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Author Topic: [Aus] Meth/Ice, Overdose and Death + Clinical Pharmacology of Methamphetamine  (Read 7299 times)

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source: https://theconversation.com/ice-causes-death-in-many-ways-overdose-is-just-one-of-them-81752

note: the LD50Wiki for Meth in humans is unknown

Ice causes death in many ways, overdose is just one of them

July 31, 2017

Most people are unaware of the severe impact ice has on the heart.

Methamphetamine (usually colloquially referred to as “ice”) is a major public health problem in Australia. When we think of methamphetamine-related death, however, we tend to focus on overdose. This is a very real and valid concern. But the extent of the problem extends far beyond drug toxicity.

Methamphetamine dependence is associated with an array of serious social, mental and physical health problems that include heart disease, stroke, suicide, mood and anxiety disorders, psychosis, and violence. The footprint of methamphetamine is far wider than that of many other drugs. Close to half of deaths occur in rural and regional areas, a great many users are employed, and half have never injected a drug. These are not the “usual suspects” for drug-related death.

In a new study we looked at all of the methamphetamine-related deaths that occurred in Australia from 2009 to 2015. There were 1,649 such deaths over that period, and the annual rate doubled from around 150 a year to 300. Of these deaths, 43% were due to drug toxicity.

In the case of methamphetamine, overdose typically results in heart arrhythmias (where the heart isn’t beating properly) and seizures caused by the drug. Importantly, even modest amounts of methamphetamine may cause heart arrhythmia and death. The remainder, however, were due to other causes.

How methamphetamine affects the heart long-term

In a fifth of cases, death was due to methamphetamine combined with disease, most commonly heart disease. Methamphetamine is cardiotoxic, meaning it causes damage to our heart muscle, and causes disease in our arteries.

There’s a circular pattern here. Methamphetamine damages the cardiovascular system. The drug also places strain on this system by increasing the force of the blood against the artery walls (it’s a “hypertensive”). Users are then placing strain on damaged hearts. And this damage accumulates and does not reverse.

There’s also a real risk of stroke, and we saw 38 such cases among young people, a demographic not commonly affected by stroke. Importantly, the damage to the cardiovascular system occurs regardless of how the drug is used. Smoked, injected or swallowed – it is the drug that does the damage.

How methamphetamine fatally reduces inhibition

Methamphetamine is also associated with traumatic injury and death, as it causes a high degree of disinhibition, impulsivity, aggression and impaired critical judgement. There were 300 completed suicides related to methamphetamine over our study period.

There were around 300 deaths from suicide linked to methamphetamine, and the methods used were more violent, which is linked to the aggression, violence and aggravation caused by the drug.

Some 15% of all methamphetamine-related deaths were due to traumatic accidents, most commonly motor vehicle accidents. Methamphetamine users commonly believe the drug improves their driving. It does not. What it does improve is the risk of injury and death. All of these deaths were avoidable.

What can we do?

Knowledge of the risks is a start. Many users might assume a racing heart and chest pains are part of the experience of using methamphetamine and not realise these are signs of a system under stress. The heart disease we are seeing in methamphetamine users will be a problem for decades to come, long after they cease use.

In terms of our treatment system, drug treatment centres need to be aware their methamphetamine patients may be at risk of heart disease. Doctors also should ask about methamphetamine involvement if young people are presenting with heart conditions.

Over the past few years there has a been an intense focus on methamphetamine in the wake of evidence of increasing use and harms, including in rural and regional areas. By examining the causes of these deaths we have uncovered that, unlike many other drugs, the harms are very diverse, particularly with regard to the extensive association with heart disease.

This suggests that even if use goes down, we will have a major public health problem for our hospital and community health services for many years to come.

Another striking finding of this research is that very few of those who died were in treatment at the time. Our treatment services are already under intense pressure and this underlines the urgent need for more resources to go into treatment and trials of new medications.



According to What is the toxicity dose of Methamphetamine in Rats and human ?

For rat and mouse, the LD50Wiki for METH with intraperitoneal (ip = the injection site should be in the lower left or right quadrant of the abdomen because vital organs are absent from this area) administration is 55 and 57 mg/kg, in rat and mouse, respectively (Davis et al., 1987; Yamamoto, 1963). But temperature is very important eg. at 29oC 80% of rats were died with 9 mg/kg i.p. administration  just 4-5 degree above ambient temp.

For human, A lethal dose of methamphetamine varies depending on characteristics of the drug and the user. In fact, each person has a different sensitivity to a specific amount of methamphetamine due to personal tolerance to meth. Therefore, toxic levels are different for each individual. Meth overdose may also be complicated by other drugs the user may have taken. Diseases that the person may have developed also play a role due to the current health condition of the body.

Toxic doses:

Oral administration = ~ 150mg a day

Injection (IV)= ~100mg or higher

Smoking and snorting = ~50 mg or higher



To examine the literature regarding clinical pharmacokinetics, see A review of the clinical pharmacology of methamphetamine

some excerpts:

ABSTRACT

Aims To examine the literature regarding clinical pharmacokinetics, direct effects and adverse clinical outcomes associated with methamphetamine use. Methods Relevant literature was identified through a PubMed search. Additional literature was obtained from relevant books and monographs. Findings and conclusions The mean elimination half-life for methamphetamine is approximately 10 hours, with considerable inter-individual variability in pharmacokinetics. Direct effects at low-to-moderate methamphetamine doses (5–30 mg) include arousal, positive mood, cardiac stimulation and acute improvement in cognitive domains such as attention and psychomotor coordination.

At higher doses used typically by illicit users (50 mg), methamphetamine can produce psychosis. Its hypertensive effect can produce a number of acute and chronic cardiovascular complications. Repeated use may induce neurotoxicityWiki, associated with prolonged psychiatric symptoms, cognitive impairment and an increased risk of developing Parkinson’s disease. Abrupt cessation of repeated methamphetamine use leads to a withdrawal syndrome consisting of depressed mood, anxiety and sleep disturbance. Acute withdrawal lasts typically for 7–10 days, and residual symptoms associated with neurotoxicity may persist for several months.

MOLECULAR MECHANISMS

Chemistry

‘Amphetamine’ is a contraction of ‘a-methylphenethylamine’, an older description of the prototypical compound of which methamphetamine (methylamphetamine, metamfetamine, N-methyl-1-phenylpropan-2-amine) is the N-methyl derivative. S-methamphetamine (dextro-methamphetamine) is the more biologically active optical isomer.

S-methamphetamine hydrochloride presents as white or translucent crystals and is referred to commonly as ‘ice’ or ‘crystal meth’. Samples of crystalline methamphetamine seized in Australia have had, typically, a  purity of 80%, although purity may be significantly less where the cutting agent dimethyl sulphone (also known as MethylsulfonylmethaneWiki or MSM) is present. The more common powder form of methamphetamine is typically 10% pure, and the purity of ‘base’, a damp oily form, is generally 20%.

The crystalline form is suitable for vapour inhalation because high purity S-methamphetamine hydrochloride vaporizes without pyrolysisWiki. Relative to lower purity forms, crystalline methamphetamine is associated with an increased incidence of dependence.

Methamphetamine withdrawal syndrome

Abrupt cessation of regular methamphetamine use induces a withdrawal syndrome designated ‘amphetamine-type stimulant withdrawal syndrome’ by the American Psychiatric Association. Methamphetamine withdrawal may arise from the depletion of presynaptic monoamine stores, down-regulation of receptors and neurotoxicity. The most prominent signs and symptoms of methamphetamine withdrawal are disturbed sleep, depressed mood and anxiety, craving and cognitive impairment. Other significant symptoms include hyperphagiaWiki, agitation, vivid or
unpleasant dreams, reduced energy and methamphetamine craving.

The severity and profile of withdrawal is related to the dosage and duration of methamphetamine use.

Early case reports have indicated that, initially, acute withdrawal features a period of increased sleep duration,
particularly rapid eye movement sleep, from 3 to 8 days in duration. Protracted insomnia following the period of hypersomnolenceWiki has been reported  but is not a consistent finding. Some researchers report reduced sleep quality but not quantity while others have not found insomnia to be a significant symptom. Where observed, impaired sleep quality during later withdrawal has been associated with reduced clear-headedness upon waking, suggesting a link between sleep, mood and cognitive function during methamphetamine withdrawal.

Depressed mood and anxiety associated with methamphetamine withdrawal can reach the level of suicidal
ideation and panic. Depression associated with methamphetamine withdrawal typically features dysphoric mood, anhedonia, irritability, inactivity and impaired concentration. Depression and anxiety are most severe after 2–3 days of abstinence, with gradual improvement over 7–10 days. Although in most cases depression largely resolves after 2 weeks of abstinence, 24% report depression in the moderate to severe range after 3 weeks’ abstinence, and some may experience significant depression for several months. Neuroimaging studies suggest that persistent depression may be associated with methamphetamine-induced neurotoxicity. The high incidence of psychological trauma among methamphetamine users may exacerbate anxiety and depression.

Neurotoxicity

Repeated exposure to amphetamines leads to damage at dopaminergic and serotonergic axons.The mechanisms of
neurotoxicity are not understood completely, but the selectivity of damage may be explained by the oxidation of
cytosolic dopamine and serotonin to 6-hydroxydopamine and 5,6-dihydroxytryptamine, which can oxidize proteins
and lipids in dopamine and serotonin-rich neurones. Elevated cerebral temperature is also thought to be an
important contributing factor. Neuronal damage induced by amphetamines is localized generally to axons and termini, while cell bodies are typically spare.

In vivo human positron emission tomography and magnetic resonance imaging data also indicate brain  abnormalities that persist beyond the period of methamphetamine consumption. Abnormalities include inflammation, reduced neuronal density and reduced density of dopaminergic markers such as DAT, D2 receptor,
VMAT-2 and the serotonergic marker SERT. StriatalWiki abnormalities can persist for years after cessation
of dependent methamphetamine use, but may recover partially after 6–12 months of abstinence .

