Neurotoxicity of drugs when taken infrequently?

[jjacobsen]

Does anyone have any information / links about the long-term effects on the brain of various drugs? I find the information so elusive, particularly for infrequent users. Almost every study I read about the long term effects on the brain of drugs such as methamphetamines and heroin, is studying those who are using every day (or close to) for a period of years. Are there any studies on the neurotoxicity of using these drugs, say, once a month?
I for example, have either snorted or IV'd methamphetamine at a rate of approximatley every three months for the last 4 years, and would like to know how that effects my brain.
Thanks for your time.

 

[LuxEtVeritas]

it would of course depend upon how abusive the acute usage was, but likely you have not in any meaningful way harmed your brain

 

[mindtools]

As I know, for most drugs (probably some stimulants like meth or crack are not the ones I'm taling about) the effects of rare usage are quite minimal. But if someone can find some good studies about it, I would be grateful

 

[nuke]

Acute injections of methamphetamine usually always cause neurotoxicity if I remember right.

The neurotoxic effects of a single administration of methamphetamine (MA) were studied under conditions conducive to MA-induced hyperthermia. After a single dose of MA (10, 20, 30, or 40 mg/kg, s.c.) or saline (3 ml/kg) to Sprague–Dawley CD rats, rectal temperatures were monitored for 9 h in a room with an ambient temperature of 22.0±0.5°C. MA induced significant dose-dependent hyperthermia, however, no significant increase in mortality occurred. Neostriatal DA, 5-HT, TH, and GFAP were assayed 3 days following treatment. MA induced dose-dependent reductions of DA, 5-HT and TH, and increased GFAP. For DA, at doses of 20, 30, or 40 mg/kg the reductions were to 71%, 49%, and 29%, and for 5-HT were to 73%, 44%, and 19% of control values. No reductions were seen after the 10 mg/kg dose. Semiquantitative analysis Western blots of TH and GFAP demonstrated that TH was reduced to 52%, 75%, and 28%, and GFAP was increased to 125%, 134%, and 149% of control values at MA doses of 20, 30, or 40 mg/kg, respectively. No significant changes in TH or GFAP were seen at the 10 mg/kg MA dose. These results demonstrate that a single-dose of MA can be as effective as the widely used four-dose every 2 h regimen. Moreover, mortality can be minimized by monitoring core body temperature and preventing MA-induced hyperthermia from exceeding 41.5°C.

This is difficult data to extrapolate to humans though... I don't think 700mg (10mg/kg) is a small dose for a human, but it could be a whole lot less, however this is subcutaneous so it's probably less.

However, there is also this study:

The results of the present study indicate that doses of methamphetamine
on the order of those used recreationally by some
humans (see below) produce lasting effects on brain DA axonal
markers in baboons. Furthermore, the present results indicate
that PET imaging with [ 11C]WIN-35,428 is suitable for detecting
partial methamphetamine-induced reductions in brain DAT in
living nonhuman primates. Together, these findings suggest that
PET imaging with [ 11C]WIN-35,428 will be useful for evaluating
humans for possible methamphetamine-induced DA neurotoxicity,
and they raise further concerns about the neurotoxic potential
of methamphetamine in humans.

Surprisingly, methamphetamine produced long-term decreases
on brain DA axonal markers in baboons at all doses tested,
including the 0.5 mg/kg dose (Fig. 1, Tables 1–3). These results
confirm and extend those of Melega and colleagues (1993) who
observed decreases in 6-[ 18F]fluoro-DOPA uptake in vervet monkeys
injected with 4 mg/kg amphetamine (two injections of 2
mg/kg, i.m.) 1 week and 1 month previously. Using interspecies
scaling methods (Harwood, 1963; Mordenti and Chappell, 1989;
Chappell and Mordenti, 1991), it is possible to estimate equivalent
doses in humans by taking into account known relationships
between body mass and surface area. When this is done for the
two lower doses of methamphetamine used in the present study
(0.5 and 1 mg/kg), the equivalent human doses (for an individual
weighing 70 kg) are 26 and 52 mg, respectively. These doses are
well within the range of those reported to be used by human
methamphetamine users on a repeated basis (Jaffe, 1985;
Konuma, 1994), particularly after tolerance has developed
(Kalant, 1966; Kramer et al., 1967; Lukas, 1997). The notion that
only extraordinarily high doses of methamphetamine can produce
DA neurotoxicity needs to be reconsidered, at least in primates
exposed to repeated doses of methamphetamine.

