I was reading about 5-HTP on wikipedia when this came up:

Similar deficits have been observed in long term/high dose psychostimulant users. Such deficits are especially apparent in those who have used amphetamine and methamphetamine. Amphetamines, and to a lesser extent cocaine, can damage serotonergic neurons in the CNS. Similar benefits have been seen in those with cognitive deficits resulting from psychostimulant use.<sup id="cite_ref-10" class="reference">[11] (http://en.wikipedia.org/wiki/5-HTP#cite_note-10)
Source: http://en.wikipedia.org/wiki/5-HTP

Which has me kind of worried because ever since starting dexedrine I've been having problems with depression, which I have never had in my life!!!
</sup>

Yikes, glad I started taking my 50mg of Zoloft a day then...!

I was reading about 5-HTP on wikipedia when this came up:


Source: http://en.wikipedia.org/wiki/5-HTP

Which has me kind of worried because ever since starting dexedrine I've been having problems with depression, which I have never had in my life!!!
</sup>

Looking up the reference:
^ Eur J Pharmacol. 2002 Jun 12;445(3):221-9. Involvement of 5-hydroxytryptamine neuronal system in Delta(9)-tetrahydrocannabinol-induced impairment of spatial memory., Egashira N, Mishima K, Katsurabayashi S, Yo****ake T, Matsumoto Y, Ishida J, Yamaguchi M, Iwasaki K, Fujiwara M.
I get this abstract:
1: Eur J Pharmacol. 2002 Jun 12;445(3):221-9.
Links
Involvement of 5-hydroxytryptamine neuronal system in Delta(9)-tetrahydrocannabinol-induced impairment of spatial memory.
Egashira N, Mishima K, Katsurabayashi S, Yo****ake T, Matsumoto Y, Ishida J, Yamaguchi M, Iwasaki K, Fujiwara M.

Department of Physiology and Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Japan.

The present study investigated the involvement of the serotonin (5-hydroxytryptamine, 5-HT) neuronal system in the Delta(9)-tetrahydrocannabinol-induced impairment of spatial memory in the eight-arm radial maze in rats. Delta(9)-Tetrahydrocannabinol (6 mg/kg, i.p.), which impairs spatial memory, significantly increased the 5-HT content in the ventral hippocampus. A microdialysis study showed that Delta(9)-tetrahydrocannabinol (6 mg/kg, i.p.) decreased 5-HT release in the ventral hippocampus. The 5-HT precursor, 5-hydroxy-L-tryptophan (5-HTP; 50 mg/kg, i.p.), the 5-HT re-uptake inhibitor, clomipramine (0.01 and 0.1 mg/kg, i.p.), the 5-HT receptor agonist, 5-methoxy-N,N-dimethyltryptamine (5-MeODMT; 0.01 and 0.03 mg/kg, i.p.), and the 5-HT(2) receptor agonist, 1-(2,5-dimethoxy 4-iodophenyl)-2-amino propane (DOI; 10 microg/kg, i.p.), significantly attenuated the Delta(9)-tetrahydrocannabinol-induced impairment of spatial memory. These results suggest that the 5-HT neuronal system may be involved in the Delta(9)-tetrahydrocannabinol-induced impairment of spatial memory.

PMID: 12079687 [PubMed - indexed for MEDLINE]

With no mention of amphetamines.

But the theory in the wikipedia article is fine. Excessive dopamine gets oxidized
to a neurotoxic substance. And studies show mega dose use of amphetamines damage both serotonergic and dopaminergic neurons. But were back to what was mention in this thread.

http://www.addforums.com/forums/showthread.php?t=52642

The relative neurotoxicity of typical anti-ADHD stimulant use is maybe 50 times less than extreme abuse/neurotoxicity studies.

That risk can be reduce even more by using neuroprotection strategies. There are a lot of studies on different substances that reduce or eliminate neurotoxicity from stimulants.

http://www.addforums.com/forums/showthread.php?t=48296

I vaguely recall a discussion about the differences between amphetamine and methamphetamine. Someone mentioned methamphetamine was more 'neurotoxic' because it causes dopamine and serotonin release, then when dopamine reenters the vesicles, it also enters the serotonin vesicles causing damage to the serotonin system.

I have no idea if that is accurate and I'm still trying to find the discussion ...

