What is the pharmacology of psychoactive drugs? - Chapter 9

Introduction: psychostimulants, psychedelics and marijuana

In this chapter and the next, we will look at all different kinds of drugs ranging from caffeine to crack and cocaine. Most drugs that will be discussed in this chapter exists for hundreds or even thousands of years. The use of drugs became alarming up till 2000. Since that year, the use of drugs by teenagers is stable. There is even a little decline and the decline of alcohol and tobacco use is bigger. Only the trend of marijuana use is an increasing one.

Drug schedule refers to the potential for abuse of a drug and this has been described by the Controlled Substance Act in 1970. Schedule I drugs do have less potential for abuse than schedules II to V.

Psychostimulants: Cocaine

Cocaine is extracted from the coca plant, which grows in the mountains of South America. People used to chew on the leaves of this plant, because it produced feelings of confidence. Nowadays, cocaine is most exported as cocaine sulphate or cocaine hydrochloride.

Cocaine compounds are extracted by crushing the leaves in a solution (such as kerosene, gasoline or alcohol). The liquid mixture that remains is processed under heat with sulfuric acid to isolate the cocaine alkaloids and to remove the waxy residues. The cocaine sulphate paste that remains contains about 60% cocaine and is then further processed into a water-soluble crystal composition called cocaine hydrochloride.

In South America, many of the waste products that originate during the extraction process of cocaine are dumped in the river. This has very harmful ecological consequences.

History of cocaine use

Cocaine alkaloid was first isolated in 1855 by Friedrich Gaedcke, he called it erythroxyline . Albert Niemann then called it cocaine. It was used as a local anesthetic, especially in eye and nose operations. It was also added to many drinks, given the stimulating effects and you could buy cocaine in local drugstores. Freud was enthusiastic about the substance and recommended it to other people. It was only in 1914 that the use of cocaine in all forms was banned by the Harrison Narcotic Tax Act and was described as a dangerous narcotic.

Pharmacology of cocaine

Cocaine hydrochloride is a water soluble substance that divides itself into cocaine-H + and Cl - ions after its administration. The positively charged cocaine ions are able to quickly pass cell membranes and enter the brain. Snorted and orally administered cocaine goes slower and will be absorbed less complete than intravenously administered, inhaled or vaporized cocaine.

Crack cocaine

Methylbenzoulecgonine is a composition that is the result of dissolving cocaine hydrochloride in a mild ammonia solution. This composition can be vaporized for inhalation and is called crack because of the cracking sound in this process. Crack can also be manufactured by heating cocaine hydrochloride in water and sodium ('sodium') bicarbonate. The cocaine rocks that arise as a result (called 'freebase' cocaine) are then heated until they can be vaporized. Inhalation causes peaks in plasma concentrations within 5 minutes.

Benzoylecgonine and ecgonine are the major metabolites of cocaine and can be found for weeks in both blood and body tissue. Cocaethylene is produced when cocaine is used together with alcohol. It can cause hypertension, ventricular arrhythmia and reduced blood flow with potentially fatal consequences.

Mechanisms of cocaine

Because cocaine binds to the dopamine transporter, it can pass through cell membranes in the brain. Cocaine binds to the dopamine transporter (DAT) and as a consequence blocks the normal reuptake of dopamine in the synaptic cleft, resulting in prolonged dopamine activity on postsynaptic receptors. Cocaine has similar effects on noradrenaline and serotonin receptors, but these are less important than the effects on the dopamine receptors. Blocking the dopamine transporter happens very quickly after the administration of cocaine. The rapid increase in dopamine activity in the mesolimbic system is believed to cause the pleasant effects of cocaine.

Place preference conditioning is a conditioning process in which one has a preference for the space where cocaine is administered. This has been shown by research with rats, a process that is evident from the rats' preference to spend time in the room where they were given cocaine. It is a demonstration of Pavlovian conditioning in which the signals of the specific context or space are associated with the use of drugs.

Cardiac toxicity is a dangerous effect of cocaine. It can cause myocardial infarction, arrhythmias and sudden death, because of the Na + channel blockade in neurons.

Psychostimulants: Amphetamine and meta-amphetamine

Amphetamines are compositions that are very similar to dopamine in chemical structures. The first used composition was ephedrine, also known as the old Chinese medicine ma huang. More recently the drug is called ephedra, which has been marketed as a substance for weight loss and it increases vigilance and performance. Although the effectiveness of this product remains controversial, it has been banned in the sports world. Due to many deaths, the drug has been completely banned since 2004.

Amphetamine was first synthesized in 1887. Around 1930 it came onto the market under the name Benzedrine as an antihistamine inhaler. Dextroamphetamine (Dexedrine) is structurally related to amphetamine and was introduced to treat narcolepsy, attention deficits, nasal congestion and obesity. In 1940, amphetamines were used to treat nearly 40 different disorders.

