**1. Introduction**

Cannabis was (re) introduced into British medical practice in the early 1840's by Irish physician Dr. William O'Shaughnessy, an army surgeon serving in Calcutta, India [1]. In the Victorian period, cannabis was widely used for a variety of ailments, including muscle spasms, menstrual cramps, rheumatism, the convulsions of tetanus, rabies, and epilepsy, and as a sedative. Cannabis extracts were typically administered orally in the form of an alcoholic tincture and were commonly incorporated in proprietary medicines [2]. With the introduction of synthetic drugs, herbal remedies were increasingly viewed as unpredictable and many of them, including cannabis extracts and tinctures, were removed from the British Pharmacopoeia of 1932 but retained in the British Pharmaceutical Codex of 1949. Under the Dangerous Drugs Act 1964, which implemented the 1961 UN Single Convention on Narcotic Drugs in the United Kingdom, the prescription of cannabis tinctures continued

**Citation:** Moreno-Sanz, G.; Madiedo, A.; Lynskey, M.; Brown, M.R.D. "*Flower Power*": Controlled Inhalation of THC-Predominant Cannabis Flos Improves Health-Related Quality of Life and Symptoms of Chronic Pain and Anxiety in Eligible UK Patients. *Biomedicines* **2022**, *10*, 2576. https:// doi.org/10.3390/biomedicines10102576

Academic Editor: Wesley M.Raup-Konsavage

Received: 19 September 2022 Accepted: 13 October 2022 Published: 14 October 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

to be permitted due to a "license of right" received under the Medicines Act 1968. However, this license of right was subsequently not renewed, and the original Misuse of Drugs Regulations of 1973 listed cannabis, cannabis resin, cannabinol and its derivatives in Schedule 4 (now Schedule 1) completely prohibiting medical use [2]. In November 2018, the UK's Home Office (re) established a legal route for the prescription of cannabis-based products for medicinal use in humans (CBPMs) through the amendment of both the Misuse of Drugs Regulations 2001 and Misuse of Drugs Order 2015, rescheduling CBPMs as Schedule 2 drugs [3]. CBPMs remain strictly regulated and include both cannabis extracts for oral administration ("oils") and dried cannabis flowers for inhalation ("flos"). These products may only be prescribed by a specialist medical practitioner as "special" or "bespoke" medications following processes common to all unlicensed medications.

Whilst smoking of cannabis and CBPMs is expressly prohibited in the legislation, cannabis flos remains the most popular cannabis galenic formulation in the UK, a situation similar to that which occurs in other jurisdictions with established medicinal-cannabis access schemes, such as Germany, Canada, and Israel [4]. Qualitative research studies have shown that patients using cannabis for therapeutic purposes tend to choose the inhalation of flos as their preferred method of administration, as it provides a greater control over dosage and speed of onset, as well as a more robust relief of symptoms compared to the oral route [5]. Additionally, the development of vaporizers and inhalers for flos, some of which have attained certification as medical devices, affords patients greater control over administration and dosing of the pharmacologically active molecules present in cannabis, namely cannabinoids Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), limiting the occurrence of side effects related to the central nervous system and the inhalation of toxic by-products of combustion [6].

Oral THC has been clinically approved for the treatment of several health conditions, such as chemotherapy-induced nausea and vomiting, wasting syndrome associated with AIDS and cancer, and spasticity in patients with multiple sclerosis, and its ability to treat other neurological conditions is under investigation [7]. A large body of scientific literature indicates that inhalation of chemotype I (THC-predominant) cannabis flos can mitigate symptoms associated with chronic pain, increase relaxation, and facilitate resilience to cope with disability. A series of small placebo-controlled, randomized control trials (RCT) conducted with cannabis flos have shown that this therapy option is efficacious and safe at treating neuropathic pain, whilst also improving mood and daily functioning to a similar extent during treatment periods [8–13]. Analogous results were observed in a placebo-controlled crossover trials investigating patients with multiple sclerosis, in which perception of pain was a secondary outcome [14], or patients with chronic pain of varying etiology [15]. In addition to these RCTs, numerous observational studies contribute to a robust body of real-world evidence (RWE) which suggests that the inhalation of chemotype I cannabis flos could effectively ameliorate other types of chronic pain including pelvic pain [16], migraines [17], or fibromyalgia [18], as well as markedly improve various traumatic psychiatric conditions such as stress, anxiety, or depression [19–21].

A recent single-center, observational study explored the clinical outcomes associated with the use of CBPMs in British patients diagnosed with chronic pain, a condition that affects approximately 28 million people in the UK with an estimated direct and indirect cost of £21.2 billion [22]. To minimize the variability in the formulation, participants were prescribed one single oral cannabis extract normalized in medium-chain triglycerides (MCT) oil. Product composition and route of administration are typically difficult to control for and a frequent confounding factor in observational studies. Authors reported significant improvements in health-related quality of life, pain interference and sleep quality, accompanied by a 30% incidence of side effects of mild or moderate intensity [22]. Following a similar rationale and experimental design, in the present work we aimed at investigating the efficacy and safety of the inhalation of THC-predominant cannabis flowers on a treatmentresistant cohort of patients enrolled in Project Twenty21 (T21), the first multi-center registry of patients receiving bespoke CBPMs in the UK [23,24]. We analyzed clinical outcome

measures, collected prospectively through validated questionnaires [25], reported by patients receiving treatment with KHIRON 20/1, the most frequently prescribed chemotype I cannabis flower in T21.

#### **2. Materials and Methods**
