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Oral delta-9-tetrahydracannabinol (delta-9-THC) and palmitoylethanolamide (PEA), in a proprietary combination known as THX-110, is promising for reducing tic symptoms in adults with Tourette syndrome (TS), new research suggests.
In a small phase 2 trial, investigators administered THX-110 to 16 adults with treatment-resistant TS for 12 weeks. Results showed a reduction of more than 20% in tic symptoms after the first week of treatment compared with baseline.
“We conducted an uncontrolled study in adults with severe TS and found that their tics improved over time while they took THX-110,” lead author Michael Bloch, MD, associate professor and co-director of the Tic and OCD Program at the Child Study Center, Yale University, New Haven, Conn., told this news organization.
Dr. Bloch added that the next step in this line of research will be to conduct a placebo-controlled trial of the compound in order to assess whether tic improvement observed over time in this study “was due to the effects of the medication and not related to the natural waxing-and-waning course of tic symptoms or treatment expectancy.”
The findings were published online August 2 in the Journal of Neuropsychiatry and Clinical Neurosciences.
‘Entourage effect’
“Several lines of evidence from clinical observation and even randomized controlled trials” suggest that cannabis (cannabis sativa) and delta-9-THC may be effective in treatment of tic disorders, Dr. Bloch said.
“Cannabinoid receptors are present in the motor regions important for tics, and thus, there is a potential mechanism of action to lead to improvement of tics,” he added.
However, “the major limitations of both cannabis and dronabinol [a synthetic form of delta-9-THC] use are the adverse psychoactive effects they induce in higher doses,” he said.
Dr. Bloch noted that PEA is a lipid messenger “known to mimic several endocannabinoid-driven activities.”
For this reason, combining delta-9-THC with PEA is hypothesized to reduce the dose of delta-9-THC needed to improve tics and also potentially lessen its side effects.
This initial open-label trial examined safety and tolerability of THX-110, as well as its effect on tic symptoms in adults with TS. The researchers hoped to “use the entourage effect to deliver the therapeutic benefits of delta-9-THC in reducing tics with decrease psychoactive effects by combining with PEA.”
The “entourage effect” refers to “endocannabinoid regulation by which multiple endogenous cannabinoid chemical species display a cooperative effect in eliciting a cellular response,” they write.
The investigators conducted a 12-week uncontrolled trial of THX-110, used at its maximum daily dose of delta-9-THC (10 mg) and a constant 800-mg dose of PEA in 16 adults with TS (mean age, 35 years; mean TS illness duration, 26.6 years).
Participants had a mean baseline Yale Global Tic Severity Scale (YGTSS) score of 38.1 and a mean worst-ever total tic score of 45.4.
All participants were experiencing persistent tics, despite having tried an array of previous evidence-based treatments for TS, including antipsychotics, alpha-2 agonists, VMAT2 inhibitors, benzodiazepines, and topiramate (Topamax).
Significant improvement
Results showed significant improvement in tic symptoms with TXH-110 treatment over time (general linear model time factor: F = 3.06, df = 7.91, P = .006).
At first assessment point, mean YGTSS improvement was 3.5 (95% confidence interval, 0.1-6.9; P = .047). The improvement not only remained significant but continued to increase throughout the 12-week trial period.
At 12 weeks, the maximal improvement in tic symptoms was observed, with a mean YGTSS improvement at endpoint of 7.6 (95% CI, 2.5-12.8; P = .007).
Four patients experienced a greater than 35% improvement in tic symptoms during the trial, whereas 6 experienced a 25% or greater improvement. The mean improvement in tic symptoms over the course of the trial was 20.6%.
There was also a significant improvement between baseline and endpoint on other measures of tic symptoms – but not on premonitory urges.
The patients experienced “modest” but not significant improvement in comorbid symptoms, including attentional, anxiety, depressive, and obsessive-compulsive symptoms.
Adverse events
All participants experienced some mild side effects for “a couple hours” after taking the medication, particularly during the course of dose escalation and maintenance. However, these were not serious enough to warrant stopping the medication.
These effects typically included fatigue/drowsiness, feeling “high,” dry mouth, dizziness/lightheadedness, and difficulty concentrating.