http://www.jneurosci.org/cgi/reprint/18/1/419.pdf

So, it appears primates are many folds more sensitive to the neurotoxicity of METH compared to rodents. Not even that, but the above states that even high doses of amphetamines may be toxic.

 

[jjacobsen]

thanks Nuke, that helps. Any similar info for heroin, cocaine, or LSD?

 

[Synesthesia]

I too am curious about the neurotoxicity of opiates, regarding both frequent and infrequent use. I had always believed them them to be fairly benign in regards to nuerotoxicity.

 

[nuke]

thanks Nuke, that helps. Any similar info for heroin, cocaine, or LSD?

LSD is not neurotoxic, though it increases the amounts of certain growth factors in some areas of the brain while decreasing the amount in others.

Heroin and cocaine are not really known for their neurotoxicity, however because much street heroin contains morphine, and heroin can metabolize to morphine, which is known to exhibit neurotoxicity. Acute, non-repetitive use of either drug is probably unlikely to exhibit any amount of measurable neurotoxicty, I would think, but heroin hasn't really been studied nearly as extensively as MDMA or METH.

Street heroin induces mitochondrial dysfunction and apoptosis in rat cortical neurons.
Cunha-Oliveira T, Rego AC, Garrido J, Borges F, Macedo T, Oliveira CR.

Institute of Biochemistry, University of Coimbra, Coimbra, Portugal.

Cortical function has been suggested to be highly compromised by repeated heroin self-administration. We have previously shown that street heroin induces apoptosis in neuronal-like PC12 cells. Thus, we analysed the apoptotic pathways involved in street heroin neurotoxicity using primary cultures of rat cortical neurons. Our street heroin sample was shown to be mainly composed by heroin, 6-monoacetylmorphine and morphine. Exposure of cortical neurons to street heroin induced a slight decrease in metabolic viability, without loss of neuronal integrity. Early activation of caspases involved in the mitochondrial apoptotic pathway was observed, culminating in caspase 3 activation, Poly-ADP Ribose Polymerase (PARP) cleavage and DNA fragmentation. Apoptotic morphology was completely prevented by the non-selective caspase inhibitor z-VAD-fmk, indicating an important role for caspases in neurodegeneration induced by street heroin. Ionotropic glutamate receptors, opioid receptors and oxidative stress were not involved in caspase 3 activation. Interestingly, street heroin cytotoxicity was shown to be independent of a functional mitochondrial respiratory chain, as determined using NT-2 rho(0) cells. Nonetheless, in street heroin-treated cortical neurons, cytochrome c was released, accompanied by a decrease in mitochondrial potential and Bcl-2/Bax. Pure heroin hydrochloride similarly decreased metabolic viability but only slightly activated caspase 3. Altogether, our data suggest an important role for mitochondria in mediating street heroin neurotoxic effects.

