VAPE OIL ADDITIVES – CUTTING AGENTS, THICKENERS, THINNERS, PRESERVATIVES, FLAVORS, COLORANTS – AND CART COMPONENTS ARE NOT REQUIRED TO BE TESTED OR LISTED(WITH THE RECENT EXCEPTION OF MASSACHUSSETTS)

Compiled by Jason Keehn

Welcome to an open research doc with clustered links, quotes & mild commentary. Not quite a live blog, but will try to keep updating every couple days. Updated 9/28.

• Highlights
• Official Pronouncements
• Industry Responses
• The Science – What Is Known So Far  
• Current Case Reports
• Past Relevant Research
  • Breakdown Products of Common Terpenes and Additives
  • Vitamin E Acetate Formaldehyde
  • Synthetic Cannabinoids
  • Myclobutanil
  • Metals
• Mass Media Stories (Descending Order of Usefulness)
• Addendum: Forward Options for Regulators

Highlights

• As of 9/27, 13 deaths; closing in on 1000 cases to date, “more expected”; 38 states affected, including dozens in CA, but, so far, seems mostly concentrated in states with no medical or adult use program. Most patients report having purchased illicit product.
• Trump Wants to Ban Flavored E-cigs
• House Hearing with CDC on 9/24, Senator Durbin threatens to hold a separate hearing shortly; FDA asks for 3 weeks to design guidance (or by May 2020 – conflicting info);
• Vape oil additives – cutting agents, thickeners, thinners, preservatives, flavors, colorants – are neither tested for nor banned in any legal state, currently; states don’t set recommendations on dilution ratios; and there is relatively little long term health research on aerosolized terpenes or other additives.
• Latest State Actions:
  • MI bans flavored e-cigs
  • NY subpoenas 3 vape brands, moves to ban e-cigs as well
  • CA DPH issues harsh warning, and Newsom authorizes $20M education campaign and warning notices to be posted on retail storefronts
  • Mass mandates all ingredients to be listed on labels
  • WA asks retailers to review all product, threatens recalls; sets 21 year age limit for vaping purchases
  • Hawaii goes after… CBD and… gummies?!
  • OR issues guidance, retailers to post warning letter and report any novel / suspicious ingredients
• First marker identified by Univ of Utah – “lipid-laden macrophages”.

• Most cases seem to involve both THC and nicotine use; most in NY involve Vitamin E Tocopheral Acetate (synthetic chemical), and it appears implicated in cases in other states as well – but medical authorities are not ruling out other additives, synthetic cannabinoids or interactions.
• Various sources suggest inverted ratios of THC/DBD to additives may be standard in street carts – from 70 THC extract /30 diluents, to 30/70, for example.Even terpenes at high concentrations could be a problem.
• California licensed operators ConstanceTherapeuticsand WercShop both issue statements — Constance has a patent on plant-based ALPHA-Tocopherol, and deems it safe for human use in their formulations. WercShop was using a trace amount of Alpha-Tocopheral from a plant source as a stabilizer in its patented, proprietary “Nexus 2.0” formulation, but has now stopped. TrueTerpenes states it does not currently use Tocopheral Acetate, denying anonymous claims and testing results on Reddit. Various licensed prominent brands declare they use only 100% cannabis and terpenes. Honeycut, a LA-based supplier of Vitamin E, has taken its website down.
• Some scattered research exists on aerosolized Tocopheryl, one study indicates the Alpha version may be beneficial and the acetate version dangerous.
• Best place to start if you’re not already following all this closely — David R. Downs’ coverage (@davidrdowns):
  • Vape Pen Lung Disease – Here’s What You Need to Know
  • Vape Pen Lung Disease Has Insiders Eyeing Misuse of New Additives
  • Journey of a Tainted Vape Cartridge: From China’s Labs to Your Lungs