I vaguely recall a discussion about the differences between amphetamine and methamphetamine. Someone mentioned methamphetamine was more 'neurotoxic' because it causes dopamine and serotonin release, then when dopamine reenters the vesicles, it also enters the serotonin vesicles causing damage to the serotonin system.

I have no idea if that is accurate and I'm still trying to find the discussion ...

1: Neuropsychopharmacology. 2005 Nov;30(11):2026-34.
Links
Impaired object recognition memory following methamphetamine, but not p-chloroamphetamine- or d-amphetamine-induced neurotoxicity.
Belcher AM, O'Dell SJ, Marshall JF.

1Department of Neurobiology and Behavior, University of California, Irvine, CA, USA.

Repeated moderate doses of methamphetamine (mAMPH) damage forebrain monoaminergic terminals and nonmonoaminergic cells in somatosensory cortex, and impair performance in a novelty preference task of object recognition (OR). This study aimed to determine whether the memory deficit seen after a neurotoxic mAMPH regimen results from damage to dopamine (DA) and/or serotonin (5-HT) terminals. Animals were given a neurotoxic regimen of mAMPH, p-chloroamphetamine (PCA, preferentially damages 5-HT terminals), d-amphetamine (d-AMPH, preferentially damages DA terminals), or saline. After 1 week, animals were trained and tested for OR memory. Rats treated with mAMPH showed no recognition memory during the short-term memory (STM) test, whereas both PCA- and d-AMPH-treated rats showed OR STM scores comparable to controls. After behavioral testing, the specificity of monoaminergic lesions was determined by postmortem [125I]RTI-55 binding to dopamine (DAT) and serotonin (SERT) transporter proteins. Tissue from a separate group of animals killed 3 days after drug treatment was processed for Fluoro-Jade (F-J) fluorescence histochemistry to detect damaged cortical neurons. mAMPH-treated rats showed reductions in striatal DAT and hippocampal (HC) and perirhinal (pRh) SERT, as well as degeneration of neurons in primary somatosensory cortex. In PCA-treated rats, HC and pRh SERT were substantially depleted, but striatal DAT and cortical neuron survival were unaffected. By contrast, d-AMPH-treated animals showed marked depletions in striatal DAT and cortical neurodegeneration, but HC and pRh SERT were unaffected. This pattern of results indicates that no single feature of mAMPH-induced neurotoxicity is sufficient to produce the OR impairments seen after mAMPH treatment.

PMID: 15900317 [PubMed - indexed for MEDLINE]

That suggest serotonergic neuron damage applies to methamphetamine but
not d-amphetamine.

http://www.nature.com/npp/journal/v30/n11/full/1300771a.html

From the full study.

Rats were treated with amphetamines in two separate experiments. In Experiment 1, rats were treated subcutaneously with mAMPH (four injections of 4.0 mg/kg, N=18; three of 21 animals succumbed to complications associated with hyperthermia) or saline (1 ml/kg, N=13), at 2-h intervals. Animals' rectal temperature was measured 1 h after each injection. In Experiment 2, rats were treated subcutaneously with PCA (one injection of 5 mg/kg, N=17), d-AMPH sulfate (d-AMPH) (four injections of 5 mg/kg separated by 2 h, N=20; nine of 29 animals succumbed to complications associated with hyperthermia), or saline (N=16). Rectal temperatures were checked 1, 3, 5, and 7 h following the single injection of PCA, and 1 h following each injection of d-AMPH. All drug and vehicle injections were administered at a volume of 1 ml/kg. All drug doses were chosen based on their known profiles of neurotoxicity, and are expressed as the free base. All drugs were obtained from Sigma Chemical Company (St Louis, MO).

methamphetamine 4 x (4mg/kg/2hr) 3 out 21 rats died .
d-amphetamine 4 x (5mg/kg / 2h) 9 out 29 rats died.

So that was 16 mg/kg of methamphetamine in 8 hours.
And 20 mg/kg of d-amphetamine in 8 hours.

