduced the latency to feed in the novelty-suppressed feeding test, and reversed behavioral deficits caused by chronic unpredictable stress test, which are characteristics for an antidepressant. In the clinical study, sarcosine substantially improved scores of Hamilton Depression Rating Scale, Clinical Global Impression, and Global Assessment of Function more than citalopram treatment. Sarcosine-treated patients were much more likely and quicker to remit and less likely to drop out. Sarcosine was well tolerated without significant side effects.

Conclusions
Our preliminary findings suggest that enhancing NMDA function can improve depression-like behaviors in rodent models and in human depression. Establishment of glycine transporter-I inhibition as a novel treatment for depression waits for confirmation by further proof-of-principle studies.
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Synthesis and Structure–Activity Relationships of N-Benzyl Phenethylamines as 5-HT2A/2C Agonists

http://pubs.acs.org/doi/abs/10.1021/cn400216u

<quote>N-Benzyl substitution of 5-HT2A receptor agonists of the phenethylamine structural class of psychedelics (such as 4-bromo-2,5-dimethoxyphenethylamine, often referred to as 2C-B) confer a significant increase in binding affinity as well as functional activity of the receptor. We have prepared a series of 48 compounds with structural variations in both the phenethylamine and N-benzyl part of the molecule to determine the effects on receptor binding affinity and functional activity at 5-HT2A and 5-HT2C receptors. The compounds generally had high affinity for the 5-HT2A receptor with 8b having the highest affinity at 0.29 nM but with several other compounds also exhibiting subnanomolar binding affinities. The functional activity of the compounds was distributed over a wider range with 1b being the most potent at 0.074 nM. Most of the compounds exhibited low to moderate selectivity (1- to 40-fold) for the 5-HT2A receptor in the binding assays, although one compound 6b showed an impressive 100-fold selectivity for the 5-HT2A receptor. In the functional assay, selectivity was generally higher with 1b being more than 400-fold selective for the 5-HT2A receptor</quote>
 
This article appears to be hot shit. When in search of selectivity for 5ht2a over 5ht2c and compounds that act more as partial agonists, it looks like there are some quite overlooked moieties. Let me give more elaborate commentary when I'm less high. ;)

ebola
 
Okay, so it looks like the cyano substitution at the 4 confers high selectivity for 5ht2a. And it looks like methylenedioxybenzyl (and to some extent, fluorobenzyl) confers partial agonism. So we know where to turn for increased safety. The nboh series seems super-similar to the prior nbomes, so the recent emergency scheduling essentially accomplished nothing.

PRL-8-53
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What an interesting compound. It looks like cholinergic enhancement is its most likely mechanism. I bet it would make for a good adjunct to stimulant use (ideally with reduced stimulant dosages).

ebola
 
Based upon back-of-the-napkin calculations, the NBOH's seem like overall "better" drugs from a pharmacokinetic point of view; the little bit of extra polarity from the OH means they will be eliminated a little faster.
 
mmm...I'm not sure whether this is good or bad, as the nbomes are hardly 'long-burners' already, and redosing with these compounds works particularly poorly. Sometimes, you just want something more enduring than, say, metocin, for example. Also, wouldn't we expect clearance to be mainly hepatic (via the same enzymes that metabolize benzphetamine)? Would increased polarity mainly increase the rate of clearance by the kidneys?

ebola
 
ebola? said:
mmm...I'm not sure whether this is good or bad, as the nbomes are hardly 'long-burners' already, and redosing with these compounds works particularly poorly. Sometimes, you just want something more enduring than, say, metocin, for example. Also, wouldn't we expect clearance to be mainly hepatic (via the same enzymes that metabolize benzphetamine)? Would increased polarity mainly increase the rate of clearance by the kidneys?

ebola
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Speaking of clearance. There is another paper out by the same group about metabolism of NBOMes

Correlating the Metabolic Stability of Psychedelic 5-HT2A Agonists with Anecdotal Reports of Human Oral Bioavailability

2,5-Dimethoxyphenethylamines and their N-benzylated derivatives are potent 5-HT2A agonists with psychedelic effects in humans. The N-benzylated derivatives are among the most selective 5-HT2A agonists currently available and their usage as biochemical and brain imaging tools is increasing, yet very little is known about the relationships between the structure of the ligands and their pharmacokinetic profile. In order to evaluate the potential of these compounds for in vivo applications we have determined the microsomal stability of 11 phenethylamines and 27 N-benzylated derivatives thereof using human liver microsomes. We found that the N-benzylated phenethylamines have much higher intrinsic clearance than the parent phenethylamines. We hypothesize that their low hepatic stability renders them orally inactive due to first pass metabolism, which is supported by anecdotal data from recreational use of these compounds.

http://dx.doi.org/10.1007/s11064-014-1253-y
 
J Clin Psychopharmacol. 2014 Feb 12. [Epub ahead of print]
Methylphenidate Enhances Cognitive Performance in Adults With Poor Baseline Capacities Regardless of Attention-Deficit/Hyperactivity Disorder Diagnosis.
Agay N, Yechiam E, Carmel Z, Levkovitz Y.
We compare the view that the effect of methylphenidate (MPH) is selective to individuals with attention-deficit/hyperactivity disorder (ADHD) with an alternative approach suggesting that its effect is more prominent for individuals with weak baseline capacities in relevant cognitive tasks. To evaluate theses 2 approaches, we administered sustained attention, working memory, and decision-making tasks to 20 ADHD adults and 19 control subjects, using a within-subject placebo-controlled design. The results demonstrated no main effects of MPH in the decision-making tasks. In the sustained attention and working-memory tasks, MPH enhanced performance of both ADHD and non-ADHD adults to a similar extent compared with placebo. Hence, the effect of MPH was not selective to ADHD adults. In addition, those benefitting most from MPH in all 3 task domains tended to be individuals with poor task performance. However, in most tasks, individuals whose performance was impaired by MPH were not necessarily better (or worse) performers. The findings suggest that the administration of MPH to adults with ADHD should consider not only clinical diagnosis but also their functional (performance-based) profile.
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More evidence that, maybe, stimulants are just good at making people task-oriented, rather than are a "treatment" for anything? I never really bought into the whole "stimulants effect people with AD(H)D differently"... given that, y'know, people in general experience drugs differently, and set and setting need to be considered. Also, given that stimulants like methylphenidate, amphetamine and the like precede the ADHD explosion, and have been known to enhance cognitive performance (in some contexts) for a long damn time.
 
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