Dr Wallace Pickworth | Manipulating pH in Smokeless Tobacco: Unlocking the Chemistry of Addiction

Tobacco addiction remains a significant public health challenge, with millions of people using smokeless tobacco (SLT) products worldwide. Dr Wallace Pickworth from Battelle Life Sciences Research is investigating how the chemical properties of these products influence their addictiveness. His groundbreaking research has confirmed that the pH level of SLT and other oral tobacco products plays a crucial role in determining how quickly nicotine enters the bloodstream, with important implications for tobacco regulation and public health.

A Hidden Chemical Dance

When someone uses smokeless tobacco (SLT), they might not realise they’re participating in a complex chemical interaction. Nicotine, the addictive component in tobacco, exists in two forms: ‘free-base’ (unprotonated) and protonated. The proportion of each form depends largely on the product’s pH level – a measure of acidity or alkalinity.

This chemical state matters because only the free-base form of nicotine can easily cross the tissues in the mouth to enter the bloodstream. The higher the pH, the more free-base nicotine is available for absorption. Commercial SLT products show a wide range of pH levels, from quite acidic (pH 5.3) to quite alkaline (pH 8.4), suggesting that manufacturers may manipulate this characteristic to influence how quickly and effectively nicotine reaches the user.

The Hidden Dangers of Smokeless Tobacco

Nearly six million adults in the United States regularly use SLT, representing about 2.4% of the adult population. This seemingly small percentage translates into a significant public health concern, as regular use is associated with increased risks of various cancers, cardiovascular disease, and premature death. Further, many SLT users transition to combustible tobacco.

While most of tobacco’s harmful health effects come from components other than nicotine, it is nicotine that drives the addiction that keeps users coming back. Understanding how nicotine is delivered to the body has, therefore, become a crucial area of research in the fight against tobacco addiction.

A Novel Approach to Understanding Addiction

Previous studies had suggested a connection between pH levels and nicotine absorption, but other varying factors between products, such as tobacco cut, flavourings, and overall nicotine content, complicated these investigations. To truly understand the role of pH, researchers needed to isolate this single variable – a challenging task given the complex nature of tobacco products.

Dr Pickworth, working with colleagues at the University of Maryland School of Pharmacy and the US Food and Drug Administration, Center for Tobacco Products, took a single commercial product – Copenhagen Long Cut Original – and carefully modified it to create four versions identical in every way except their pH levels.

Addressing the Technical Challenge

Creating these experimental products proved to be a significant technical challenge. The team needed to ensure that only the pH changed while maintaining consistent levels of nicotine, moisture, and other components. They designed an innovative study to examine this relationship by creating four versions of the same SLT product that were identical in every way except their pH levels. This required careful modification of a popular commercial product using precise amounts of citric acid or sodium carbonate to achieve the desired pH values.

The team selected pH levels of 5.0, 7.7, 8.2, and 8.6, corresponding to free-base nicotine percentages of 0.1%, 32%, 60%, and 79% respectively. This range represented the spectrum found in commercial products while allowing the researchers to examine how different pH levels affected nicotine absorption.

The modified products underwent extensive stability testing over 19 months. This included regular measurements of pH, nicotine content, tobacco-specific nitrosamines (cancer-causing compounds), moisture levels, and even mould and yeast growth. This rigorous testing ensured

A Groundbreaking Clinical Study

Dr Pickworth recruited 40 regular SLT users for a carefully controlled study. Each participant tried all four products in random order across different sessions, keeping the tobacco in their mouth for exactly 30 minutes each time. The researchers collected blood samples before and after product use, tracking nicotine levels for four hours. They also monitored heart rate and blood pressure to understand how the body responded to different rates of nicotine absorption.

The results were remarkable in that the amount of nicotine absorbed varied dramatically based on the product’s pH level. The product with the highest pH (8.6) delivered more than four times as much nicotine into the bloodstream compared to the lowest pH product (5.0) despite containing the same amount of total nicotine. This was reflected in both the maximum concentration of nicotine in the blood and the total amount absorbed over time. The average maximum nicotine concentration in participants’ blood increased from 3.9 ng/ml with the pH 5.0 product to 16.7 ng/ml with the pH 8.6 product.

Interestingly, the relationship between pH and nicotine absorption wasn’t entirely straightforward. The team discovered that even at very low pH levels, some nicotine was still absorbed, likely due to the buffering effects of saliva. This highlighted the complex interplay between product chemistry and human physiology.

The study revealed that pH levels affected not just nicotine absorption but also physical responses. Products with higher pH levels led to greater increases in heart rate and blood pressure, though these changes were relatively modest. This demonstrated that the chemical properties of the product influenced both how much nicotine entered the body and its physiological effects.

The Body’s Response to Nicotine

The cardiovascular effects closely mirrored the nicotine absorption patterns. Products with higher pH levels caused larger increases in heart rate and blood pressure, though these changes remained within safe levels. For example, heart rate increased by nearly 9 beats per minute with the highest pH product but showed almost no change with the lowest pH version.

These cardiovascular changes provided clear evidence that pH levels influence not just how much nicotine enters the bloodstream but also how quickly the body responds to it. This speed of delivery is crucial for understanding addiction potential, as faster-acting drugs typically have a higher addiction risk.

Engineering Addiction Through pH Levels

This research has revealed how tobacco manufacturers can potentially manipulate a product’s addictiveness by adjusting its pH level. Products with higher pH levels deliver nicotine more quickly and efficiently, which could influence their addictive potential. This rapid delivery of nicotine is known to be an important factor in the development and maintenance of nicotine dependence.

Commercial SLT products currently available in the United States have pH levels ranging from 5.3 to 8.4, suggesting that some products may be significantly more addictive than others based on their pH alone. The implications of this pH variation are significant. A product’s pH level effectively controls what proportion of its nicotine content is available for rapid absorption. At pH 5.0, only 0.1% of nicotine is in the free-base form, while at pH 8.6, this rises to 79% – an 800-fold difference that dramatically affects how quickly users feel nicotine’s effects.

Implications for Public Health and Regulation

The findings suggest that considering only the total nicotine content of a product may be insufficient – the pH level plays a crucial role in determining how much of that nicotine actually reaches the user. Dr Pickworth and his colleagues are now advocating for both total nicotine content and pH levels to be considered in tobacco product regulation. Current approaches focusing primarily on nicotine content may be insufficient, as pH levels play such a crucial role in determining a product’s addictiveness.

The research also has implications beyond traditional SLT. New nicotine products, including pouches that contain nicotine but no tobacco, are becoming increasingly popular. These products often use pH manipulation to control nicotine delivery, making Dr Pickworth’s findings particularly relevant to their regulation.

This knowledge could influence how regulatory bodies approach SLT products. It also has implications for the development of less harmful nicotine delivery systems, where controlled absorption rates might help people transition away from more dangerous tobacco products.

Future Directions for Addiction Research

The research team’s innovative approach of studying one product characteristic in isolation could serve as a model for future research. Similar methods could be used to investigate how other product features – such as flavourings, tobacco cut, or moisture content – influence addiction and health risks.

Dr Pickworth has a continuing interest in how product characteristics influence nicotine delivery and addiction potential. The work may help inform the development of less addictive tobacco products while also providing crucial information for regulatory agencies.

As new tobacco and nicotine products continue to emerge, the insights from this research become increasingly valuable. Dr Pickworth’s work provides a crucial foundation for understanding how chemical properties influence addiction, potentially paving the way for more effective regulation and reduced public health impact from these products. By understanding these fundamental mechanisms of nicotine delivery, researchers and regulators can work more effectively to combat tobacco addiction and its devastating health consequences.