Introduction
The purpose of this review is to summarize the literature to date related to pyrolysis and heated vapor ingestion of methamphetamine and the accompanying thermal degradation processes. Methamphetamine is a common smokable drug of abuse. Smoking of a drug generally gives a rapid onset of action, comparable regarding methamphetamine to intravenous administration.
In most cases, thermal decomposition begins with cleavage of the weakest bond (often C-N) to generate free radicals that then form the most stable sterically favoured products. The heating process often produces thermal decomposition products as well as those that are metabolites. The acute and chronic toxicity of these by-products are poorly understood, if understood at all.
Inhalation of vapors as a mode of ingestion delivers compounds to the lungs via the mouth and nose. While the mucous membranes of the mouth and nose are intended to filter out particulates, trapping of water-soluble compounds can occur on these surfaces. Once in the lungs, molecules partition into the bloodstream at a compound-dependent rate. Factors that influence the degree of absorption include how far the inhaled substances travel into the lungs, intrinsic solubility in blood, and the rate of blood flow through the lungs. Once in the bloodstream, compounds are distributed to the tissues without the first-order metabolism that occurs with drugs absorbed from the GI tract. As a result, the effective dose of a given drug ingested by smoking can be much higher than the same amount of drug ingested orally. In addition, pharmacological effects can occur nearly instantaneously with a smoked drug. The rapid and intense onset of pharmacological effects is the motivating force to smoke or inject a given substance, as opposed to oral ingestion.
In most cases, thermal decomposition begins with cleavage of the weakest bond (often C-N) to generate free radicals that then form the most stable sterically favoured products. The heating process often produces thermal decomposition products as well as those that are metabolites. The acute and chronic toxicity of these by-products are poorly understood, if understood at all.
Inhalation of vapors as a mode of ingestion delivers compounds to the lungs via the mouth and nose. While the mucous membranes of the mouth and nose are intended to filter out particulates, trapping of water-soluble compounds can occur on these surfaces. Once in the lungs, molecules partition into the bloodstream at a compound-dependent rate. Factors that influence the degree of absorption include how far the inhaled substances travel into the lungs, intrinsic solubility in blood, and the rate of blood flow through the lungs. Once in the bloodstream, compounds are distributed to the tissues without the first-order metabolism that occurs with drugs absorbed from the GI tract. As a result, the effective dose of a given drug ingested by smoking can be much higher than the same amount of drug ingested orally. In addition, pharmacological effects can occur nearly instantaneously with a smoked drug. The rapid and intense onset of pharmacological effects is the motivating force to smoke or inject a given substance, as opposed to oral ingestion.
The heating process
One of the challenges associated with identifying thermal decomposition products of smoked drugs of abuse are determining realistic and representative temperature ranges of the process from both the user and analytical perspectives. There is no one method of ‘smoking’ but rather a range of conditions from mild to moderate heating with paraphernalia to more aggressive heating that occurs in a cigarette-like system. In the simplest case, heating volatilizes the drug for delivery to the bloodstream via the lungs. Other processes are possible, including volatilization of other components and contaminants; volatilization followed by thermal degradation; or thermal degradation on a surface followed by volatilization (Figure 1).
Figure 1. Upper Frame: Pathways by which a drug or drug salt can reach the gas phase. The generic B represents a basic drug in the unprotonated (free base) form; TD refers to thermal decomposition products.
The methamphetamine is basic and contain one amine group. The solid may be in the free base form (B), the salt form (typically but not exclusively the hydrochloride salt), or in the protonated form (BH+). Vaporization, the prerequisite condition for smoking as defined in this review, can involve more than a phase change (Figure 1, Path 1), the degree of which will depend on the mode of heating, temperature, matrix, and drug in question. Thermal degradation of the salt to the free-base form may first occur, followed by subsequent vaporization (Figure 1, Path 2). Under different heating conditions, the base or salt can undergo thermal degradation before vaporization (Figure 1, Paths 3 and 4) where additional degradation may take place.
