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Synthetic Analogs of Naturally-Occurring Drugs

Psychoactive drugs act by mimicking natural transmitters, or blocking them, or in some other way interfering with them or boosting their levels. As knowledge of neuro­transmitters accumulates, scientists are able to synthesize more substances with psychoactive effects.

Synthetic analogs of natural drugs are sometimes called designer drugs. Many drug experts dislike that label because it glamorizes drug taking.

Whatever they are called, the synthetic analogs pose a problem. Their chemistry is complex, and there is no way to know exactly what ingredients are in a drug purchased on the street. The dosage is unknown, and the effects can be different from natural drugs.

What is a big problem with synthetic drugs purchased "on the street"?

In one of the earliest cases involving synthetic drugs, a 23-year-old chemistry graduate student tried to synthesize Demerol. Demerol is a synthetic opioid: a chemical with effects similar to heroin.

The student made a slight error and produced a batch containing a by­product called MPTP. This chemical proved to destroy dopaminergic areas in a brain region called the substantia nigra.

The young chemist arrived at the hospital "mute, unable to move or swallow, and he had a tremor. His symptoms subsided when he was given L-Dopa" (Kolata, 1983). The young man had accidentally given himself Parkinson's disease.

His reaction led to a breakthrough for Parkinson's disease research because it pinpointed the brain area involved. Unfortunately, it left the young man (and a number of other drug users who tried similar substances) with a permanent disability.

How did MPTP lead to a breakthrough in Parkinson's disease research?

Many synthetic opioids exist. The list includes Demerol, Fentanyl, Dilaudid, Methadone, Buprenor­phine, and oxycodone, the chemical in Oxycontin.

Some of these synthetic opioids (such as Fentanyl) are so powerful that overdose is a serious risk at small doses. One young man died after taking a single draw on a pipe heating a Fentanyl patch.

MDMA (ecstasy)

Ecstasy or MDMA (3,4-methyl­enedioxy­methamphetamine) is another in a long series of synthetic drugs resembling amphetamine in chemical structure. (Several others, such as the so-called smart drugs, were discussed on the page about stimulants.)

Ecstasy produces symptoms similar to LSD. The trip is not as dramatically visual as that produced by high doses of LSD, nor is it as likely to result in a bad trip or feelings of anxiety. MDMA was first synthesized in 1912, but it became widely known as a party drug in the 1980s and 1990s.

Users of MDMA reported a sensation of well-being, oneness with the world, and loving everybody. However, warning signs emerged early.

A team of researchers (Ricaurte et al, 1985) reported the dose of MDMA required to kill neurons in lab animals was only three times the dose required to get a behavioral effect. The drug destroyed serotinergic neurons in the brain.

One of the researchers, Seiden, des­cribed scary aftereffects. "We've looked at rats eight weeks after they've re­ceived MDMA," said Seiden. "Their brains are still depleted in serotonin, and there doesn't seem to be a hint that it's going to come back." (Roberts, 1986).

Such warnings earned MDMA a section in Goode and Ben-Yehuda's book: Moral Panics: The Social Construction of Deviance (1994). Moral panic or not, users reported pleasant effects, so ecstasy became very popular.

During the 1990s in Britain, MDMA was associated with raves or all-night dance parties. By 2000 it was called "the rave drug" in the United States as well.

Deaths at raves occurred when MDMA was combined with other drugs, notably alcohol or other amphetamines. The immediate cause was hyperthermia or overheating.

Through the decade of the 2000s deaths from MDMA were relatively rare. Gable (2006) estimated there were less than 35 deaths from MDMA in the entire English-language medical literature, and almost all involved alcohol as well.

Ecstasy continued to grow in popularity. By the 2010s, trance festivals attracting tens of thousands of young people spread across Europe, Asia, and the U.S. Many of the festivals had explicitly spiritual themes about oneness or connecting to nature and the cosmos.

With thousands of young people using ecstasy, casualties started accumulating. Bamadhaj (2015) shared a collection of news reports about ecstasy-related deaths during the year before he wrote:

The list below is not exhaustive:

Bamadhaj also talked to a doctor who did autopsies on three victims from a festival in Malaysia (Dr. Nadesan, Professor of Forensic Pathology at University of Malaya). "They did not die of overdoses," the doctor said. "The three deaths were clearly from heat stroke." Bamadhaj explains:

"Typically the mistakes are sun exposure (even hours before), being physically active (danc­ing) in a crowd of hot bodies, not drinking water, wearing clothes that don't breathe and then throw in Malaysian 99% humidity...

"What happens is your body temperature rises so much and fast that the brain's thermometer (hypothalamus) stops working and you stop sweating so your body temperature rises even more and you bleed internally and/or your organs shut down and you die quite quickly."

Deaths due to heat stroke are not included when doctors calculate a dose/toxicity ratio for MDMA using lab animals. The dose/toxicity ratio for MDMA is 16, a more favorable number than alcohol's dose/toxicity ratio of 10, according to Gabler (2006).

Why might the dose/toxicity ratio for MDMA be misleading, when evaluating its dangers?

