Irreversibele MDMA tolerantie

Hashja schreef:Zeer interessante vraag.
Bij overstimulatie van teveel serotonine agonisten (en dus serotonine zelf) treed desensitisatie van receptoren op. Dit is een proces waarbij je hersenen proberen te compenseren voor het te veel aan signalen van de betreffende cel. Dit gebeurt door vermindering van receptoren van deze cel.
Dit zou ik als verklaring geven op jou vraag.

Petrovic schreef:Iets wat ik zelf merk maar ook veel van anderen lees is dat men na verloop van tijd steeds minder van de MDMA gaat merken. Ook al heeft iemand bijvoorbeeld al ruim een jaar geen MDMA genomen. Ook lees ik het bij mensen die zich altijd netjes aan de 3 maanden hebben gehouden.

Hieruit zou ik zelf toch zeggen dat MDMA toch echt wat met je hersenen doet terwijl ik toch ook best vaak lees dat er onderzoeken zijn die zeggen dat ze niets kunnen vinden.

Er zijn al zoveel onderzoeken uitgevoerd. Mijn vraag is; wat zijn de stand van zaken op dit moment over de schadelijkheid. Hoeveel studies zeggen dat het wel wat doet en hoeveel niet?

Drug tolerance often develops to some effects of a drug but not others. In fact, tolerance may develop to some effects of a drug while sensitivity to other effects of the same drug increases.

Drug tolerance is not a unitary phenomenon; that is, there is no single mechanism that underlies all examples of it. Two categories underlie drug tolerance: metabolic and functional. Drug tolerance that results from changes that reduce the amount of the drug getting to its site of action is called metabolic tolerance. Drug tolerance that results from changes that reduce the reactivity of the sites of action to the drug is called functional tolerance. Tolerance to psychoactive drugs is largely functional. Functional tolerance to psychoactive drugs can result from several different types of neural hanges. For example, exposure to a psychoactive drug can reduce the number receptors for it, decrease the efficiency with which it binds to existing receptors, or diminish the impact of receptor binding on the activity of the cell.

Contingent drug tolerance refers to demonstrations that tolerance develops only to drug effects that are actually experienced.

Conditioned drug tolerance refers to demonstrations that tolerance effects are maximally expressed only when a drug is administered in the same situation in which it has previously been administrated. There have been dozens of other demonstrations of the situational specificity of drug tolerance: The effect is large, reliable, and general. Addicts may be particularly susceptible to the lethal effects of a drug overdose when the drug is administered in a new context. Their hypothesis (Siegler and colleagues) is that addicts become tolerant when they repeatedly self-administer their drug in the same environment and, as a result, begin taking larger and larger doses to counteract the diminution of drug effects. Then, if the addict administers the usual massive dose in an unusual situation, tolerance effects are not present to counteract the effects of the drug, and there is a greater risk of death from overdose.

The central assumption of the theory is that conditional stimuli that predict drug administration come to elicit conditional responses opposite to the unconditional effect of the drug. (Conditioned compensatory responses). The theory is that as the stimuli that repeatedly predict the effects of a drug come to elicit greater and greater conditioned compensatory responses, they increasingly counteract the unconditional effects of the drug and produce situationally specific tolerance. For example both the feelings produced by the drug taking ritual and the first mild effects of the drug experienced soon after administration can, through conditioning, come to reduce the full impact of a drug (Siegel, 2005).

Do stimulants have long-term adverse effects on the health of habitual users? Mounting evidence suggests that stimulants are neurotoxins. Research has focused on the effects of MDMA because of its powerful effects. The results of experiments on nonhuman animals are cause for concern: There is good evidence from experiments on laboratory animals that MDMA can have toxic effects on both serotonergic and dopaminergic neurons (See McCann & Ricaurte, 2004). The question is whether the high doses used in these laboratory experiments are relevant to typical patterns of human use. In addition to the studies with laboratory animals, studies of human MDMA users have found reason for concern about the possibility of MDMA-produced brain damage (See Barr et al., 2006). Former users of MDMA have been found to have deficiencies in various measures of dopaminergic and serotonergic function, and they often display functional brain scan abnormalities in many areas of the cortex and limbic system during tests of executive functioning, inhibitory control, and decision making (See Aron & Paulus, 2007; Baicy & London, 2007; Chang et al., 2007; Volz, Fleckenstein, & Hanson, 2007). It still remains to be established whether these effects are permanent.

