“Dosage forms must be chosen sensitively and individually”


Interview with pharmacist Alexander Daske (Part 2)

In cannabis therapy, oral therapy and inhalative therapy via vaporizer are opposed to each other. Both dosage forms have different areas of application, and both have their justification – depending on the symptoms, patient status and therapy goal. Alexander Daske, cannabis expert and pharmacist at Collini Apotheke in Mannheim, talks about these and other exciting, innovative dosage forms of cannabis medicines. In this second part of our interview, we also talk about the difficulties of cannabis clinical trials and how doctors can incorporate the terpene profile of cannabis flowers into treatment.

Kalapa: There are different dosage forms to choose from in cannabis therapy. The prescriber can decide which form is most appropriate. What are your experiences?

Alexander Daske: We have two primary dosage forms in Germany: oral therapy with cannabis extracts and inhalative therapy via vaporizers with cannabis flowers and now also with cannabis concentrates. These two forms of application are very different in their pharmacokinetics. Inhalation bypasses the gastrointestinal tract, hence the first-pass effects. From the beginning, we have better bioavailability and consequently higher availability of THC in the blood plasma and a very different effect than with an orally administered extract.

When taking orally, it is important that we have a depot effect. That is a delayed onset effect that lasts 6 to 8 hours. This is associated with increased metabolization in the liver. Therefore, we need to investigate for which patient groups this dosage form is suitable.

Kalapa: At Collini Pharmacy, you also work intensively on new dosage forms.

Alexander Daske: The development of new dosage forms is a very exciting topic. In the pharmacy, I am working intensively on innovative dosage forms such as mucosal or intranasal therapy – i.e. absorption via the mucosa or the nose. For certain symptoms, the use of suppositories, administered rectally or vaginally, is very interesting. In addition, I am currently working on the development of a faster-acting form – faster than oral extracts – but one, that cannot produce such high plasma concentrations as inhalation and may therefore also make more sense in terms of the risk-benefit ratio for the patient. 

“Oral and inhaled therapy have different applications”

Kalapa: Where do you use the different application forms?

Alexander Daske: At the moment, we are still working mainly with oral therapy and inhalative therapy. And we clearly have two different areas of application here. One central area is chronic disease patterns in which there are no acute pain attacks. Here, oral therapy, a sustained-release drug that also has a more favorable benefit-risk profile, is the best option. With an extract, we have better dose-response control than with inhalation. In addition, the ratio between effect and side effect is more favorable. This is because there is always a risk of cognitive impairment at very high THC plasma concentrations. THC is a highly psychoactive substance, and if it enters the blood plasma too quickly and in too high a concentration, we consequently also have a higher risk of patients developing side effects.

Therefore, one has to proceed very sensitively and individually: What is the patient’s status, is he/she cannabis-naive or cannabis-experienced? Which symptoms do I treat and how do I set the treatment goal? Do I want to numb chronic pain? Then I reach for a depot extract. Or do I want to treat cluster headaches, acute migraines, or a pain attack? Then I reach for a dosage form that is directly inhaled and thus offers the patient a direct therapeutic effect. The appropriate dosage form must be chosen according to the symptoms.

Kalapa: And what do you recommend for palliative patients?

Alexander Daske: If we look at the SOPC area, it looks different. Here, combination therapy is always recommended, and I also support that. What does that mean? The patient receives a combination of an oral extract for long-lasting pain relief and then in acute neuropathic or acute nociceptive pain attacks, inhalation should be considered. It is also important for me to emphasize that in palliative care, it does not matter if the patient still has an increased potential for dependence at the end of life. In palliative care, we want to achieve a better quality of life, that the patient feels less pain and is better able to cope with pain.

“There are particular difficulties with clinical trials in the area of cannabinoids.”

Kalapa: Doctors usually want ready-to-use medicines. In the field of cannabis, there is not much choice. What is your opinion on this topic and how do you see the future of cannabis-based ready-to-use medicines?

Alexander Daske: We now have several clinical trials by manufacturers who want to bring ready-made cannabinoid medicines on the market. But here are particular difficulties as well: With cannabinoids, we have a highly individualized therapy and a natural product. We don’t have exact concentrations of the main psychoactive ingredient THC in the cannabis flowers, as we do with a finished drug. Cannabis extracts can also be subject to fluctuations due to the polyactive ingredient system, but here the cannabinoid concentration is more reproducible because the extract is set to a fixed THC concentration. There are always individual fluctuations. 

Looking at the requirements for a study, the problem of blinding is right at the beginning. With the inhalation of cannabis with the main active ingredient THC, it is practically impossible to conduct a randomized double-blind study, as the unblinding takes place right there. We are working with a psychoactive substance that has a certain degree of cognitive impairment in high plasma concentrations, so the whole process of a study is relatively difficult.

With cannabis, we also have to keep in mind that we have an endogenous, well-functioning cannabinoid system. We know from other countries that we can measure endocannabinoids and thus determine ECS tone. But this diagnostic is not yet recognized and established in Germany. And consequently, we do not know at all how our body reacts in the course of a cannabis therapy.

