Case Study to Develop NDIs for Cannabis Oil

In their final trimester, Masters students in the Herbal Product Design and Manufacture Program at Maryland University of Integrative Health (MUIH) take a case study course where companies and various stakeholders present real world problems for our students to solve. The current iteration will investigate the significant public interest in cannabis (hemp)-based and CBD-containing food and herbal products. Image of Marijuana leaf with CBD molecule superimposed over it.

Many questions were generated about the science, safety, and quality of these products at the May 31, 2019 public hearing with the Food and Drug Administration.  Key take-away messages from this meeting are the following:

  • Data are needed to determine safety thresholds for CBD.
  • Datasets/information should be objective, of adequate quality and available for transparent review.
  • Lab testing and data analyses need to be replicable.
  • Consumers need consistent information and labeling.
  • State/government entities need support in knowing what to do.
  • We need to understand the implications for children when they take CBD-containing products at different dosage ranges.

Because public has expressed considerable interest in marijuana products (see state legal status map: https://disa.com/map-of-marijuana-legality-by-state,)the FDA is considering how to issue a regulation creating an exception, such as allowing the marketing of CBD in conventional foods or as a dietary supplement.  Regardless, the former FDA commissioner noted that such foods must safe based standards for food additives and related food safety assessment procedures, such as those presented in the NDI guidance (https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-signing-agriculture-improvement-act-and-agencys).

This has its own challenges.  The FDA has identified several safety based-questions about CBD products that need answers as noted above.  For example:

  • How much CBD is safe to consume in a day?
  • How does it vary depending on what form it’s taken?
  • Are there drug interactions that need to be monitored?
  • What are the impacts to special populations, like children, the elderly, and pregnant or lactating women?
  • What are the risks of long-term exposure?

Many industry insiders believe that hemp-based cannabis products, such as cannabis oil or tinctures will be addressed using the DSHEA statutory framework, but that these products will require New Dietary Ingredient (NDI) filings. A description of the 2016 NDI guidance document can be found at https://www.fda.gov/media/99538/download.

To that end, our case study this trimester students will collaborate with stakeholder Dr. Roger Clemens.  He is internationally known scientist, and Professor of Pharmacology and Pharmaceutical Sciences and Assistant Professor of Regulatory Science within USC’s School of Pharmacy, International Center for Regulatory Science. Dr. Clemens is a past president of the Institute of Food Technologists (IFT) and is the current presiding officer of the International Academy of Food Science and Technology.  He co-founded, established and contributes to a Food, Medicine and Health column published monthly in Food Technology for the past 15 years.  He continues to serve on several editorial boards (e.g., Food Chemical Toxicology, Journal of Food Science, Toxicology Research and Applications, Journal of Dietary Supplements) and continues to serve as a reviewer for many high-impact journals.  Dr. Clemens has published > 50 original manuscripts and commentaries. In addition, he has presented more than 250 invited lectures at domestic and international scientific conferences.  He is an elected Fellow in four scientific organizations.

They will be tasked with designing an effective model for a hemp oil NDI (New Dietary Ingredient), which will serve them in two important ways: 1) acquire a deeper understanding of hemp constituents and their safety (classic ADME and toxicology), public health implications, and potential medicinal application; and 2) learn to write an NDI, which is vital in the herbal supplement industry.

Wish them the best of luck.

Plant Defense Signaling: How is this related to good medicine?

Botrytis cinerea growing on a PDA
Botrytis cinerea growing on a PDA (Wikipedia)

Plants make numerous small molecules (metabolites) that are either directly toxic to insects, grazing animals, fungi and bacteria, or that stimulate the production of other toxic metabolites. The production of various types of metabolites such as alkaloids, terpenes, and phenolics can be turned on (induced) after damage to the plant occurs. The control mechanisms involve  jasmonate, salicylate, phytohormone (plant hormone) ethylene, the volatile (gaseous) methyljasmonate and methylsalicylate signaling pathways.

The signal process is complex. It works on a local level or systemically by traveling throughout the entire plant. It behaves like a network, allowing chemical communication between parts of a plant or within a population of plants in a given locale. With recent developments in metabolic profiling, highly sensitive separation and detection systems are used to create metabolite profiles, high-throughput gene expression analysis is used to detect genes transcripts and rigorous statistical mining resulted in some interesting data that reveals more about how plant defense signaling is controlled.

Researchers used metabolic profiling of overall patterns rather than relying on targeted metabolites. This is important, since previous work focused on a few major metabolites and provided conflicting data. They found differences in profiles from plants exposed to generalist insect feeders versus plants treated with phytohormones. Although both jasmonate and salicylate pathways were activated in each treatment (co-induced), the metabolite patterns were distinct; both treatments lead to a stronger localized rather than systemic response; and there appeared to be a great deal of cross-talk between both pathways influencing pools of precursor metabolites.