Hashja schreef:Het Trimbos kwam met een artikel dat je laaste quote ter discussie stelt.
http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2010.03252.x/full

Verder lijkt het me een interessant boek/artikel.

Findings: We found little evidence of decreased cognitive performance in ecstasy users, save for poorer strategic self-regulation, possibly reflecting increased impulsivity. However, this finding might have reflected a pre-morbid attribute of ecstasy users, rather than a residual neurotoxic effect of the drug.

Hashja schreef:Klopt wat je zegt, hier een quote uit dat artikel:

Findings: We found little evidence of decreased cognitive performance in ecstasy users, save for poorer strategic self-regulation, possibly reflecting increased impulsivity. However, this finding might have reflected a pre-morbid attribute of ecstasy users, rather than a residual neurotoxic effect of the drug.

Toch vond ik dit artikel wel discussie waardig materiaal.

Halpern et al. (2004) described some intriguing findings from a study of young ravers in Salt Lake City, where the prevailing religious beliefs have led to very low rates of tobacco, alcohol, cannabis or other illicit drug consumption. However, many of these ravers did use MDMA and, while moderate users were not cognitively impaired, high users (60–450 lifetime occasions) displayed significant deficits on many of the cognitive test measures, particularly those associated with processing speed, memory and impulsivity (Table 6.1).

These deficits remained even after controlling for a range of potential confounding factors. However, cognition and memory are not the only areas of psychobiological deficit. Regular Ecstasy/MDMA users have been reported to experience sleep impairments, eating disorders, reduced sexual functioning, phobic anxiety, depression, heightened impulsivity, aggressiveness and a range of occu- pational, health and financial problems (McCann et al., 2000; Parrott, 2000; Schifano et al., 1998; Schifano, 2000; Topp et al., 1999)

Many recreational users are fully aware of these problems. In a World Wide Web (WWW) study of 283 unpaid volunteers (Parrott et al., 2002), around 73% of the excessive Ecstasy users stated that they had experienced memory problems that they attributed to the use of Ecstasy, while many other problems were also reported (Table 6.2).

Life-time episodes of ecstasy use: 43.5

The standard approach is to compare drug users with non-users as controls; but, there are many problems with this design. The main one is that groups are self-selected and may differ in important characteristics related to the decision to use illicit drugs. It is often possible to measure or match groups on some of these factors: age, gender and socioeconomic background can all be measured fairly easily; and intellectual ability could be estimated by measures of school attainment or verbal comprehension tasks.

Although, both these measures may be affected by drug use. Similarly, a variety of personality questionnaires might be administered. However, even if the different groups were matched on a range of factors, it could be that they still differed a priori on some important but unassessed attributes.

Another problem is lack of control over drug administration. The standard approach is to ask subjects to recall which drugs they have taken; but, this raises the question of how accurate these estimates might be – particularly with heavy users. There is also the question of drug strength and purity, since illicit drug supplies can sometimes be quite variable (Parrott, 2004).

However, there are several ways in which the influence of these disparate factors could be investigated. For instance, it is often possible to statistically control for the influence of other psychoactive drugs, by multiple regression or partial correlation. Where this has been done the cognitive/memory deficits displayed by Ecstasy users still remain (Verkes et al., 2001).

While current evidence suggests a profile of specific cognitive deficits in regular MDMA users, a number of important questions remain, nevertheless. How much MDMA needs to be taken before problems develop? The answer would seem to be not a lot (Halpern et al., 2004). Is there evidence for neural recovery once drug taking has stopped? Morgan et al. (2002) suggested that psychobiological problems recovered whereas selective memory deficits remained. Another core topic is the contributory role of high tempera- ture. Animal studies have shown that neuronal toxicity is heightened when rats are allowed to become hyperthermic; this raises the question of whether neurotoxicity also develops most in those recreational Ecstasy users who become overheated (McCann et al., 2000; Parrott, 2000, 2002; Ricaurte et al., 2000).

MDMA/Ecstasy and neurotoxicity
One of the main concerns about MDMA is the laboratory animal data demonstrating that it is neurotoxic. In rats and monkeys, brain levels of serotonin are reduced by repeated doses of MDMA, a finding replicated in numerous studies (e.g., Steele et al., 1994), while there is also evidence for dopaminergic nerve damage (Ricaurte et al., 2002).