Side effects of moderate or greater severity necessitating changes in medication dosing were “less common,” the investigators report. No participants experienced significant laboratory abnormalities.
One patient discontinued the trial early because he felt that the study medication was not helpful, and a second discontinued because of drowsiness and fatigue related to the study medication.
Twelve participants elected to continue treatment with THX-110 during an open extension phase and 7 of these completed the additional 24 weeks.
“THX-110 treatment led to an average improvement in tic symptoms of roughly 20%, or a 7-point decrease in the YGTSS total tic score. This improvement translates to a large effect size (d = 0.92) of improvement over time,” the investigators write.
More data needed
Commenting on the findings, Yolanda Holler-Managan, MD, assistant professor of pediatrics (neurology), Northwestern University, Chicago, cautioned that this was not a randomized, double-blind, parallel-group placebo-controlled study.
Instead, it was a clinical study to prove safety, tolerability, and dosing of the combination medication in adult patients with TS and “does not provide as much weight, since we do not have many studies on the efficacy of cannabinoids,” said Dr. Holler-Managan, who was not involved with the research.
She noted that the American Academy of Neurology’s 2019 practice guideline recommendations for treatment of tics in individuals with TS and tic disorders reported “limited evidence” that delta-9-THC is “possibly more likely than placebo to reduce tic severity in adults with TS, therefore we need more data.”
The current investigators agree. “Although these initial data are promising, future randomized double-blind placebo-controlled trials are necessary to demonstrate efficacy of TXH-110 treatment,” they write.
They add that the psychoactive properties of cannabis-derived compounds make it challenging to design a properly blinded trial.
“Incorporation of physiologic biomarkers and objective measures of symptoms (e.g., videotaped tic counts by blinded raters) may be particularly important when examining these medications with psychoactive properties that may be prone to reporting bias,” the authors write.
The study was supported by an investigator-initiated grant to Dr. Bloch from Therapix Biosciences. The state of Connecticut also provided resource support via the Abraham Ribicoff Research Facilities at the Connecticut Mental Health Center. Dr. Bloch serves on the scientific advisory boards of Therapix Biosciences, and he receives research support from Biohaven Pharmaceuticals, Janssen Pharmaceuticals, NARSAD, Neurocrine Biosciences, NIH, and the Patterson Foundation. The other investigators and Dr. Holler-Managan have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Oral delta-9-tetrahydracannabinol (delta-9-THC) and palmitoylethanolamide (PEA), in a proprietary combination known as THX-110, is promising for reducing tic symptoms in adults with Tourette syndrome (TS), new research suggests.
In a small phase 2 trial, investigators administered THX-110 to 16 adults with treatment-resistant TS for 12 weeks. Results showed a reduction of more than 20% in tic symptoms after the first week of treatment compared with baseline.
“We conducted an uncontrolled study in adults with severe TS and found that their tics improved over time while they took THX-110,” lead author Michael Bloch, MD, associate professor and co-director of the Tic and OCD Program at the Child Study Center, Yale University, New Haven, Conn., told this news organization.
Dr. Bloch added that the next step in this line of research will be to conduct a placebo-controlled trial of the compound in order to assess whether tic improvement observed over time in this study “was due to the effects of the medication and not related to the natural waxing-and-waning course of tic symptoms or treatment expectancy.”
The findings were published online August 2 in the Journal of Neuropsychiatry and Clinical Neurosciences.
‘Entourage effect’
“Several lines of evidence from clinical observation and even randomized controlled trials” suggest that cannabis (cannabis sativa) and delta-9-THC may be effective in treatment of tic disorders, Dr. Bloch said.
“Cannabinoid receptors are present in the motor regions important for tics, and thus, there is a potential mechanism of action to lead to improvement of tics,” he added.
However, “the major limitations of both cannabis and dronabinol [a synthetic form of delta-9-THC] use are the adverse psychoactive effects they induce in higher doses,” he said.
Dr. Bloch noted that PEA is a lipid messenger “known to mimic several endocannabinoid-driven activities.”