Drugs can be ingested via inhalation in therapeutic and recreational settings. Therapeutic agents can be delivered via inhalation, but these modes do not involve aggressive heating; rather, the goal is to generate an inhalable aerosol. The only significant therapeutic use of vaporized substances is in anaesthesia, where the agents are typically in the vapor phase at room temperature. Electronic cigarettes are increasing in popularity as a means of nicotine delivery. These devices gently heat solutions of diols, flavouring, and nicotine to generate an inhalable aerosol. Heat is delivered via a battery with temperatures in the range of 40–65 °C. At these temperatures, thermal degradation is expected to be minimal. As of the writing of this paper, no published reports specifically discussing ingestion of abused drugs via electronic cigarettes have been located.
As shown in Figure 2a, the reactive areas are the combustion zone (exothermic reactions) and the pyrolysis zone, where endothermic reactions dominate. Active combustion occurs in the tip and is accentuated when the user "puffs" on the cigarette and draws air through the region. During the puff, the temperature rises quickly and can approach 950 °C. Oxygen is depleted from the air as it flows through the combustion region to the pyrolytic region.
Drugs can be ingested via inhalation in therapeutic and recreational settings. Therapeutic agents can be delivered via inhalation, but these modes do not involve aggressive heating; rather, the goal is to generate an inhalable aerosol. The only significant therapeutic use of vaporized substances is in anaesthesia, where the agents are typically in the vapor phase at room temperature. Electronic cigarettes are increasing in popularity as a means of nicotine delivery. These devices gently heat solutions of diols, flavouring, and nicotine to generate an inhalable aerosol. Heat is delivered via a battery with temperatures in the range of 40–65 °C. At these temperatures, thermal degradation is expected to be minimal. As of the writing of this paper, no published reports specifically discussing ingestion of abused drugs via electronic cigarettes have been located.
As shown in Figure 2a, the reactive areas are the combustion zone (exothermic reactions) and the pyrolysis zone, where endothermic reactions dominate. Active combustion occurs in the tip and is accentuated when the user "puffs" on the cigarette and draws air through the region. During the puff, the temperature rises quickly and can approach 950 °C. Oxygen is depleted from the air as it flows through the combustion region to the pyrolytic region.
Figure 2. Upper frame: Heated zones and airflow in a cigarette. Lower left: Heated zones and airflow in an improvised heating device. Lower right: Heating process in open air as in “chasing the dragon”.
Chemical reactions here are dominated by reductive decomposition. Condensation and filtration of particulate matter occurs as products near the mouth. A 2004 paper discussed experiments to determine to what degree volatilized compounds were thermally degraded during cigarette smoking. Using an analytical pyrolysis inlet to a GC-MS, the authors found that for most compounds, the majority of the parent compound is transferred to the smoker. This study demonstrated that the degree of intact transfer depended on formula weight and volatility (the smaller the molecular weight, the greater the intact transfer) and to a lesser degree on functional groups and matrix. The authors compared analytical pyrolysis results to smoking using radiolabelled compounds and for relatively volatile compounds (<~300Da) reported that analytical pyrolysis was a good model for smoking. They noted one caveat: this methodology overestimated the degree of pyrolysis of larger, less volatile compounds. This limitation is not critical in the context of drugs of abuse, most of which have molecular weights less than 400Da.
Cigarette smoking does not mimic the typical process used to ingest drugs such cocaine, methamphetamine, amphetamine, heroin, and fentanyl. In these instances (Figures 2b and 2c), drugs are placed on a surface or in a makeshift pipe such as a light bulb and heated using a lighter. The vapour is drawn into the lungs using a straw or similar device. Depending on the design of the device, the user can draw air over the heated material, or in the cases of pipes, through the material. There is no combustion zone comparable to that in cigarettes. Accordingly, many modes of smoking are better described as open-air heating under oxidative conditions. In the method referred to as ‘chasing the dragon’, the substance is placed on a surface such as aluminum foil and heated with a lighter. The foil reaches elevated temperatures of up to 600 °C within a few seconds, although absorption of heat by the matrix (determined by heat capacities) may limit the temperature of the solid to ~400 °C.