In 1960 the production of amphetamines increased, due to the use for weight loss. The funds were also used extensively by students and athletes, with sometimes deadly consequences. In 1970 the use of amphetamines was limited to only medical applications (narcolepsy and attention disorders).

Metamphetamine was first synthesized from ephedrine in 1893 and became very popular in the United States in 1980 due to its strong euphoric effects. It differs structurally from amphetamine by the added methyl group (CH3), which increases the solubility in fat. As a result, it can only cross the blood-brain-brain barrier a few seconds after the injection. Pure metamphetamine has a crystal form, which explains the name Crystal Meth.

Pharmacology of the amphetamines

Amphetamines can be administered in various ways, including: taking a pill orally (peak plasma concentration 2-3 hours), sniffing (inhalation through the nose), smoking and intravenous injection (peak plasma concentration 5 minutes). The metabolic half-life of amphetamines is between 10 and 15 hours.

Mechanisms of amphetamine

Amphetamines increase the synaptic concentrations of noradrenaline and dopamine through different mechanisms. The first is that they bind to the presynaptic membranes of dopaminergic and noradrenergic neurons to increase the release of norepinephrine and dopamine from synaptic vesicles. They also block reuptake transporters of norepinephrine and dopamine.

Besides, amphetamines increase the dopamine activity by different mechanisms. They ensure that the dopamine transporters occur in reserve, through which vesicular dopamine is transported back into the terminal. Furthermore, this "free" dopamine is transported to the synaptic gap.

The contribution to behavioral stimulation and euphoria of amphetamines is also complex. They do this via the mesolimbic-mesocortical pathways in the ventral tegmental area (VTA). The euphoria is mediated in these regions of the brain and dopamine neurons from the VTA project tot the frontal cortex. This is called the mesocortical pathway.

Other amphetamine related drugs

A known composition structurally related to amphetamines is XTC (ecstasy) or also MDMA (methylenedioxymethamphetamine). The popularity of this drug began in 1970 when it was used as an aid for psychotherapy. The recreational use increased rapidly and the drug has been banned by the FDA since 1985. Users of this drug report euphoria, increased self-perception, an increase in sensations and promotion of intimacy with others. Dangerous side effects can include an increased heart rate and blood pressure, intense sweating and, severe tooth grinding (breaking of the teeth is not uncommon).

The neurotoxic consequences of MDMA are the strongest effects. This includes the significant damage to cortical serotonergic and dopaminergic neurons. These degenerative effects can persist for years after use of the drug. Even low to average use reduces or worsens many cognitive domains.

MDMA is a potent dopamine agonist. This means that it directly increases serotonin activity by enhancing the release of serotonin during neuronal signaling and by preventing reuptake. The dopamine activity in the nucleus accumbens is increased by blocking dopamine transporters and indirectly activating serotonergic neurons that regulate dopamine activity in the VTA.

Psychedelics: LSD and Psilocybin

LSD stands for 'lysergic acid diethylamide'. The strong hallucinogenic effects can occur in any modality, but the most striking hallucinations are visual. Color and movement is disturbed and music or sound can be observed with greater intensity and complexity. The hallucinations are sometimes described as synaesthesia. LSD was synthesized for the first time in 1938 by Albert Hoffman, who became an increasingly strong proponent of his responsible use during his lifetime.

Pharmacokinetics of LSD and Psilocybin

Two hours after oral intake, peaks in plasma concentrations will be reached. The drug crosses the blood-brain brain barrier and is quickly distributed over the body tissue. LSD is the most powerful means of all psychoactive drugs. However, there is still no confirmed lethal dose. Psilocybin is a psychedelic composition that has been found in a specific type of mushroom. The pharmacological properties of LSD and Psilocybin are comparable to each other. However, research focuses more on LSD, so the emphasis in this book is more on LSD.

There are a number of harmful side effects of LSD known: increase in body temperature, heart rate and blood pressure, pupil dilation, dizziness, and nausea. The psychological side effects are: confusion, acute panic and, noticeable disturbances in both time and space. Because some users report flashbacks that persist long after using LSD, there is a separate category for the Hallucinogen Persistent Perception Disorder created in DSM-5. To get this diagnosis, one may not have used a hallucinogenic drug recently and show no signs of drug intoxication. For more information about the diagnostic criteria, see page 229. There is no agreement about the treatment of this disorder.

Pharmacodynamics of LSD and Psilocybin

LSD and Psilocybin are partial serotonin agonists with high affinity for 5-HT receptor subtypes. This is probably due to their molecular structure. Partial agonists are drugs that have an affinity for a receptor, but have a lesser effect than agonists or endogenous ligands (in this case serotonin).

The current theory is that the hallucinogenic effects of LSD and Psilocybin are mediated by partial agonism of 5-HT2A receptors in the brainstem and in multiple cortical areas (middle prefrontal cortex, cingularis anterior and the somatosensory cortex). Research on the patterns of neuronal signals (neuronal signaling) generated by hallucinogens is done with laboratory animals.

