*2.2. Drugs*

KHIRON 20/1 (Pharmadrug Production GmbH, Rostock, Germany) is a chemotype 1 cannabis variety which contains 20% ( *w*/*w*) of THC and less than 1% ( *w*/*w*) of CBD in dried weigh. This variety is also referred to by the breeder's name *Hindu Kush* and is classified as an indica-type plant. Indica/sativa terminology relates to structural and botanical features of the cannabis plant and, contrary to what commonly misconstrued, does not provide robust information on the chemical composition nor on the pharmacological characteristics of the flos [26]. The batches of KHIRON 20/1 flos prescribed to T21 participants were produced in full compliance with good manufacturing practices (GMP) requirements and to the standards established in the German monograph for cannabis flos [27].

#### *2.3. CBPM Administration Protocol*

The UK´s Misuse of Drugs Regulations 2018 explicitly prohibits smoking of cannabis and CBPMs, therefore, an herbal vaporizer/inhaler is required for the therapeutic administration of cannabis flos. Currently, there are two vaporizers that have attained the EU certification of medical devices for the inhalation of cannabis flowers, both manufactured by the German company Storz&Bickel: the Volcano medic, a tabletop model [28], and the battery-operated, handheld device Mighty Medic [29]. Although most clinical research on vaporizing medicinal cannabis has been performed using the Volcano device, the majority of T21 participants typically prefer a handheld device, such as the Mighty Medic (Figure 1A), both for convenience and economic reasons. Owing to the more rapid effect onset, inhalation allows the experienced patient to easily titrate the dosage to maximize therapeutic benefit and minimize side effects typically related to overt THC-related psychoactivity, by controlling the number, duration, and frequency of inhalations. Figure 1C

illustrates the dosing protocol we developed to guide T21 prescribers and cannabis-naïve participants through the process of personalizing cannabis inhalation depending on the needs of each individual patient. In brief, to vaporize THC-predominant flowers, patients are advised to:


**Figure 1.** Proposed protocol to initiate naïve patients and prescribing doctors safely into the inhalation of THC-predominant cannabis flos. (**A**) The herbal vaporizer mightly medic is powered by rechargeable batteries and attained EU-mark as a medical device; (**B**) Pharma-grade aluminum dosing capsules holding up to 0.25 g of grinded cannabis flos can be loaded into the mighty heating unit. (**C**) Flowchart depicting a proposed 5-day familiarization plan for naïve users, with daily increases in number and frequency of inhalations to minimize the risk of CNS-related side effects.

#### *2.4. Patient-Reported Outcome Measures (PROMS)*

PROMS questionnaires are completed by T21 participants both at baseline/treatment entry and then every 3 months at scheduled follow-ups. The following questionnaires were employed to capture outcome measures that were either common for all participants (HRQoL, Mood and Sleep) or specific for each diagnosed condition (chronic painful conditions or anxiety-related disorders).

#### 2.4.1. Health-Related Quality of Life

The EuroQol 5 Dimensions (EQ-5D-5L) is a widely used, validated, and reliable tool to assess the quality of life of patients in many disease areas through evaluating the severity of each of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) [31]. Two measures of HRQoL were considered:

