In the News: Tom Petty

The Los Angeles County, California Medical Examiner/Coroner's Office released Tom Petty's official cause and manner of death yesterday.

The cause of death was "multisystem organ failure due to resuscitated cardiopulmonary arrest due to mixed drug toxicity (fentanyl, oxycodone, temazepam, alprazolam, citalopram, acetylfentanyl, and despropionylfentanyl).

Other conditions listed included coronary artery atherosclerosis and emphysema.

Manner of death was accident.

Tom Petty's family released a statement on social media and his personal website. The statement can be read here.

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What were the substances found in his system?

Several central nervous system depressants or related substances and an antidepressant.

Fentanyl is an synthetic opioid typically prescribed as the pharmaceutical medications Duragesic (transdermal), Actiq (oral transmucosal), or Fentora (buccal). Historically, it has been used to treat breakthrough pain and is used in pre-operation procedures as an analgesic and anesthetic. Fentanyl is a mu opioid receptor agonist that is considered to be approximately 100-200 times as potent as morphine as an analgesic. It is metabolized to norfentanyl. The substance is also illicitly manufactured in clandestine laboratories and has been found as a very common adulterant in street heroin and counterfeit tablets over the last few years. Fentanyl is a Schedule II controlled substance in the USA.

Oxycodone is a semisynthetic opioid that is derived from thebaine. Trade names of the  pharmaceutical medication include OxyContin, OxyIR, Roxicodone, Percocet, or Endocet. It is typically used for the relief of moderate to severe pain. It functions as a mu opioid receptor agonist. Oxycodone is metabolized to oxymorphone and noroxycodone. Oxycodone is a Schedule II controlled substance in the USA.

Temazepam is a benzodiazepine routinely prescribed as the brand name Restoril. Chemically, it is a 3-hydroxyl derivative of diazepam (trade name Valium). It is used for the treatment of short term insomnia. It functions as a GABAA receptor agonist. Temazepam is metabolized to the oxazepam. Temazepam is also a metabolite of diazepam. Temazepam is a Schedule IV controlled substance in the USA.

Alprazolam is a potent benzodiazepine prescribed as the brand name Xanax. It is typically used to treat anxiety and panic disorders. Much like temazepam (and other benzodiazepines), it functions as a GABAA receptor agonist. Alprazolam is metabolized to alpha-hydroxyalprazolam. Alprazolam is a Schedule IV controlled substance in the USA.

Citalopram is a drug prescribed as an antidepressant under the brand name Celexa. It functions as a selective serotonin reuptake inhibitor (SSRI) and is approved for treatment of major depressive disorder and is prescribed off-label for a multitude of other conditions including anxiety and panic disorders and obsessive-compulsive disorder. From a chemistry standpoint, citalopram is sold as a racemic mixture of the R and S enantiomers, with the S enantiomer having an antidepressant effect. A medication named Lexapro is sold as only the S enantiomer otherwise known as escitalopram. Citalopram is metabolized to desmethylcitalopram and didesmethylcitalopram. Citalopram is not a controlled substance, but is only available via prescription.

Acetylfentanyl is a synthetic fentanyl derivative that is considered to be about fifteen times more potent than morphine as an analgesic. It is not available as a prescription medication and is a true designer/research chemical substance. It functions as a mu opioid receptor agonist, much like fentanyl and oxycodone. Chemically, acetylfentanyl differs from fentanyl by a replacement of the propionyl group with an acetyl group. Acetylfentanyl has been found in the USA since 2013 and has been detected in street heroin and counterfeit pharmaceutical tablets. It was made a Schedule I controlled substance in the USA in 2015.

Despropionylfentanyl is also known as 4-ANPP. It is a very minor metabolite of fentanyl and is a precursor in the illicit (non-pharmaceutical) synthesis of illicitly manufactured fentanyl and related fentanyl analogs. The substance itself has very little pharmacological activity, but its presence in the human body can be used to aid in determining the source of fentanyl used, e.g. consumption of pharmaceutical fentanyl vs. ingestion of illicitly manufactured fentanyl.

My thoughts?

I won't give many thoughts because I am not privy to the case specifics. I do not know all the details. The only people that know the details are those who investigated his death and formulated the final autopsy report and cause of death certification. Any general comments I make are speculative in nature, but are based on my knowledge and experience in the field.

From a general forensic toxicology standpoint, the real takeaway is that this is a dangerous combination of substances to use concurrently. He was consuming two powerful opioid and two potent benzodiazepines which when used together can create synergistic effects and exaggerated central nervous system depression. Add that situation to an already compromised cardiovascular and respiratory system, and it's a recipe for disaster.  For my own information, I would love to see the full toxicology report with quantitative measures of drug, etc. How much fentanyl was present? How much temazepam and alprazolam were detected? Not that any of that really matters though.

With the detection of acetylfentanyl and despropionylfentanyl, it seems as if Tom Petty was supplementing his pharmaceutical medications with illicitly manufactured substances. Acetylfentanyl is not a pharmaceutical medication anywhere in the world and is only found as a designer opioid/analog meant to skirt the controlled substances act in the USA. Fentanyl does not metabolize to acetylfentanyl. As despropionylfentanyl is a precursor/intermediate used in the illicit (non-pharmaceutical) synthesis of fentanyl, it generally used as a marker for exposure to illicitly manufactured fentanyl. The presence of this substance has also been associated with the use of various fentanyl analogs including acetylfentanyl, acrylfentanyl, and furanylfentanyl. No one knows if the use of illicit opioid was intentional or not. Remember the situation surrounding Prince's death. Multiple pills were found in his residence that looked like pharmaceutical hydrocodone/acetaminophen but turned out to be counterfeit tablets containing fentanyl and the opioid research chemical U-47700.

As a conclusion, I'll say, please do not mix depressant drugs. Do not mix opioids with benzodiazepines. Do not mix either of them with ethanol. Stay safe, folks.

Addendum:

I just saw that the great Dr. David Kroll wrote an article on this matter over at Forbes. Go read his work here. He is one of the best writers on these sorts of topics.