Botrytis cinerea growing on tomato leaf
Botrytis cinerea growing on tomato leaf

Another study followed the spatial accumulation of hydroxycinnamates (phenylpropanoids) and lignins in cell walls of Arabidopsis (a model organism) in response to changes in the ethylene signaling induced by the necrotrophic fungal pathogen, Botrytis cinerea. They correlated metabolic profiles with cytological (cell based) changes to provide biological validation of the analytical data.

When a fungus like Botrytis attacks a plant, it generally destroys cells and eventually the entire plant. In the presence of the fungus, plant genes for the biosynthesis of phenylpropanoids and lignins are expressed (turned on) to modify and reinforce the plant cell wall against fungal penetration. Botrytis induces over 30 ethylene regulated transcription factors – cellular molecules that target and induce underlying genes to become active. So these researchers used a metabolite profile of 3 ethylene mutants, plants that had gene mutations at different DNA sequence points of the ethylene signaling pathway.

It turned out that the mutant plants were less resistant to the fungus and that ethylene resistance, when present, appeared after the fungus had made contact with the plant cell wall and had begun to build the structures necessary to penetrate the cell wall barrier. One phenylpropanoid metabolite in particular, ferulate, seemed to be highly influenced by ethylene signaling. Ferulate cross-links the polymer strands of cell wall polysaccharides, enhancing their structural integrity as a barrier.

So what does this have to do with good medicine? Don’t focus on one or two metabolites to make an efficacious extract. Despite what you hear, we are not trying to mimic “magic bullet” medicine. Expose plants to a full set of ecological challenges to produce a metabolite profile of greater diversity. Mono-crop farming doesn’t cut it. Damn if those hippies had it right after all.

Using ePortfolios to Guide Student Learning, Part I

This post also focuses on complex ecologies, found in education, not the wild. It reviews the adoption of an ePortfolio in our Therapeutic Herbalism Masters program at Maryland University of Integrative Health, which was designed to accomplish three main tasks:

  1. Encourage and provide opportunities for our students to experience meta-cognitive learning about the competencies they have acquired/developed..
  2. Create a professional web presence for the student to market their expertise.
  3. Assess whether our program learning outcomes are being met in the classroom.

The Student Learning Portfolio allowed student to collect artifacts of their acquired competencies. These were often based on assignments from each of their courses.  Ideally, they reflected skills developed, competencies, and career readiness resulting from each course and the integration of those experiences. The process was meant to enhance the ability of students to be self-sufficient reviewing their ability to succeed in a chosen profession.

Image of learning Zones

Their final product was creation of a Professional ePortfolio, where the competency artifacts selected by a student showcased the knowledge, skills, and abilities that are in demand in the professional marketplace.

During our review of the tool it became apparent two important lynch pins were missing. Firstly was the articulation of appropriate professional competencies as measurable program learning outcomes. Secondly, our faculty had limited experience applying learning outcomes and reviewing meta-cognitive tools such as the ePortfolio. They were not prepared to highlight the connection between chosen artifact from their course, as well as the underlying learning process and how it was linked to an overriding professional competency.

A series of faculty retreats refined more effective and measurable program learning outcomes. In addition, the institutional assessment process that emerged out of a regular Middle States Higher Education Commission review of the university helped create more specific measurement goals. The combined effect enabled both faculty and students to identify appropriate artifacts and learning processes.

We articulated specific competencies that were missing or ill-defined in previous versions, including:

  • Improved research literacy skills – finding and assessing the validity of scientific research – in support of their analytical work on assignments.
  • Succinct summarization of primary, peer-reviewed resources and the synthesizing of new ideas from those summaries that contribute unique ideas to the field
  • For clinical students, populated their portfolio with case study write-ups.
  • Created effective narratives of how they worked with incomplete data (medicine making, research or diagnosis) in finding a solution using iterative problem solving.

Other challenges that appeared included the need to help students learn how to select learning artifacts that reflect project-based learning. Since the feedback loop in assessment provides data about how program outcomes are being met in the classroom, the process of student metacognitive review of both object and learning processes revealed difficulty in effectively linking the two.

Apparently this is not unusual in ePortfolio development (Land & Greene, 2000). At the core of this issue is the requirement for more engaged and knowledgeable faculty to embed assignments and course long assessment arcs focused on strengthening the linkage between an object (paper, case study, etc.…) and the underlying programmatic learning objective.

Faculty training in applying ePortfolio to their own professional development would improve their the ability to guide students into choosing suitable learning artifact and how to articulate those to employment marketplace.

Reference

Land, S.M. & Greene, B.A. (2000) Project-based learning with the world wide web: A qualitative study of resource integration. Educational Technology Research and Development. 48: 45. https://doi.org/10.1007/BF02313485.