Cigarette smoking does not mimic the typical process used to ingest drugs such cocaine, methamphetamine, amphetamine, heroin, and fentanyl. In these instances (Figures 2b and 2c), drugs are placed on a surface or in a makeshift pipe such as a light bulb and heated using a lighter. The vapour is drawn into the lungs using a straw or similar device. Depending on the design of the device, the user can draw air over the heated material, or in the cases of pipes, through the material. There is no combustion zone comparable to that in cigarettes. Accordingly, many modes of smoking are better described as open-air heating under oxidative conditions. In the method referred to as ‘chasing the dragon’, the substance is placed on a surface such as aluminum foil and heated with a lighter. The foil reaches elevated temperatures of up to 600 °C within a few seconds, although absorption of heat by the matrix (determined by heat capacities) may limit the temperature of the solid to ~400 °C.
Terminology and mechanism
The term most frequently used to describe the smoking process in the context of drugs of abuse is pyrolysis. Pyrolysis is a type of gas phase thermal degradation reaction that can occur in aerobic or an aerobic conditions. Strictly defined, pyrolysis is not combustion, but pyrolysis can lead to the initiation of combustion. The temperature range at which pyrolysis occurs depends on the material undergoing decomposition. In this review, pyrolysis will be used generically to describe breaking of bonds yielding free radicals that generate, directly or indirectly, product molecules. In the majority of cases, initial cleavage is based on bond strength and the compounds formed can be predicted based on the relative stability of the products and potential rearrangement products. Pyrolysis reactions (in order of frequency) include eliminations, rearrangements, oxidations, reductions, substitutions, and additions. It is worth noting that gas phase pyrolysis has been extensively studied in areas such as combustion, biomass burning, polymers, and energy/fuels but there are no ready tools or applications that afford rapid in-silico prediction of what pyrolytic products may form from a given small molecule under a given set of conditions. Of the noted reaction types, pyrolytic elimination is the most commonly observed and can be categorized as α-eliminations, β-eliminations, 1,3-eliminations, etc., depending on what atoms are involved in the initial bond cleavage and which atoms are eliminated. Many of these elimination reactions follow an Ei mechanism, an intra-molecular (i) elimination process. The transition state is cyclic, and any newly formed double bond generally goes toward the least substituted carbon (Hoffmann’s rule). If a double bond already exists within the molecule prior to the reaction, the formation of a conjugated system will be favoured if sterically feasible.
A few papers have addressed the influence of the protonation state and acid salt form of the basic drugs evaluated for pyrolytic products. The chloride anion (from an HCl salt) can act as a nucleophile and as a result, chlorinated products have been observed as pyrolysis products.
A few papers have addressed the influence of the protonation state and acid salt form of the basic drugs evaluated for pyrolytic products. The chloride anion (from an HCl salt) can act as a nucleophile and as a result, chlorinated products have been observed as pyrolysis products.
Figure 3. Reported pyrolytic products of methamphetamine.
There are seven main pyrolysis products: amphetamine (17, Figure 3), trans-phenylacetone (18, Figure 3), dimethylamphetamine (19, Figure 3), n-acetyl, n-propionyl, n-formyl-methylmethamphetamine (20, Figure 3), andn-cyanomethylmethamphetamine (21, Figure 3). A 1999 study confirmed many of these pyrolytic products and identified numerous others including furfurylmethylamphetamine, 2-propenylbenzene, benzyl methyl ketoxime, 3,4-dihydro-2-naphthaleone, n-formylamphetamine, n-acetylamphetamine, and bibenzyl although identifications were not confirmed by reference standards.
A paper published in 2007 by Ely et al. utilized an analytical pyroprobe and identified amphetamine, ethyl benzene, 1-phenylpropene (22, Figure 3), toluene, styrene, ephedrine, nor-ephedrine, and several metabolites as pyrolytic products. A few mixtures were evaluated (with caffeine, lidocaine, and benzocaine) with no notable differences in the methamphetamine pyrolytic products. Bibenzyl was also reported, but the identification was not confirmed by reference standards.
The last listed components do not have a significant effect on the consumer's body due to extremely small quantities. For example, the sublimation of 1 g of methamphetamine produces no more than 0.00001 g of ephedrine and norephedrine, which is 1000 times lower than the minimum effective dose. Probably, during sublimation, a number of other substances are formed, but in such insignificant quantities that it is not possible to identify them at this stage of development of control methods.
A paper published in 2007 by Ely et al. utilized an analytical pyroprobe and identified amphetamine, ethyl benzene, 1-phenylpropene (22, Figure 3), toluene, styrene, ephedrine, nor-ephedrine, and several metabolites as pyrolytic products. A few mixtures were evaluated (with caffeine, lidocaine, and benzocaine) with no notable differences in the methamphetamine pyrolytic products. Bibenzyl was also reported, but the identification was not confirmed by reference standards.