A 75 kg person that equates to 1200 mg methamphetamine and 1500 mg of
d-amphetamine in 8 hours. Interesting while methamphetamine has serotonergic and dopaminergic neurotoxicity d-amphetamine at the doses in the study was even more toxic to dopaminergic neurons.

mAMPH treatment induced significant depletions (approximately 41%) in levels of binding to DAT in the ventral caudate putamen (multivariate ANOVA, =17.436, p<0.001), and a slight, nonsignificant 20% decrease in DAT binding in the dorsal caudate putamen =4.171, p=0.051). DAT binding in the nucleus accumbens was unaffected

Animals treated with d-AMPH showed highly significant loss of RTI binding to dopaminergic transporters in three subregions of the striatum, the dorsal caudate–putamen (45%; =18.829, p<0.0001), ventral caudate–putamen (65%; =33.426, p<0.0001), and to a lesser degree, the nucleus accumbens (25%; =5.376, p<0.01). However, serotonergic terminals were spared from damage following d-AMPH treatment

Oh I should add this could just be downregulation to.

From the study:

but the issue of whether mAMPH induces DA terminal degeneration has been challenged by studies of mAMPH-treated animals (Harvey et al, 2000) and human mAMPH abusers (Wilson et al, 1996; Volkow et al, 2001a, 2001b). Whether or not the decreases in markers of DA and 5-HT terminals constitute terminal degeneration or a long-lasting phenotypic downregulation, the focus of the present study was to determine the cognitive consequences of this loss of monoaminergic markers.

oh well, theres always more dexedrine! :) even if I need to take 100mg at a time in 20 years. :P

MDMA is an amphetamine (methylenedioxymethamphetamine) as well as MDA. I would imagine that these would be the problem substances in this respect.

1: Nat Med. 1996 Jun;2(6):699-703.
Links
Striatal dopamine nerve terminal markers in human, chronic methamphetamine users.
Wilson JM, Kalasinsky KS, Levey AI, Bergeron C, Reiber G, Anthony RM, Schmunk GA, Shannak K, Haycock JW, Kish SJ.

Human Neurochemical Pathology Laboratory, Clarke Institute of Psychiatry, Toronto, Ontario, Canada.

Methamphetamine is a drug that is significantly abused worldwide, Although long-lasting depletion of dopamine and other dopamine nerve terminal markers has been reported in striatum of nonhuman primates receiving very high doses of the psychostimulant, no information is available for humans. We found reduced levels of three dopamine nerve terminal markers (dopamine, tyrosine hydroxylase and the dopamine transporter) in post-mortem striatum (nucleus accumbens, caudate, putamen) of chronic methamphetamine users. However, levels of DOPA decarboxylase and the vesicular monoamine transporter, known to be reduced in Parkinson's disease, were normal. This suggests that chronic exposure to methamphetamine does not cause permanent degeneration of striatal dopamine nerve terminals at the doses used by the young subjects in our study. However, the dopamine reduction might explain some of the dysphoric effects of the drug, whereas the decreased dopamine transporter could provide the basis for dose escalation occurring in some methamphetamine users.

PMID: 8640565 [PubMed - indexed for MEDLINE]

Some people have suggested vesicular monoamine transporter (VMAT) is
a better way to evalue neurotoxicity of methamphetamine than dopamine transporter(DAT). The above study suggest typical methamphetamine use did
not reduce VMAT levels.

http://brain.oxfordjournals.org/cgi/content/full/127/2/363

The animal findings of long-term reduction of brain dopaminergic markers, together with histological signs suggestive of nerve terminal injury following acute MA exposure , have led to the prevailing assumption that MA is toxic to brain dopamine neurons . However, the actual structural extent of long-term MA toxicity to brain dopamine neurons in primates remains uncertain and even controversial because of the impossibility of establishing whether the persistent [but substantially reversible in the non-human primate ] reduction of dopamine nerve terminal/axonal markers is associated with actual physical loss of part of the dopamine neuron or only with loss of expression of dopaminergic markers therein .

Thanks again for the excellent references, theta. :D

methamphetamine 4 x (4mg/kg/2hr) 3 out 21 rats died .
d-amphetamine 4 x (5mg/kg / 2h) 9 out 29 rats died.

So that was 16 mg/kg of methamphetamine in 8 hours.
And 20 mg/kg of d-amphetamine in 8 hours.

A 75 kg person that equates to 1200 mg methamphetamine and 1500 mg of
d-amphetamine in 8 hours. Interesting while methamphetamine has serotonergic and dopaminergic neurotoxicity d-amphetamine at the doses in the study was even more toxic to dopaminergic neurons.