Official Pronouncements

• CADPH 9/24 Major statement: “We are seeing something that we have not seen before… There are numerous unknown factors at this time, and due to the uncertainty of the exact cause, it is our recommendation that consumers refrain from vaping until the investigation has concluded… do not discard any used vaping cartridges you might have, as CDPH is interested in testing the remaining substance in used cartridges. Those cartridges are being collected by local health departments and sent to CDPH labs for analysis.”
• IRRCH Issues Warning to Avoid Focusing Prematurely on Vitamin E Acetate or Specific Additives (PDF) ” IRCCH acknowledges that root cause of this problem may be in the dilution of cannabis and hemp but emphasize that no single causative agent has been identified by any agency or group that explains the symptoms being reported.” 9/17
• CDC: Initial State Findings Point to Clinical Similarities in Illnesses Among People Who Use E-cigarettes, No Single Product Linked to All Cases of Lung Disease 9/6
• FDA: Federal and State Collaboration to Investigate Respiratory Illnesses Reported after Use of E-cigarette Products 8/30
• Mass Cannabis Commission to Require Detailed Labeling of Pot Vapes
• Mayo Clinic: Vaping Unknowns, Expert Answers Questions (but what does Mayo know about cannabinoids or street vapes?!)
• Sen. Durbin’s Letter to FDA (PDF)
• NY State DOH: Update on Investigation into Vaping-Associated Pulmonary Illnesses / Department Warns Against Use of Black Market Vaping Products / Lab Test Results Show High Levels of Vitamin E Acetate, Now Focus of Investigation 9/5
• LA County DPH, one local death; 1 death in Tulare County; 80 cases reported in the state as of 9/24
• State Health Officers Report on E-Cigarettes: A Community Health Threat – 2015

Industry Responses

• Juul CEO Resigns, Company Suspends all Advertising
• Statement from American Vaping Association (Nicotine-centric) – Pushes the Focus to Illicit THC
• VTA Responds to CDC and FDA, Asks Them to Stop Conflating Nicotine E-cigs and THC Vaporizers 9/6“…several public health agencies have failed to provide clear information and, instead, are unnecessarily frightening consumers by failing to distinguish between e-cigarettes and non-nicotine vaporizers.”
• Constance Therapeutics
• PAX LABS – CA Vape Pen Supplier – Announces Health Advisory Committee
• WercShop’s Jeff Raber
• Another Canna Industry POV: “Mr. Extractor’s Statement about Thickeners and Vitamin E Acetate”
• TrueTerpenes – Responses to FDA Questions
• Finally – Uncle Ike’s Pot Shop Actually Sends Product to a Testing Lab
• CannaSafe Finds Myclobutanil in Illicit Carts (no surprise there!); Licensed Brands Clean
• “M.E.D. Catch-all” Regulatory / Industry Working Group Meeting in Colorado9/20 (audio file) “Definitions of ‘additives’ and ‘ingredients’ under way – modeled after FDA food policies, baby steps towards GMP and risk disclosures.” NEW

The Science – What Is Known So Far

Current Case Reports

• First Marker for Mysterious Vaping Illness Identified 9/9
• Pulmonary Illness Related to E-Cig Use in IL and WI — Preliminary Report
• Imaging of Vaping Lung Disease
• Outbreak of E-Cigarette–Associated Acute Lipoid Pneumonia NC, 7-8/2019
• Respiratory Failure Caused by Lipoid Pneumonia from Vaping E-cigarettes2018