For this reason, combining delta-9-THC with PEA is hypothesized to reduce the dose of delta-9-THC needed to improve tics and also potentially lessen its side effects.
This initial open-label trial examined safety and tolerability of THX-110, as well as its effect on tic symptoms in adults with TS. The researchers hoped to “use the entourage effect to deliver the therapeutic benefits of delta-9-THC in reducing tics with decrease psychoactive effects by combining with PEA.”
The “entourage effect” refers to “endocannabinoid regulation by which multiple endogenous cannabinoid chemical species display a cooperative effect in eliciting a cellular response,” they write.
The investigators conducted a 12-week uncontrolled trial of THX-110, used at its maximum daily dose of delta-9-THC (10 mg) and a constant 800-mg dose of PEA in 16 adults with TS (mean age, 35 years; mean TS illness duration, 26.6 years).
Participants had a mean baseline Yale Global Tic Severity Scale (YGTSS) score of 38.1 and a mean worst-ever total tic score of 45.4.
All participants were experiencing persistent tics, despite having tried an array of previous evidence-based treatments for TS, including antipsychotics, alpha-2 agonists, VMAT2 inhibitors, benzodiazepines, and topiramate (Topamax).
Significant improvement
Results showed significant improvement in tic symptoms with TXH-110 treatment over time (general linear model time factor: F = 3.06, df = 7.91, P = .006).
At first assessment point, mean YGTSS improvement was 3.5 (95% confidence interval, 0.1-6.9; P = .047). The improvement not only remained significant but continued to increase throughout the 12-week trial period.
At 12 weeks, the maximal improvement in tic symptoms was observed, with a mean YGTSS improvement at endpoint of 7.6 (95% CI, 2.5-12.8; P = .007).
Four patients experienced a greater than 35% improvement in tic symptoms during the trial, whereas 6 experienced a 25% or greater improvement. The mean improvement in tic symptoms over the course of the trial was 20.6%.
There was also a significant improvement between baseline and endpoint on other measures of tic symptoms – but not on premonitory urges.
The patients experienced “modest” but not significant improvement in comorbid symptoms, including attentional, anxiety, depressive, and obsessive-compulsive symptoms.
Adverse events
All participants experienced some mild side effects for “a couple hours” after taking the medication, particularly during the course of dose escalation and maintenance. However, these were not serious enough to warrant stopping the medication.
These effects typically included fatigue/drowsiness, feeling “high,” dry mouth, dizziness/lightheadedness, and difficulty concentrating.
Side effects of moderate or greater severity necessitating changes in medication dosing were “less common,” the investigators report. No participants experienced significant laboratory abnormalities.
One patient discontinued the trial early because he felt that the study medication was not helpful, and a second discontinued because of drowsiness and fatigue related to the study medication.
Twelve participants elected to continue treatment with THX-110 during an open extension phase and 7 of these completed the additional 24 weeks.
“THX-110 treatment led to an average improvement in tic symptoms of roughly 20%, or a 7-point decrease in the YGTSS total tic score. This improvement translates to a large effect size (d = 0.92) of improvement over time,” the investigators write.
More data needed
Commenting on the findings, Yolanda Holler-Managan, MD, assistant professor of pediatrics (neurology), Northwestern University, Chicago, cautioned that this was not a randomized, double-blind, parallel-group placebo-controlled study.
Instead, it was a clinical study to prove safety, tolerability, and dosing of the combination medication in adult patients with TS and “does not provide as much weight, since we do not have many studies on the efficacy of cannabinoids,” said Dr. Holler-Managan, who was not involved with the research.
She noted that the American Academy of Neurology’s 2019 practice guideline recommendations for treatment of tics in individuals with TS and tic disorders reported “limited evidence” that delta-9-THC is “possibly more likely than placebo to reduce tic severity in adults with TS, therefore we need more data.”
The current investigators agree. “Although these initial data are promising, future randomized double-blind placebo-controlled trials are necessary to demonstrate efficacy of TXH-110 treatment,” they write.
They add that the psychoactive properties of cannabis-derived compounds make it challenging to design a properly blinded trial.