http://www.ncbi.nlm.nih.gov/pubmed/17250679

Research on the neurocognitive characteristics of heroin addiction is sparse and studies that do exist include polydrug abusers; thus, they are unable to distinguish neurocognitive effects of heroin from those of other drugs. To identify neurocognitive correlates specific to heroin addiction, the present study was conducted in St. Petersburg, Russia where individuals typically abuse and/or become addicted to only one substance, generally alcohol or heroin. Heroin addicts were recruited from an inpatient treatment facility in St. Petersburg. Three comparison groups included alcoholics, addicts who used both alcohol and heroin, and non-abusers. Psychiatric, background, and drug history evaluations were administered after detoxification to screen for exclusion criteria and characterize the sample. Executive Cognitive Functions (ECF) that largely activate areas of the prefrontal cortex and its circuitry measured include complex visual pattern recognition (Paired Associates Learning), working memory (Delayed Matching to Sample), problem solving (Stockings of Cambridge), executive decision making (Cambridge Decision Making Task), cognitive flexibility (Stroop Color-Word Task) and response shifting (Stop Change Task). In many respects, the heroin addicts were similar to alcohol and alcohol+heroin dependent groups in neurocognitive deficits relative to controls. The primary finding was that heroin addicts exhibited significantly more disadvantageous decision making and longer deliberation times while making risky decisions than the other groups. Because the nature and degree of recovery from drug abuse are likely a function of the type or pattern of neurocognitive impairment, differential drug effects must be considered.

http://www.ncbi.nlm.nih.gov/pubmed/17382488

 

[ebola?]

>>I don't think 700mg (10mg/kg) is a small dose for a human, but it could be a whole lot less, however this is subcutaneous so it's probably less.>>

700 mg is well past the LD50 for those without tolerance (400-500 mg).
...
Just logically, if we operationalize "damage" as permanent negative effects, each use either elicits or fails to elicit damage. Now it might be that precautions taken in between uses can either keep temporary changes in the brain temporary, or make temporary negative effects permanent, but I would imagine that such dynamics would be minor.

The degree of damage may be minimized by low dosages and little or no redosing (limiting the length of each "session) and coadministration of protective agents. What using infrequently will do is limit the sum cumulative damage, and if your regimen is sufficiently effective, the damage you incur will have few or no behavioral and subjective manifestations.

ebola

 

[jjacobsen]

Again, really helpful. How do you guys determine these things. Are some of you scientists by trade, or simply good casual researchers?
In response to Ebola -where can I find a list of appropriate 'protective agents' to be coadministered with each drug?
Thanks again.

 

[dunwich]

LSD ... increases the amounts of certain growth factors in some areas of the brain while decreasing the amount in others.

Any further information you might provide on this topic would be appreciated!

 

[MurphyClox]

"Protective Agents":
In lots of threads antioxidants were recommended. Like ascorbic acid, tocopherol (= Vitamin E), fish oil, flavonoids, ...
All may help to a certain degree. I guess plenty of fresh fruits and vegetables already would be a good idea.

 

[nuke]

Yes, antioxidants or MAO-B inhibitors are the primary lines of protection against amphetamine toxicity, as the toxicity is modulated by oxidative radicals. MAO-B inhibition (with drugs like selegiline) is of questionable safety, however, and dosages are often reduced and durations extended. Your best bet is probably with very potent antioxidants like idebenone, n-acetylcysteine, inosine, large amounts of cocoa, and others. NMDA antagonists may also be protective.

the damage you incur will have few or no behavioral and subjective manifestations.

This is questionable -- you really need something like an fMRI or PET scan to be able to determine the extent of damage. There haven't been any studies of humans who've employed these methods tested on animals to see how effective they are.

Any further information you might provide on this topic would be appreciated!

There's a thread on neuronal growth factors and LSD here: http://www.bluelight.ru/vb/showthread.php?t=243015

 

[ebola?]

>>the damage you incur will have few or no behavioral and subjective manifestations.
This is questionable -- you really need something like an fMRI or PET scan to be able to determine the extent of damage. There haven't been any studies of humans who've employed these methods tested on animals to see how effective they are.>>

Well, I mean't that iff the protective regimen is successful, he'll avoid behavioral deficits. It could just be me, but I don't rely on the looks of my brainscans to negotiate daily life.

Also, fMRIs and PET scans cannot differentiate permanent damage from temporary adaptation.

>>How do you guys determine these things. Are some of you scientists by trade, or simply good casual researchers?>>

Some are scientists, but I am just a hobbyist. That probably accounts for how they are more informative than I.

>>where can I find a list of appropriate 'protective agents' to be coadministered with each drug?>>

It's all way speculative. I'd hunt around in threads in this forum.