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Chemistry, Pharmacology, and Toxicology of Tobacco, Marijuana, and Related Substances: Pyrolysis Products and Chemical Research on the Toxicology of Drugs of Abuse

A NIDA and ACS Joint Meeting
March 26-27, 2000

Overview and Outstanding Questions

Pharmacology: A campaign of educating the public on the increased potency of drugs like heroin (and marijuana) may be important.
The uniqueness of delivery by inhalation or insufflation (versus oral routes) of some of these agents makes their pharmacology distinct.
The importance of multiple centers and interdisciplinary national group approaches was stressed, for example, PET centers, and magnetic resonance imaging capability.

Questions- Is marijuana smoking more rewarding than delivery of THC alone?

What is the influence on pregnancy of the use of the nicotine patch?

What are the changes in developing brain function in fetus and particularly in adolescents due to tobacco exposure?

How long do DNA adducts of tobacco/smoke persist in the young after forming? This is also a question for those who have stopped smoking.

What more can be learned from examining matrices in the young, such as in-utero matrices, neonatal hair, meconium, etc, where metabolism differs from adult metabolism.

What are the consequences of second-hand or passive smoke (marijuana, tobacco)?

What are further details of the fetal transfer process of exposure to cigarettes and marijuana? Rat models may not extend well to sheep, primate models.

What is the availability of industry-obtained or industry-generated cigarette data?

What is the mechanism of action of drugs like bupropion in the presence/absence of nicotine exposure?

Is the full extent of multiple receptor influence by nicotine well enough understood?

Have smoking combinations of marijuana/tobacco and methamphetamine/tobacco been adequately studied?

Toxicology: Does long term use of marijuana cause cancer? Epidemiologic studies very limited (Tashkin) and not easy to design. The exposure time to marijuana may now be 20-30 years in some human subjects.

Is there a good animal model(s) for a cancer study?

Are there hemoglobin adducts formed with THC/cannabinoids via smoking?

Is there evidence for emphysema due to marijuana smoking in small and large airways?

On the other hand, are there any alveolar protective effects of THC?

Are there carcinogenic metabolites of THC? Is there data on toxicology of individual cannabinoids?

Is lung tumor growth in mice enhanced by THC exposure?

Do cannabinoids enhance oxidative stress and cell "death"?

What is known about a possible relationship between asthma and cocaine or heroin use?

What is known about the toxicology of pyrolysis products of marijuana?

The toxicology of MDMA exposure is a topic for further investigation, i.e., human safety in view of effects on the DAT and serotonin, effects on long-term memory, and evidence for Parkinsonian-like symptoms.

Therapy/Medications: We need to understand that therapy should address useful reduction in drug abuse, not "cure", needs to be individualized to patients, and may need to be tailored to the stages of abuse (craving, withdrawal, etc).

Many of the possible medications will be of orphan drug status (limited use), and the incentive of the pharmaceutical industry can be limited (example of PCP and cocaine antibody).

For methamphetamine use, neuroprotective active of dopamine antagonists would have to be available within hours. There is a potential in methamphetamine abuse for using drugs relieving depression.

Are there possible antagonists for cannabis abuse, such as the Sanofi compounds?

Is there room for additional combination drugs in patches (such as nicotine and mecamylamine)?

There may be a role for neurotensin, substance P, Y, etc or related compounds as agonists/antagonists in cocaine use, particularly if tied to other uses affecting mental health.

Can a safer marijuana cigarette be developed (which heats, not burns the material)?

What is the potential for a metered dose THC inhaler device?

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