Part 2
pathology, addiction, and treatment
This post focuses on neuropathology, addiction, and treatment options related to amphetamine use. Illicit methamphetamine is manufactured and distributed on an industrial scale primarily by large drug cartels. The recent spike in methamphetamine supply coincides with the shift to manufacture of the synthetic opioid fentanyl around 2012.
Deaths from unintentional drug overdose are at unprecedented record levels. Despite media messages prescription drugs are minor contributors and declining. By far illegally manufactured fentanyl and methamphetamine outnumber all other causes of drug death and overdose. Stimulant overdose death is most often due to intentional or unintentional mixture of amphetamine or cocaine with fentanyl and other additives. Street preparations are often mixed or sold as counterfeit pills or powders.
The above diagram shows the chemical steps needed for synthesis of methamphetamine from phenylephrine (Sudafed).
Sudafed is now restricted in many locations and most methamphetamine is now imported from illicit labs using more sophisticated chemical methods and equipment.
WHO flow chart of methamphetamine supply chains. Major export centers are located in Southeast Asia and the Americas. Due to economy of scale, production and smuggling supply is cost efficient and highly profitable despite some loss due to law enforcement efforts.
One of the most significant consequences of long term higher dose amphetamine use is neurotoxicity. Because of major shifts in function cellular apoptosis, cell destruction, may occur. The above map represents composite data of cellular volume loss due to amphetamine use. Areas most affected are the hippocampus and limbic system. Users frequently report short term memory loss, cognitive deficits, and emotional dysregulation.
Postmortem samples of serotonin labeled brain sections in the primate cortical hippocampus after 7 week amphetamine treatment. From left to right are controls, 2 weeks post, and 7 years post exposure demonstrating the irreversible nature of tissue loss.
Diagram of cellular mechanisms underlying neurotoxicity. Amphetamines cause marked increases in excitatory glutamate production and shifts in intracellular Calcium ion. This results in generation of oxidative free radicals, superoxide, nitric oxide and peroxynitrite. Electron transfer from cellular components such as DNA due to oxidative stress results in cellular damage and eventual cell death.
Additional neuroplastic changes occur in key areas of the brain. This image is one of the most frequently reproduced in addiction literature and presentations. It is from a study published in 2001 by researchers at the NIH with Nora Volkow as the lead author. It was one of the first to demonstrate long term changes in functional brain deficits occurring in addiction supporting a growing body of evidence for the brain disease model of addiction.
These are from a PET study on Methamphetamine users in early and late abstinence. A radioactive agent was given binding to dopamine D2 receptors. Red indicates greater concentration of receptors. Control is on the left. In the center recently detoxed individuals show markedly decreased dopamine receptors in the Striatum, a key component of the reward system. This partially recovers at 2 years abstinence.
Another long term neuroplastic change. This is from animal experiments following 4 weeks of amphetamine administration. Shown are diagrams of neurons in the Nucleus Accumbens. The little knob like things along the dendrites are dendritic spines. There are more of these after amphetamine. This means more synapses and increased sensitivity of the neuron.
These cellular changes have been linked with increased drug seeking behavior in lab animals. Sensitization is thought to be a key component in progressive substance addiction and relapse in humans.
This mechanism is most pronounced in stimulant use.
The most commonly prescribed prescription amphetamine is Adderall containing mixed d- and l- amphetamine salts and related drugs prescribed for ADHD in children and adults.
The above study looked at adults presenting for addiction treatment and reporting non prescription drug use. Of the types reported stimulants were the lowest reported. Opiates and sedatives were much more common.
While this represents only a subset of prescription diversion and misuse it indicates that use in adults requiring treatment is lower than other addictive drugs. Non prescription use has been reported to be common among college students as a study aid. Reports indicate a rate as high as 17% among undergraduates. Interestingly additional studies have not shown higher academic achievement in user groups.
At this time there is no useful pharmacotherapy to aid in preventing relapse or withdrawal symptoms in stimulant addiction. Several strategies have been tested. This study was a placebo controlled randomized trial for a total of 13 weeks. The study employed a combination of injected naltrexone and oral bupropion. Mild improvement about 10% vs placebo was found for relapse prevention in the treated group.
This long term study looked at relapse rates over a five year period following discharge from a treatment facility. They were divided into three risk groups by history of prior drug selling and/or IV drug use. They also looked at if the subject had received any sort of treatment or self help involvement after discharge. Treatment or self help involvement resulted in a significantly better outcome. Prior history of drug sales or IV use was a significant risk factor in predicting relapse.
This recent study was a randomized double blinded placebo controlled trial to evaluate efficacy of the amphetamine derivative MDMA (ecstasy) as an adjunct to psychotherapy in patients with severe PTSD. MDMA is an amphetamine derivative with strong activity in Serotonin and Dopamine pathways.
All subjects received 16 psychotherapy sessions. A total of 3 doses of either MDMA or placebo was administered during the trial period along with therapy.
Results are as shown above with significantly increased reduction of symptoms in the MDMA group. No demographic or confounding factors were observed.
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The neurobiology of amphetamines and the pathophysiology of dependence and addiction are well defined. Although there have been some advances in pharmacotherapy for opiates and alcohol there are none currently for Amphetamines. Psychosocial and support/self help measures offer high probability of disease remission and significant harm reduction.
The use of MDMA as an adjunct in treatment for PTSD is gaining rapid acceptance and has been proven in clinical trials. In the study noted history of Alcohol and substance use disorder did not affect therapeutic outcomes and would not present a barrier to treatment.
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Thank you for your consideration in reviewing this post. Comments and suggestions are welcome.
For educational and information purposes only. No commercial or institutional interest. All data and images obtained from sources freely available on the World Wide Web. This post should not be considered medical or professional advice.
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Sober Synthesis 
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