The last listed components do not have a significant effect on the consumer's body due to extremely small quantities. For example, the sublimation of 1 g of methamphetamine produces no more than 0.00001 g of ephedrine and norephedrine, which is 1000 times lower than the minimum effective dose. Probably, during sublimation, a number of other substances are formed, but in such insignificant quantities that it is not possible to identify them at this stage of development of control methods.
Pyrolysis products brief overview
Amphetamine is a central nervous system stimulant that, like methamphetamine, is based on an increase in the release of catecholamines (dopamine, norepinephrine and serotonin) from the presynaptic endings, which reduces fatigue, induces a surge of energy, reduces the need for sleep and suppresses appetite.
Phenylacetone is a substance used for the synthesis of amphetamine and methamphetamine, as well as an inactive metabolite of these surfactants. In the body, it undergoes oxidation to benzoic acid, conjugation with glycine to form hippuric acid, which is excreted by the kidneys. Does not have a noticeable psychoactive effect on the body with this method of use.
Dimethylamphetamine is a CNS stimulant that is less potent than amphetamine and methamphetamine, with similar effects. N-formylmethamphetamine is a toxic substance that irritates the skin and mucous membranes, causes metabolic disorders, tends to accumulate in the body, causing mental disorders, organic lesions of the central nervous system. It is reduced to methamphetamine in an acidic environment.
N-formylmethamphetamine is a toxic substance that irritates the skin and mucous membranes, causes metabolic disorders, tends to accumulate in the body, causing mental disorders, organic lesions of the central nervous system.It is reduced to methamphetamine in an acidic environment.
1-Pnylpropene is a carcinogen and mutagen; does not accumulate in the body. Frequent inhalation causes lung cancer.
N-cyanomethylmethamphetamine is a strong poison, has a local irritating effect on the skin and mucous membranes, in the body it is metabolized to cyanides, which inhibit cellular respiration. It is formed only when methamphetamine is sublimated together with tobacco (for example, when smoking a cigarette with methamphetamine).
Phenylacetone is a substance used for the synthesis of amphetamine and methamphetamine, as well as an inactive metabolite of these surfactants. In the body, it undergoes oxidation to benzoic acid, conjugation with glycine to form hippuric acid, which is excreted by the kidneys. Does not have a noticeable psychoactive effect on the body with this method of use.
Dimethylamphetamine is a CNS stimulant that is less potent than amphetamine and methamphetamine, with similar effects. N-formylmethamphetamine is a toxic substance that irritates the skin and mucous membranes, causes metabolic disorders, tends to accumulate in the body, causing mental disorders, organic lesions of the central nervous system. It is reduced to methamphetamine in an acidic environment.
N-formylmethamphetamine is a toxic substance that irritates the skin and mucous membranes, causes metabolic disorders, tends to accumulate in the body, causing mental disorders, organic lesions of the central nervous system.It is reduced to methamphetamine in an acidic environment.
1-Pnylpropene is a carcinogen and mutagen; does not accumulate in the body. Frequent inhalation causes lung cancer.
N-cyanomethylmethamphetamine is a strong poison, has a local irritating effect on the skin and mucous membranes, in the body it is metabolized to cyanides, which inhibit cellular respiration. It is formed only when methamphetamine is sublimated together with tobacco (for example, when smoking a cigarette with methamphetamine).
Conclusions:
1. Do not smoke methamphetamine with tobacco under any circumstances.
2. In case when you are smoking pure methamphetamine, it is advisable to pass vapors through a liquid containing a weak acid (lemon, apple or orange juice, dry wine, etc.) before inhalation. The gases are cooled in water and do not damage the respiratory system. If you follow these recommendations, inhalation of methamphetamine is no more dangerous than intranasal or oral use.
2. In case when you are smoking pure methamphetamine, it is advisable to pass vapors through a liquid containing a weak acid (lemon, apple or orange juice, dry wine, etc.) before inhalation. The gases are cooled in water and do not damage the respiratory system. If you follow these recommendations, inhalation of methamphetamine is no more dangerous than intranasal or oral use.
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