The main dangers from MDMA appear to be: (1) death from heat stroke, aggra­vated by ecstasy's disturbance of heat regulation in the body, and (2) long-lasting "gray moods" (mild depression or anhedonia) due to lowered serotonin levels.

If Ricaurte and colleagues were correct that MDMA killed neurons at sub-lethal doses (without necessarily killing the animal) that is also worth noting. Nobody has determined whether similar cell death occurs in humans taking a triple dose of ecstasy, but any dosages that high should be avoided.

What are the major dangers from MDMA?

MDMA or ecstasy was legal for months after it was discovered. There was no law specifically prohibiting it.

At the urging of law enforcement officials, the United States congress passed a law banning any synthetic drug that resembled a drug currently abused. Now it is illegal in the United States to produce or sell any drug that alters consciousness in a way resembling existing psycho­active drugs.

Amphetamine Derivatives

Chemists experimented with variations on the amphetamine molecule, producing drugs they hoped would lack some of the dangers of amphetamine. One of these, Adderall, became widely prescribed in the United States to combat ADHD (attention deficit with hyperactivity disorder).

Adderall became a "drug of abuse," as teenagers shared prescrip­tion medications. A generation of young adults appeared with dependencies on the newer drugs.

Newer amphetamine-related drugs are sometimes called "smart drugs" or nootropics. They are said to boost the performance of workers, increasing the ability to focus.

A 2015 New York Times article noted Adderall and smart drug dependency among workers in the 25-to-45 age group. Some felt they could not work without the drug (Schwarz, 2015).

Armodafinil and modafinil are among the most widely used of these drugs. They increase alert­ness and are said to facilitate reasoning and problem solving ability.

They are also prescribed for excessive daytime sleepiness and narcolepsy. In children, they are used as an alternative to amphet­amines.

Modafinil and armodafinil are dopamine re-uptake inhibitors. They lessen the removal of dopamine from synapses, allowing more of it to accumulate. Modafinil and armodafinil are removed slowly from the nervous system. They have a half-life of 15 hours.

What are the most common nootropics?

A half-life of 15 hours means that half the drug is broken down over a 15 hour period. After 30 hours, a quarter of it is still there.

After 45 hours–nearly two days–an eighth of a dose is still in the blood. It takes more than three days to clear the substance out of a person's system after one dose.

Therein lies a problem with smart drugs. They can build up quickly if taken every day. The only way to stop this accum­ulation is to follow each period of use with three days of abstention.

What is "the problem with smart drugs"?

Adderall's half-life is 11 hours, slightly better. Two days of abstention elim­inates a dose of Adderall.

Synthetic marijuana

A new synthetic drug epidemic emerged in 2015, this time involving synthetic marijuana. A Clemson University professor, John W. Huffman, synthesized a compound that targeted anandamide receptors (those responding to cannabis) in 1993. He called it JHW-018.

Underground chemists used the information in the paper to begin manufacturing "synthetic marijuana." Mixtures with names like K2 and Spice appeared in convenience stores around 2015, often marketed as herbal incense.

The implication was that cannabis-like herbs were in the mixture, but analysis revealed synthetic compounds such as cannabicyclo­hexanol and several others. The compounds were not detectable by drug tests for cannabis, but the effects were more powerful and unpre­dictable than natural cannabis.

How is synthetic marijuana different from natural marijuana?

During 2015 several professional football players in the U.S. were hospitalized for bad reactions to synthetic cannabis. Symptoms included psychotic episodes, violent outbursts, and erratic driving resulting in crashes. In July , 2016, the New York Times reported 130 people in the area were treated in emergency rooms for bad reactions to K2 (Maslin, 2016).

Law enforcement officials stepped up enforcement of laws banning such products. State legislatures passed new laws targeting synthetic marijuana at the same time cannabis was being legalized in many states of the U.S. The synthetic cannabinoids proved to be much more danger­ous and unpredictable than the plant-based products.

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References:

Bamadhaj, H. (2015, June 11) Last Dance: What you didn't know about festival drug deaths. AddictionUnscripted.com. Retrieved from: https://addictionunscripted.com/last-dance-what-you-didnt-know-about-recent-festival-drug-deaths/

Gable, R. S. (2006) The toxicity of recreational drugs. American Scientists, 94, 206-208.

Goode, E. & Ben-Yehuda, N. (1994) Moral Panics: The Social Construction of Deviance. Oxford: Blackwell.

Kolata, G. (1983). Monkey model of Parkinson's disease. Science, 220, 705.

Maslin, S. (2016, July 15) Surge in Overdoses From a Drug: 130 in Three Days. New York Times, p.A20.

Ricaurte, G., Bryan, G., Strauss, L., Seiden, L., & Schuster, C. (1985). Hallucinogenic amphetamine selectively destroys brain serotonin nerve terminals. Science, 229, 986-988.

Roberts, M. (1986, June) MDMA: madness, not ecstasy. Psychology Today, pp. 14-15.

Schwarz, A. (2015, April 18) Workers seeking productivity in a pill are abusing A.D.H.D. drugs. New York Times. Retrieved from: https://www.nytimes.com/2015/04/19/us/workers-seeking-productivity-in-a-pill-are-abusing-adhd-drugs.html


Write to Dr. Dewey at psywww@gmail.com.


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