Another problem with conducting a placebo-controlled randomized trial is the presence of an endogenous baseline effect. Since each person has an individual ECS tone and this tone varies in its expression, each patient has different baseline conditions. That means, patients have interindividual differences in their activation of the endogenous endocannabinoid system, and therefore there are always some interindividual differences in effect. We respond differently to the medicine because of the endogenous tone of the endocannabinoids, which is then stimulated by exogenous phytocannabinoids. So, it’s very difficult for us to come up with consistent results that are relevant to a clinical trial. That’s still a problem at the moment. Nevertheless, there are more and more companies investing in the field of ready-to-use medicines studies. 

“When we replace a flower, we need to consider the overall profile, tolerability, and symptomatology”

Kalapa: Let’s look at the treatment of cannabis patients with flowers. There is always a situation where a flower variety is not available. What should be considered when cannabis flowers need to be substituted? 

Alexander Daske: The market in Germany has become increasingly complex and confusing. In 2017, we had three to five cannabis flower varieties on the market, now there are 170 – and more every week. This means that it is also becoming increasingly complicated for doctors to ensure a targeted treatment. In pharmacy and medicine, holistic patient care is a very central issue, also in the course of a targeted management process. Otherwise, medical therapy based on dose stability with a constant product is impossible. However, the large market of available cannabis flowers and cannabis extracts makes this increasingly difficult, as it becomes more and more complicated for the doctors to select a preparation specified for a particular symptomatology. Or, if this preparation is not available, to find a precise alternative. 

The only solution I see here is for experienced stakeholders to develop training or guidelines for targeted cannabis flower substitution. There are several aspects to this that we recommend to doctors. In the foreground are the two main cannabinoids THC and CBD, but this also includes the entire terpene matrix. With the terpenes, it’s not just the first three main terpenes that matter, but also the exact percentage distribution, which has been determined in the lab.

Only in this way can we effectively replace a well-adjusted flower for a patient to also ensures the safety of the patient in the context of therapy management. So, we cannot allow a substitution only according to the percentage of THC, we have to look at the overall profile, the percentage of the individual ingredients and of course also the previous tolerance and the patient with his respective symptomatology. From these many different aspects, we can then make a substitution of the flowers or extracts. This requires special guidelines, which we give to the doctors in the course of the therapy. 

“In cannabis therapy, the psyche plays a very important role”

Kalapa: What is the current importance of terpenes in cannabis therapy and what developments do you expect in the future?

Alexander Daske: The overall profile of secondary plant compounds, terpenes in particular, is currently a special and sensitive area and will remain so in the future. When I talk to doctors, terpenes are often rather irrelevant and only the psychoactive substance THC is considered. It is also correct to establish THC as the basis for the dosage. Nevertheless, it is important to be said that especially in the inhalative field, i.e. in the therapy with cannabis flowers, the complete expression of the overall profile of several hundred ingredients is considered.

We cannot yet prove with evidenced-based data how individual terpenes act. We have no basis to say that myrcene has an analgesic effect or caryophyllene has an anti-inflammatory effect. There are preclinical approaches, of course, but we don’t have any confirmed data yet. Nevertheless, we see the picture from the field. And that makes us think, especially in the field of cannabis flower therapy, to not only focus on THC, but also to pay attention to the terpene profile. We see it every day: in patients who are adjusted to a THC-dominant cannabis flower, we cannot simply exchange it for another, equally strong THC-dominant flower.

Placebo effects probably play an important role here as well. In cannabis therapy – but also in pain therapy in general – the psyche plays a very crucial role. And if we see a positive effect in the patient during the therapy, then we therefore also have a positive placebo-controlled benefit, related to the treatment goal. If, on the other hand, the patient expresses concerns, that’s a nocebo effect. And I see that also in the field of cannabis flower therapy with the terpene debate.

The terpene profile thus plays an important role in practice, but not necessarily in relation to the symptomatology and the treatment goal, but mainly in choosing the right time of application. Varieties high in myrcene are more suitable for the evening than attenuating terpenes. Varieties containing activating terpenes such as limonene or pinene thus have a concentration-enhancing and mood-lifting effect. 

These effects occur mainly with cannabis flowers, less with extracts or finished medicines. This is also because many terpenes are lost during extraction, especially monoterpenes that are predominant in flowers, such as limonene, myrcene, pine, linalool. These terpenes are no longer present in the extracts, so the effect and side effect control of the terpenes are only slight. In the area of flowers, I think the focus should be on this despite the low evidence.

Alexander Daske is a pharmacist at Collini Apotheke in Mannheim, a pharmacy specializing in pain therapy and cannabis-based medicine. He has many years of experience in the field of pain therapy, SOPC therapy and MS therapy. Alexander Daske is head of the pain department and active as a consultant and speaker in the field of cannabis as well as for associations such as the VCA.

About Gesa Riedewald

Gesa Riedewald is the managing director of Kalapa Germany. She has been working as a medical writer on the topic of pharmaceutical cannabis since 2017 and has years of experience in the healthcare sector.

Gesa Riedewald ist die Geschäftsführerin von Kalapa Deutschland. Sie ist bereits seit 2017 als medical writer für das Thema Cannabis als Medizin tätig und besitzt jahrelange Erfahrung im Bereich Healthcare.