Past Research

• CannaSafe Testing Results – Licensed vs Unlicensed Vape Brands NEW
• Cannasafe Testing Data Table
• Aerosol Gas-Phase Components from Cannabis E-Cigarettes and Dabbing: Mechanistic Insight and Quantitative Risk Analysis 9/16
• How Safe is Your Vape Pen? Jahan Marcu – 2015!
• Electronic Cigarettes Disrupt Lung Lipid Homeostasis and Innate Immunity Independent of Nicotine 2019
• Public Health Consequences of E-Cigarettes – NIH page (general)
• Harvard: Common E-cigarette Chemical Flavorings May Impair Lung Function
• Cannabis Contaminants: Regulating Solvents, Microbes, and Metals in Legal Weed
• E-Cigarette Use Exposes Teens to Toxic Chemicals, Toxic Byproducts Are Found Even in Adolescents Who Use E-cigarettes Without Nicotine
• Peering through the Mist: Systematic Review of What the Chemistry of Contaminants in Electronic Cigarettes Tells Us about Health Risks 2014
• Carbonyl Compounds Produced by Vaporizing Cannabis Oil Thinning Agents2016
• E-Cigarette Aerosol Exposure Induces Reactive Oxygen Species, DNA Damage, and Cell Death in Vascular Endothelial Cells
• “Tree-in-Bloom”: Severe Acute Lung Injury Induced by Vaping Cannabis Oil – 2017
• Electronic Cigarettes and Future Marijuana Use: A Longitudinal Study – 2018
• Acute Effects of Electronic Cigarette Aerosol Inhalation on VascularFunction Detected at Quantitative MRI, Radiology 2019
• Modeling Cardiovascular Risks of E-Cigarettes with Human-Induced PluripotentStem Cell-Derived Endothelial Cells
• Endotoxin and (1^ 3)-p-D-Glucan Contamination in Electronic Cigarette Products Sold in the United States
• Sympathominetic Effects of Acute E-Cigarette Use: Role of Nicotine and Non-Nicotine Constituents

Formaldehyde (Breakdown Product of Propylene Glycol & Related Additives)

• Hidden Formaldehyde in E-Cigarette Aerosols
• Sources of Propylene Glycol and Glycol Ethers in Air at Home 2010
• More on Hidden Formaldehyde in E-cigarette Aerosols.

Vitamin E 

• Two Faces of Vitamin E in the Lungs
• Vitamin E Acetate Study at NIH
• The Vitamin E Isoforms α-tocopherol and γ-tocopherol Have Opposite Associations with Spirometric Parameters: the CARDIA Study
• Aerosolized Alpha-tocopherol Ameliorates Acute Lung Injury Following Combined Burn and Smoke Inhalation Injury in Sheep
• Molecular Mechanism of Alpha-tocopherol Action
• Aerosol-administered Alpha-tocopherol Attenuates Lung Inflammation in Rats Given Lipopolysaccharide Intratracheally
• NIH Toxicological Database for Tocopherol Acetate
• Topical Alpha-tocopherol Acetate in the Bulk Phase: Eight Years of Experience in Skin Treatment

Synthetic Cannabinoids

• Synthetic Cannabis / K2 / Spice Study
• Vaping Synthetic Cannabinoids: A Novel Preclinical Model of E-Cigarette Use in Mice
• GSU Student Uncovers Illegal Synthetic Cannabinoid in Over-the-Counter Vaping Pen / Independent Research Project Reveals Potential Dangers of E-cigarettes
• AP Tests at Flora Research Labs Implicate Synthetic Cannabinoids 9/15

Myclobutanil (& Other Pesticides)

Terpenes

• Evaluation of Cannabinoid and Terpene Content: Cannabis Flower Compared to Super-Critical CO2 Concentrate

Metals

• Effects of Model, Method of Collection, and Topography on Chemical Elements and Metals in the Aerosol of Tank-Style Electronic Cigarettes 9/27 NEW
• Metal Concentrations in e-Cigarette Liquid and Aerosol Samples: The Contribution of Metallic Coils 2019

Mass Media Stories  (Descending Order of Usefulness)