Nitpicking here. :D

Converting animal to human dosage isn't 1:1 necessarily. The way they do it when about to start a clinical trial on humans is based on body surface area.

FDA.gov: Conversion of Animal Doses to Human Equivalent Doses (HED) Based on Body Surface Area (http://www.fda.gov/cber/gdlns/dose.htm#v)

To convert dosage for rats in mg/kg to humans in mg/kg, divide rat dosage by 6.2. So,

methamphetamine: 16mg/kg / 6.2 = 2.58mg/kg (human dose)
d-amphetamine: 20mg/kg / 6.2 = 3.23mg/kg (human dose)

So, that's roughly 190mg methamphetamine and 240mg d-amphetamine for a 75kg human.

Hmm. Those doses don't seem huge considering the damage reported in the study. Don't some people do grams of meth at a time?

Converting animal to human dosage isn't 1:1 necessarily. The way they do it when about to start a clinical trial on humans is based on body surface area.

FDA.gov: Conversion of Animal Doses to Human Equivalent Doses (HED) Based on Body Surface Area (http://www.fda.gov/cber/gdlns/dose.htm#v)

To convert dosage for rats in mg/kg to humans in mg/kg, divide rat dosage by 6.2. So,

methamphetamine: 16mg/kg / 6.2 = 2.58mg/kg (human dose)
d-amphetamine: 20mg/kg / 6.2 = 3.23mg/kg (human dose)

So, that's roughly 190mg methamphetamine and 240mg d-amphetamine for a 75kg human.



LD(9/29*100=31) d-amphetamine: 20mg/kg in rats.
The mechanism that killed the rats was hyperthermia. A small body has a greater surface area relative to its volume hence it can dissipate heat better.
HED is based on surface area so it logical that the human lethal dose would be
proportional lower based on humans having a lower surface area to volume ratio. Do rats sweat?

If it applies to the lower binding(or neurotoxicity) found in the dopamine transporters in the study in my other post then it suggest a few things: d-amphetamine is very dangerous or the neurotoxicity risk of it has been massively overstated. That study and others do show major dopamine
depletion at high levels it would seem if 3.23mg/kg d-amphetamine is the
dose that can cause that then typical ADHD doses of it should be showing
some major negative effect to(even if it just downregulation). 3.23mg/kg thats 240 mg in 75 kg person and the max suggested recommend might be 60 mg. Therapeutic safety index of around 4?

LD(9/29*100=31) d-amphetamine: 20mg/kg in rats.
The mechanism that killed the rats was hyperthermia. A small body has a greater surface area relative to its volume hence it can dissipate heat better.
HED is based on surface area so it logical that the human lethal dose would be
proportional lower based on humans having a lower surface area to volume ratio. Do rats sweat?

If it applies to the lower binding(or neurotoxicity) found in the dopamine transporters in the study in my other post then it suggest a few things: d-amphetamine is very dangerous or the neurotoxicity risk of it has been massively overstated. That study and others do show major dopamine
depletion at high levels it would seem if 3.23mg/kg d-amphetamine is the
dose that can cause that then typical ADHD doses of it should be showing
some major negative effect to(even if it just downregulation). 3.23mg/kg thats 240 mg in 75 kg person and the max suggested recommend might be 60 mg. Therapeutic safety index of around 4?
Rats sweat from their tails and the soles of their feet? "A rat's temperature is regulated though its tail (assuming it has one). A really hot rat will lay on its back so that it can "sweat" through the soles of its feet." (http://wererat.net/ratfacts.htm) I couldn't find a better source other than this paper on an Australian site (http://www.publish.csiro.au/?act=view_file&file_id=ZO9750453.pdf)(that seems to be down ATM).

It seems like it would be more likely that an overdose would be fatal through hyperthermia, stroke or heart attack than by sensitization of dopamine receptors. I could be wrong. It does seem like the dosages would need to be higher than 240mg to be fatal. Then again, I don't know of anyone taking 1/4 gram of amphetamine in that short amount of time(it's probably happened, though..).

It does seem like the dosages would need to be higher than 240mg to be fatal. Then again, I don't know of anyone taking 1/4 gram of amphetamine in that short amount of time(it's probably happened, though..).