The main effect is destruction of serotonin nerve axons in the cerebral cortex and other higher brain areas. The cell bodies in the dorsal raphe nucleus of the brainstem are spared, whereas the prolonged axon terminals and distal projections are destroyed, leading to reduced serotonin activity in the higher brain regions. Thus, there is concern over whether higher brain functions, such as information storage and retrieval, complex stimulus analysis and decision taking, might be impaired. Many other brain regions are also affected, including the hypothalamus and suprachiasmatic nucleus, areas that subserve temperature regulation, feeding behaviour and biological rhythms.

The data from laboratory animals administered MDMA raises the possibility that recreational Ecstasy may also be neurotoxic for humans. It is not possible to investigate this hypothesis directly (see below), but there is a great deal of evidence for serotonergic damage in recreational Ecstasy users. Drug-free, regular MDMA users demonstrate reduced serotonin neural activity in the cerebral cortex in PET (positron emission tomography) scans, reduced levels of cerebrospinal 5-HIAA, or hydroxyindoleacetic acid (the main serotonin metabolite) and other indices of reduced serotonin activity (McCann et al., 2000; Reneman et al., 2001).

Regular Ecstasy users display significant deficits in a number of psychobiological functions subserved by serotonin. The most thoroughly studied area is memory, and significant deficits in abstinent Ecstasy users have been found on a wide range of episodic and working memory tasks (Fox et al., 2002; Rodgers et al., 2001; Verkes et al., 2001; see Table 6.1). Deficits have also been found in some measures of cognitive planning and higher executive processing, although many basic cognitive functions remain unimpaired.

Findings We found little evidence of decreased cognitive performance in ecstasy users, save for poorer strategic self-regulation, possibly reflecting increased impulsivity. However, this finding might have reflected a pre-morbid attribute of ecstasy users, rather than a residual neurotoxic effect of the drug.

MDMA/Ecstasy and neurotoxicity
One of the main concerns about MDMA is the laboratory animal data demonstrating that it is neurotoxic. In rats and monkeys, brain levels of serotonin are reduced by repeated doses of MDMA, a finding replicated in numerous studies (e.g., Steele et al., 1994), while there is also evidence for dopaminergic nerve damage (Ricaurte et al., 2002).

However, even if the different groups were matched on a range of factors, it could be that they still differed a priori on some important but unassessed attributes.

Ecstasy may also be neurotoxic for humans. (...) Deficits have also been found in some measures of cognitive planning and higher executive processing, although many basic cognitive functions remain unimpaired.

The main effect is destruction of serotonin nerve axons in the cerebral cortex and other higher brain areas. The cell bodies in the dorsal raphe nucleus of the brainstem are spared, whereas the prolonged axon terminals and distal projections are destroyed, leading to reduced serotonin activity in the higher brain regions.

Hashja schreef:Maar in ieder geval.
Zoals jou studie ook al aangeeft is het moeilijk te zeggen omdat er verschillende factoren zijn waar men van denkt dat het van belang is maar die ze niet vast hebben staan.
Wat ik vooral uit deze artikelen opmaak is dat het simpel weg lastig is vast te stellen wanneer en hoeveel schade er optreed. Zie quotes:
[snip]
Ze tonen wel bewijzen van hersenschade in proefdieren die veel MDMA binnen krijgen, maar blijven gissen naar menselijke hersenschade omdat ze dit niet goed kunnen testen/meten.

However, there are several ways in which the influence of these disparate factors could be investigated. For instance, it is often possible to statistically control for the influence of other psychoactive drugs, by multiple regression or partial correlation. Where this has been done the cognitive/memory deficits displayed by Ecstasy users still remain (Verkes et al., 2001).

Hashja schreef:En hier nog iets wat ik niet helemaal snap. Ze hebben over destructie van de axon van de serotonine hersencellen. Bedoelen ze hier de desensitisatie mee (vermindering van receptoren), zenuw beschadiging (verstoring van signaal overdracht) of daadwerkelijke cel dood?

The main effect is destruction of serotonin nerve axons in the cerebral cortex and other higher brain areas. The cell bodies in the dorsal raphe nucleus of the brainstem are spared, whereas the prolonged axon terminals and distal projections are destroyed, leading to reduced serotonin activity in the higher brain regions.

Ik vind het in ieder geval een interessante discussie.