• Vapes Spiked with Illegal Drugs Show Dark Side of CBD Craze
• WI Bust of Underground THC VapeCart Op – WI DOH Testing Underway – 9/12
• Juul Violated Federal Rules by Marketing Vaping as Safer than Nicotine Products, FDA Says (9/6 NYT paywall)
• Sen. Durbin Calls on FDA Acting Head to Act on VAPI or Resign – Senate Hearing in One Week, Durbin-authored Cannabis Research and Down-scheduling Bill to be Fast-Tracked in Congress? 9/6 –“Most e-cigarette brands sold in the U.S. are legal, but none of them have been subject to FDA review, leaving a regulatory gray area as more and more products flood the market. The agency gained the authority to regulate tobacco products in 2009, but it wasn’t extended to vaping products until 2016. When the Trump administration took over in 2017, the FDA decided to delay enforcing the laws until 2022, much to the frustration of public health groups… If the FDA had acted initially, Durbin argued, “many of these e-cigarette devices and flavors would not be on the market, countless numbers of children would not now be addicted to nicotine, regulations would be in place to help prevent against the adulteration of e-cigarette devices, and we would have far better information about the short- and long-term health consequences of vaping.”
• Deconstructing Vape Juice Ingredients: What to Accept & What to Avoid
• Developments in the Coachella Valley
• UK: “Spice” (Synthetic Cannabinoids) Shows up in Vape Oil, 9 Hospitalizations
• “What’s in My Vape? Cautionary Notes from ABX, a Leading Licensed California Extraction Brand
• WaPo coverage – 9/5
• Highlights 7000x Myclobutanil in Illicit Extraction Bust in CA
• Visit to a Supplier Page – Top-listed Vendor of Vape Ingredients
• Denver Post – 9/5-who at least know something about Cannabis
• FDA Sent Letters in 2018 to 1200 Vaping Retailers Asking Tem to Stop Selling to Minors
• MJBiz: Cannabis Industry Insiders Brace for Potential Fallout as Health Officials Report n\New Vaping Deaths, Issue Warnings – 9/7 – “Dumas de Rauly, chairs of the ISO Committee on Vaping Standards and CEN Vaping Standards Committee, deplored the use of vitamin E acetate in MJ Biz Daily. “In no case is this a product that you should be inhaling.“When you add products like vitamin E … when you add different kind of lipid solvents to the mix, you’re making all of that oil stickier, and that stickiness is going to create these lung illnesses we’re seeing,” he said.
• “Floraplex CEO Alec Riffle told Leafly he estimates “50 MILLION” US carts may contain something labeled “Vitamin E oil” – One thickener maker previously boasted that his product was “a far healthier alternative” to other diluents. This week the product disappeared from the company website. Jones notes that the thickener is not subject to any state or federal regulations. There is nothing “to keep you from putting this in every head shop, gas station, dispensary in the country,” he says. “It tastes great, and to be honest with you, it tastes better than any e-juice on the market. … We’ve made juices out of this that are amazing. This product right here is going to revolutionize the e-juice industry.”
• CNBC Documentary – “CNBC’s Carl Quintanilla investigates the rapidly growing and controversial e-cigarette industry, a market expected to hit $9 billion by the end of 2019. CNBC gets unprecedented access inside Juul Labs, a company whose innovative product design and marketing have made it the industry leader as well as a lightning rod for criticism that vaping companies are luring teenagers into nicotine addiction. While some believe e-cigarette sales should be restricted to protect kids, others claim stricter regulation could cost the lives of many adult cigarette smokers struggling to kick their deadly habit. In “Vaporized,” CNBC explores the raging debate: are e-cigarettes a curse or a cure?
• Former FDA Head Gottlieb Defends his Tenure at FDA From Durbin’s Attack w WaPo OpEd – Scott Gottlieb: E-cigarettes are not off the hook “The established e-cig brands and the vape stores that mix legal e-liquids have been regulated by the Food and Drug Administration since summer 2017 (when I was the agency’s commissioner) for their ingredients, marketing and labeling, among other features. Since putting this framework in place, the agency has conducted more than 1,000 inspections of these businesses. … Manufacturers need to separate legitimate e-cigs from illegal adulterants by publishing detailed information on their ingredients, by taking meaningful steps to limit youths’ access to their products and its appeal to them, and by fully embracing an FDA application process that they’ve largely fought.”