Well it would be LD31 or about 1/3 of humans would die at 240 mg of dexedrine. I guess the tolerance of the user would be factor to. Someone could slowly work their way up to that dose and have near zero chance of death in other words. Oh ambient temperature has a big effect on lethal dose of amphetamine(I guess obviously since it can kill by hyperthermia).

http://cameochemicals.noaa.gov/chemical/4862
dl-amphetamine free base
Probable lethal dose in humans is 5-50 mg/kg or 7 drops to 1 teaspoon for a 70 kg (150 lb.) person.

Actually the lethal dose is irrelevant to my concern. The HED dose is around 240 mg which means neurotoxicity could be more likely seen at the max ADHD
dose ranges. Combined that with the fact that d-amphetamine is much closer to methamphetamine in its neurotoxic dose than I speculated it was.
I thought 3 Adderall to 1 methamphetamine but dexedrine is 5 to 4 methamphetamine.

I'm estimating adderall to dexedrine conversion is like:
75% d-amphetamine (1/3 d-amphetamine's potency(25% l-amphetamine)=
83% as strong as dexedrine. (its not clear if the methamphetamine I mention above is dl or d).

So my estimate a few days ago of the relative risk of 120 mg of aderall a day of 2.7% of extreme d-methamphetamine abuse is now:

120 * 0.83 / 240 x 100%= 42% risk

I'm thinking HED also applies to the CNS stimulant doses to.
The logic being blood volume is also proportional to surface area.
Most the drug would likely be in the blood and hence to get a set amount
to the brain you would have to achieve the same blood level as the rat studies.

1: FASEB J. 2008 Mar;22(3):659-61. Epub 2007 Oct 17.
Links
Dose translation from animal to human studies revisited.
Reagan-Shaw S, Nihal M, Ahmad N.

Department of Dermatology, University of Wisconsin, 1300 University Ave., Madison, WI 53706, USA.

As new drugs are developed, it is essential to appropriately translate the drug dosage from one animal species to another. A misunderstanding appears to exist regarding the appropriate method for allometric dose translations, especially when starting new animal or clinical studies. The need for education regarding appropriate translation is evident from the media response regarding some recent studies where authors have shown that resveratrol, a compound found in grapes and red wine, improves the health and life span of mice. Immediately after the online publication of these papers, the scientific community and popular press voiced concerns regarding the relevance of the dose of resveratrol used by the authors. The animal dose should not be extrapolated to a human equivalent dose (HED) by a simple conversion based on body weight, as was reported. For the more appropriate conversion of drug doses from animal studies to human studies, we suggest using the body surface area (BSA) normalization method. BSA correlates well across several mammalian species with several parameters of biology, including oxygen utilization, caloric expenditure, basal metabolism, blood volume, circulating plasma proteins, and renal function. We advocate the use of BSA as a factor when converting a dose for translation from animals to humans, especially for phase I and phase II clinical trials.

PMID: 17942826 [PubMed - indexed for MEDLINE]

http://www.google.com/url?sa=t&ct=res&cd=1&url=http%3A%2F%2Fwww.aapspharmsci.org%2Farticles%2 Faapsj0704%2Faapsj070481%2Faapsj070481.pdf&ei=6L0xSJ2pM5ys8gTV0fnUAQ&usg=AFQjCNEIxzmUv-zLFXMH2HmDIbDcvewUhw&sig2=-D2BuxEfMH3UFK_DCKnr0A

In rats, a single high-dose injection (10 mg/kg) of METH
rapidly (within 1 hour) and reversibly decreases the amount
of DA taken up into synaptosomes prepared from treated
rodents

The effects of releasing drugs become more complicated
with higher doses (such as 4 × 10 mg/kg/injection of METH
at 2-hour intervals) that cause persistent deficits in striatal
DA systems.As with a single injection of METH, multiple
high-dose administrations cause a rapid (within 1 hour after
final METH injection) decrease in DAT activity; however,
this decrease in DAT is substantially greater and may be linked to persistent DAergic deficits. Although the mechanisms of releaser-induced toxicity is not completely under-
stood, DA, hyperthermia, and oxygen radicals contribute to
this phenomenon

Thus the maxium safe dose and a dose known to cause persistent deficits has a ratio around 4 for methamphetamine.