The patient is a 75-year old white man of italian descent, married, with three children and five grandchildren. He is an autonomous farmer, countryside resident of Planalto, Paraná, Brazil, a city with roughly 14,000 people, where he participates in flea markets, church groups, and farming negotiations. He quit smoking 1 year before the start of this experimental treatment, after 45 years of daily cigarette consumption, and had no history of alcohol overconsumption. Besides that, the patient was overall healthy, with no diagnosed comorbidity of any nature, cardiovascular, kidney or hepatic dysfunction/disease, dyslipidemia, diabetes mellitus, or any other neurological diseases beyond AD. Hence, he was using no other continuous medication.
General physical examination remained unchanged while monitored throughout the entire experimental treatment, including pulse, blood oxygenation, and pressure. Further, blood work was periodically requested to assess renal, hepatic, and hemostatic functions, as well as lipidic and glucose panels. Patient showed average heart rate of 83 beats per minute and blood pressure of 112 over 76 mmHg. A summary of general good health condition, based on blood work history, is presented in Table 1.
The patient was diagnosed with AD 2 years prior to the start of this experimental treatment, according to brain magnetic resonance imaging, anamnesis, and clinical assessment, which includes and is not limited to the use of National Institute of Neurologic and Communicative Disorders and Stroke, and the Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA) criteria. Our neurologist had access to the transcripts of his imaging examinations, which revealed no significant alterations and ruled out other possible causes of dementia, namely cerebrovascular disease or stroke, frontotemporal alterations, and/or evidence of other neurological disorders.
Specifically, patient was diagnosed with AD stage 1 and 4 according to the Clinical Dementia Rating (CDR) and the Global Deterioration Scale/Functional Staging of Dementia the Alzheimer Type (GDS/FAST), respectively. Clinical neurological conditions showed memory loss; spatial and temporal disorientation; forgetfulness (for example, regarding people and facts), constant storytelling on repeat mode; lack of initiative; signs of possible depression; struggling with organization, planning, and executing actions; incapability of performing simple hygiene and cooking tasks; and, thus, inability to live unassisted.
Memantine (10 mg/day orally) was the current undergoing treatment, though he experienced rapid disease progression (decreased cognitive function) and adverse effects (mostly dizziness followed by falls, headache, and constipation). Following the neurologist’s recommendation, treatment with memantine was suspended, given the lack of efficacy and the above-mentioned rapid symptomatic progression.
Experimental AD treatment with cannabinoid microdosing
This experimental design was a pharmacological intervention using cannabinoid extract followed by mnemonic and nonmnemonic symptom assessment over the course of 22 months, conducted by the neurologist integrating our research group. It was conducted in accordance with the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects, adopted by the General Assembly of the World Medical Association (1996), and followed the Brazilian Health Ministry (from Portuguese, Ministério da Saúde do Brasil) recommendations. The ethical committee of Unioeste University under number 2788021 approved this case report, and the patient provided written informed consent to publish this case report.
The patient’s family imported the cannabis extract as a dietary supplement and approached the university for clinical anamnesis and a proper extract analysis, since THC and CBD doses are not tested in dietary supplements. As previously described at American Herbal Pharmacopoeia , we used gas chromatography—mass spectrometry (GC–MS) to determine the major cannabinoid dosage in the extract. The THC:CBD ratio was 8:1, henceforth referred to as “cannabinoid extract” (Fig. 1A and B).
Interventions with the cannabinoid extract started after a baseline assessment (T0) and are expressed in the graph as its equivalent dose of THC. Initial treatment consisted of 500 µg THC for the initial 150 days; 750 µg THC during the next 60 days; 1 mg THC for 30 days; 650 µg THC on the following 30 days; 350 µg for 60 days; 300 µg THC for 30 days; and finally, 500 µg of THC for 60 days. The dose fluctuation reflects the clinical decisions in the attempt of finding an optimal dose, 500 µg being the most used dose. Of note, the patient continues to use the extract at this dose without any additional drug of continuous use, after the official evaluation/follow-up for this case report ended.
The Mini-Mental State Examination (MMSE) and the Alzheimer’s Disease Assessment Scale (ADAS-Cog) were the scales utilized for patient evaluation and data acquisition. The former is widely employed in several neurophysiology evaluations and epidemiologic studies. It is a useful tool for the assessment of time and spatial orientation, memory, calculus capacity, language, identification patterns, comprehension, writing skills, and drawing [19, 20]. Low scores indicate negatively affected brain function that could be associated with AD. However, it should not be used as the only diagnostic tool. The latter comprises a series of assessments created to evaluate the cognitive function of patients with AD. The ADAS-Cog is composed of 11 tests assigned to evaluate memory, orientation, language, praxis, and other cognitive capabilities , in which a high score indicates high disease severity. It is one of the most frequently utilized tests to assess cognition in research studies and clinical trials for new drugs and other interventions.
The scale-oriented evaluation was carried out on day T0 (previous to treatment) and days 30 (T1), 90 (T2), 150 (T3), 210 (T4), 240 (T5), 270 (T6), 360 (T7), 420 (T8), 480 (T9), 540 (T10), and 660 (T11) following the start of the treatment. Unfortunately, we did not apply standardized scales for psychiatric assessment of mood, anxiety, and sleep quality, which were the variables qualitatively assessed using patient and caregiver testimonials, recorded at each evaluation.
Here we report evidence that the cannabinoid extract improved MMSE (Fig. 1C) and ADAS-Cog (Fig. 1D) scores in the subject evaluated. Symptom amelioration was rapid, robust, and not limited to mnemonic. We tried to titrate the dose up to 1 mg THC, but the most frequent dose was 500 µg THC. The period when the patient was treated with this dose seemed to be the period with higher symptom suppression. This well-known cannabinoid bell-shaped effect was not surprising since it has been previously reported [22,23,24,25].
Additionally, testimonials from patient and caregiver highlight other cognitive improvements. As described by the patient himself, “I used to feel forgetful, not once after the treatment. Sometimes, I did not know where I was, it has not happened to me anymore. I used to find myself lost on the streets, I could not leave home unassisted; today, I took the bus by myself to perform my clinical evaluation.” Of note, the treatment with the cannabinoid extract in microdoses appears to positively affect not only cognitive functions. Likewise, the patient has described other enhancements: “Shortly after the beginning of the treatment, I already felt more alert and excited during daily activities, and I have noticed I have been sleeping much better.”
The treatment here described mitigated AD symptoms, with rapid onset and long-term consequences. In this report, cognitive and memory enhancement lasted for more than 1 year following the start of treatment, and remained stable while we progressively evaluate/follow up with the patient, for more than 1 year after the official report ended. At that point, 42 months after using the cannabinoid extract, the cognitive assessment showed an MMSE score of 24 and an ADAS-Cog score of 10, demonstrating that our patient was still stable. Imaging tests, including computed tomography (ruling out other probable causes of dementia), neurological examination, serum tests for thyroid, kidney, liver, electrolytes, and complete blood count were all normal before the start of the experimental treatment and remained unchanged throughout the patient’s follow-up period (Table 1).