• Twitter thread from pharmacist -Eliana Golberstein Rubashkyn “I can see that nobody in the media and not many Drs understand the chemistry of surfaces and membranes, and this is key to understand why Vit E is so toxic when inhaled. This happens due to a physico-chemical process known as surface physio sorption by lipophilic bonding.  // Having in mind the #tensioactive properties of substances is key to harm reduction in #vaping e-liquid formulations with cannabinoids, we need to respect the chemistry of our lungs and be rational in a product’s formulation. #VitaminE and #MCT are terrible ideas for a safe #Vape. //   MCTs and #VitaminE are terrible thickening aids for cannabinoid #vaping formulations. Their tensioactive properties cause #occlusion in the lungs membranes (Here the Vit E and its lipophilic structure compare it to an MCT)…. Occlusion of cells by lipophilic bonding therefore induces Lipoid pneumonia like conditions. That triggers apoptosis by a sudden elevation of free radicals in the mitochondria which is involved in cellular respiration.”
• Dank Vapes Is the “Biggest Conspiracy” in Pot That Can Put You in a Coma / A thriving shadow economy is run on unsuspecting buyers and predatory sellers8/19 (!)
• A Visit to a Supplier of Vape Juice Colorant
• Are Weed Vape Pens Safe 2015
• Vaping’s Plausible Deniability Is Going Up in Smoke / Ongoing FDA investigations and a spate of hospitalizations show that “safer than cigarettes” does not mean safe.” Advocates for the nicotine-vaping industry have been quick to point to black-market cannabis products as the real source of health problems, which they claim are being used misleadingly by anti-tobacco advocates to fuel their own crusades. But that argument belies the fundamental lack of information available when evaluating nicotine vaping’s impacts on health and its potential interactions with other drugs. Many of the people who are known to have fallen sick this summer use nicotine vapes in addition to cannabis, and it’s possible that lung irritation caused by frequent use of nicotine e-cigarettes could hasten or worsen the impacts of chemicals found in black-market cannabis products.”
• Looming E-Cig Ban in NY State – Cuomo on the attack…  “The companies being served with subpoenas and their product names are: Honey Cut Diluting Agent by Honey Cut Labs LLC in Santa Monica, California; Uber Thick by Floraplex Terpenesin Ypsilanti, Michigan, and Pure Diluent by Mass Terpenes in Amherst, Massachusetts, state officials said. … Business selling vaping products in New York will also now be required to post a warning sign declaring the health risks of vaping, Cuomo said Monday, calling it a “risky adventure and risky activity.””
• VICE: China’s Vape Industry is Just Getting Started 2017!
• Home-cooked Vaping – From the Frontline
• The Mystery Lung Disease Caused by “Vaping” Was a Textbook Drug Panic

Addendum

Forward Options for Regulators:

• Move rapidly to mandate additives testing (but standards and methods need to be developed)
• Require a detailed list of all ingredients and additives (as in Massachussetts)
• Set limits for some additives/dilutants and even added terpenes, individually or in aggregate
• Require testing and health data from companies before introducing new cutting agents not on an “approved list”
• And, possibly, outright bans.
• FDA/NIH/NIDA will fund research on long-term health effects of aerosolized vape oil ingredients, terpenes, and vape trace metals, as well as testing analytics methods – university researchers, prepare your grant applications now!
• Will this crisis push FDA to now coordinate and oversee the state-level manufacturing and testing standards for legal cannabis – but can it do so without new federal legislation?

(Stay tuned for our more detailed article forthcoming in the premiere issue of theJournal of Endo-Cannabinoid Medicine)

Correspondence to twist1961 at gmail