Marijuana (Cannabinoids)

Marijuana is the name that is often used for cannabis sativa. Its use began tens of thousands of years before Christ. In 1900 the drug was mainly used for medicinal purposes. In 1937, however, the use of this drug in the United States was stopped by the Marijuana Tax Act. Cannabis was further controlled by the Controlled Substances Act in 1970. In 1992, William Devane and his colleagues isolated an endogenous cannabinoid, which they called anandamide.

Pharmacokinetics of Marijuana (THC)

THC stands for Delta 9-tetrahydrocannabinol. By heating marijuana, the THC vaporizes and enters the blood through the lungs. Only seconds after inhalation the blood-brain-brain barrier traverses. Peaks in the plasma concentration are reached within a few minutes. The concentration of THC is very variable and depends on the type of cannabis that is used and how the cannabis has grown. An average marijuana cigarette contains about 0.5 grams of plant material with a THC content of about 8.5 percent. The amount of THC that is inhaled is about 10-20 percent. This means that the bioavailability of THC in a cigarette is only about 5 milligrams.

Orally administered marijuana is absorbed slower and less completely. Peaks in plasma concentrations are reached one to four hours after ingestion. THC and its metabolites can be found in the body for a long time, up to 2 weeks after use.

In the case of frequent users of marijuana, metabolites can still be found three to four weeks after abstinence, as the THC has built up in the tissues and is only gradually metabolized.

Pharmacodynamics of Marijuana (THC)

THC has a direct interaction with neuronal signal systems. This theory is based on the fact that an extremely small dose of THC already has noticeable effects. For the exercise of this effect, THC must work directly on cell receptors and no non-specific effect can occur.

In 1988, cannabinoid (CB) receptors were found in rats using 'radioactive labeling'. Two types of CB receptors are now known:

CB1 receptors: This kind of CB receptors are located in the basal ganglia, the cerebellum, the hippocampus, the amygdala, the thalamus and the cortex. These receptors are in any case partly responsible for the behavioral effects of marijuana.

CB2 receptors: This kind of CB receptors are located on the presynaptic terminals of different types of neurons. All of these receptors are metabotropic G-protein coupled receptors that regulate the formation of cyclic AMP.

These receptors provide a process of neuronal suppression, which is a common type of short-term neuronal plasticity. The depolarization of a neuron causes a reduction in the GABA-mediated neural inhibition.

Medicinal use of cannabinoids

Dronabinol (Marinol) is a synthetic THC extract of marijuana. In the United States it can be used as a remedy for nausea and vomiting as a result of chemotherapy and radiation therapy against cancer. Nabilone (Cesamet) is a fully synthesized THC. It can be used in the United States to treat nausea and vomiting due to cancer therapy and to treat anorexia and weight loss due to AIDS.

A number of other medical conditions may also benefit from marijuana treatment, including: sight threatening ocular pressure associated with glaucoma; chronic and phantom pain on the limbs; withdrawal symptoms due to opiate and alcohol addictions; muscle spasms in patients with multiple sclerosis, Huntington's disease and Parkinson's disease.

Pharmacological effects of Marijuana, Dronabinol and Nabilon (THC)

Memory and cognition

The effects of THC are mild euphoria, anxiolysis and disturbances in the perception of time. Furthermore, it can cause confusion and an increased feeling of fear in some (especially frequent) users. Furthermore, THC damages cognitive and motor functioning. Harmful effects on memory have been known for some time, these are probably mediated by CB1 receptors in the hippocampus.

Motion control and coordination

A high dose of THC inhibits the release of glutamate in the afferent neurons in the basal ganglia, causing disturbed movement and even cataplexy. Furthermore, cannabinoids disrupt the normal cerebellar control of movement, independent of the central dopamine movement systems. Contrasting is the therapeutic effect of activation of these cannabinoid receptors in people with multiple sclerosis, Parkinson's disease and Huntington's disease.

Nausea and vomiting

An advantage of Marijuana over other antiemetic drugs is the fact that the side effects are often more tolerable for patients. Cannabinoids seem to work directly on the CB1 receptors in the area postrema, as a result of which the reflex to surrender is inhibited.

Cardiovascular effects

Initially the use of cannabinoids will cause an increase in blood pressure and heart rate. Frequent users, however, often have to deal with a fall in blood pressure as a result of vasodilation.

Immune system effects

Recent research has shown that cannabinoids (and specifically CB2 agonists) inhibit immune responses and inflammation.

Tolerance and dependence

Tolerance appears with animals and people who receive an extremely high dose of a drug. There is still no evidence for tolerance after a dose that most users and patients receive. Chronic use can cause dependence, with abstinence causing withdrawal symptoms.

Self-administration of THC

In a self-administration experiment with THC, animals had to press a lever to get the drug. In the fixed ration 10 (FR10) schedule, a small amount of it will be released every tenth press. These animals got around 40 to 50 injections in one hour. This means that THC does have abuse potential.