Methamphetamine-associated neurotoxicity in the striatumWiki correlates with psychotic symptoms,
memory deficits and impaired psychomotor coordination. Psychotic symptoms correlate with diminished DAT density in the frontal cortex and reduced global SERT density. In the anterior cingulateWiki, prefrontal
and temporal corticesWiki, reduced SERT density correlates with measures of aggression.

Neuropsychological impairment

A meta-analysis of neurocognitive impairments concluded that methamphetamine use is associated with moderate impairment in neuropsychological performance corresponding with frontostriatal and limbic abnormalities. Principle neurocognitive impairments appear to occur in the domains of executive function, learning, episodic memory, peed of information processing, motor skills, working memory and perceptual narrowing .

Among the studies reviewed, previous methamphetamine use was associated with specific impairments in impulse control, memory recall,  sustained attention, working memory, perseveration and fluency. These findings correspond with clinical  observations that methamphetamine-dependent patients tend to present as distractible and have difficulty sustaining attention. Several studies document cognitive deficits persisting for longer than 6 months after withdrawal, although some improvements have been reported with protracted abstinence.

Parkinson’s disease

Because Parkinson’s disease (PD) is a neurodegenerative disorder affecting dopamine neurones in the nigrostriatal
pathway, several investigators have examined links with methamphetamine neurotoxicity. This continues in the source document

Sexual behaviour

The effects of methamphetamine on sexual behaviour have not been examined systematically in clinical studies.
The available evidence for sexual effects stems largely from self-reported survey data, often conducted among
regular methamphetamine users with problematic sexual behaviours. It is therefore unclear how broadly these effects apply.

Methamphetamine use has been reported to enhance sexual pleasure among a sample of dependent heterosexual females users engaged in highrisk sexual behaviours. Some users reported that methamphetamine delays  orgasm, facilitating prolonged sexual activity and a particularly intense orgasm. Others have reported an
association with erectile dysfunction and that methamphetamine is used commonly in combination with drugs
such as sildenafilWiki (Viagra®) to enhance sexual performance.

Sexual effects may be mediated by excessive dopaminergic activation. Impulsiveness and impaired decision-making associated with chronic methamphetamine use may also play a role (see Neuropsychological impairment).

This continues in the source document

Teratogenic effects

In 2005, an expert panel concluded that there was insufficient evidence regarding the consequences of prenatal
exposure to amphetamines. This continues in the source document.

Other adverse effects

Methamphetamine intoxication is associated with dry mouth, which may lead to dental caries, and activation of
mandibular muscles, which may lead to bruxism and, in some cases, tooth fracture. Recent methamphetamine use appears to be a risk factor for MSRAWiki (Methicillin Resistant Staphylococcus Aureus) skin infections.

Skin infections may be associated with formication (a sensation of something crawling on the skin) and skin-picking. Tactile hallucinations are common features of methamphetamine psychosis and may contribute to skin picking and infection.

SUMMARY

Methamphetamine produces a range of direct effects including subjective euphoria, arousal and psychomotor
activation. At higher doses, stimulation of striatal dopamine D2 receptors appears to mediate psychosis.
Stimulation of the myocardium—either directly or via CNS efferents—can lead to tachycardiaWiki and hypertension, which may result in a range of severe acute and chronic cardiovascular pathologies.

Repeated dosing leads to neuroadaptation and impaired baseline functioning which may result in depressed mood, cognitive impairment and other withdrawal symptoms when use of the drug is ceased.

Neurotoxicity arising from chronic methamphetamine use is associated with long-lasting impairment in mood and
cognitive functions. Damage to dopamine neurones in the nigrostriatal pathway may increase the risk of developing Parkinson’s disease in later life. The range of potential adverse effects suggests that
clinical management of individuals presenting with problematic methamphetamine may require assessment
of cardiovascular, neurocognitive, dental, dermatological and sexual health issues in addition to dependence and
mental health concerns. This review suggests a number of potential areas for research. For example, research is necessary to examine the mechanisms underlying cardiovascular harms, sexual risk-taking behaviour, neurocognitive impairment, psychosis and Parkinson’s disease.

Determination of factors affecting individual variation in acute methamphetamine responses and chronic harms may assist in identifying individuals at particular risk. To date, many important features of high-dose illicit methamphetamine use have been explored indirectly or retrospectively. Although potentially problematic to implement, prospective observational studies of illicit methamphetamine use would be useful to clarify outstanding issues regarding the course and prognoses of methamphetamine psychosis, cardiovascular toxicity, neurotoxicity and dependence. Such studies may improve the management of methamphetamine-related disorders.

See the full PDF for more information
« Last Edit: June 04, 2023, 03:57:34 AM by Chip »
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*bump* after speaking recently with high dose users
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