“Incorporation of physiologic biomarkers and objective measures of symptoms (e.g., videotaped tic counts by blinded raters) may be particularly important when examining these medications with psychoactive properties that may be prone to reporting bias,” the authors write.
The study was supported by an investigator-initiated grant to Dr. Bloch from Therapix Biosciences. The state of Connecticut also provided resource support via the Abraham Ribicoff Research Facilities at the Connecticut Mental Health Center. Dr. Bloch serves on the scientific advisory boards of Therapix Biosciences, and he receives research support from Biohaven Pharmaceuticals, Janssen Pharmaceuticals, NARSAD, Neurocrine Biosciences, NIH, and the Patterson Foundation. The other investigators and Dr. Holler-Managan have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Oral delta-9-tetrahydracannabinol (delta-9-THC) and palmitoylethanolamide (PEA), in a proprietary combination known as THX-110, is promising for reducing tic symptoms in adults with Tourette syndrome (TS), new research suggests.
In a small phase 2 trial, investigators administered THX-110 to 16 adults with treatment-resistant TS for 12 weeks. Results showed a reduction of more than 20% in tic symptoms after the first week of treatment compared with baseline.
“We conducted an uncontrolled study in adults with severe TS and found that their tics improved over time while they took THX-110,” lead author Michael Bloch, MD, associate professor and co-director of the Tic and OCD Program at the Child Study Center, Yale University, New Haven, Conn., told this news organization.
Dr. Bloch added that the next step in this line of research will be to conduct a placebo-controlled trial of the compound in order to assess whether tic improvement observed over time in this study “was due to the effects of the medication and not related to the natural waxing-and-waning course of tic symptoms or treatment expectancy.”
The findings were published online August 2 in the Journal of Neuropsychiatry and Clinical Neurosciences.
‘Entourage effect’
“Several lines of evidence from clinical observation and even randomized controlled trials” suggest that cannabis (cannabis sativa) and delta-9-THC may be effective in treatment of tic disorders, Dr. Bloch said.
“Cannabinoid receptors are present in the motor regions important for tics, and thus, there is a potential mechanism of action to lead to improvement of tics,” he added.
However, “the major limitations of both cannabis and dronabinol [a synthetic form of delta-9-THC] use are the adverse psychoactive effects they induce in higher doses,” he said.
Dr. Bloch noted that PEA is a lipid messenger “known to mimic several endocannabinoid-driven activities.”
For this reason, combining delta-9-THC with PEA is hypothesized to reduce the dose of delta-9-THC needed to improve tics and also potentially lessen its side effects.
This initial open-label trial examined safety and tolerability of THX-110, as well as its effect on tic symptoms in adults with TS. The researchers hoped to “use the entourage effect to deliver the therapeutic benefits of delta-9-THC in reducing tics with decrease psychoactive effects by combining with PEA.”
The “entourage effect” refers to “endocannabinoid regulation by which multiple endogenous cannabinoid chemical species display a cooperative effect in eliciting a cellular response,” they write.
The investigators conducted a 12-week uncontrolled trial of THX-110, used at its maximum daily dose of delta-9-THC (10 mg) and a constant 800-mg dose of PEA in 16 adults with TS (mean age, 35 years; mean TS illness duration, 26.6 years).
Participants had a mean baseline Yale Global Tic Severity Scale (YGTSS) score of 38.1 and a mean worst-ever total tic score of 45.4.
All participants were experiencing persistent tics, despite having tried an array of previous evidence-based treatments for TS, including antipsychotics, alpha-2 agonists, VMAT2 inhibitors, benzodiazepines, and topiramate (Topamax).
Significant improvement
Results showed significant improvement in tic symptoms with TXH-110 treatment over time (general linear model time factor: F = 3.06, df = 7.91, P = .006).
At first assessment point, mean YGTSS improvement was 3.5 (95% confidence interval, 0.1-6.9; P = .047). The improvement not only remained significant but continued to increase throughout the 12-week trial period.
At 12 weeks, the maximal improvement in tic symptoms was observed, with a mean YGTSS improvement at endpoint of 7.6 (95% CI, 2.5-12.8; P = .007).
Four patients experienced a greater than 35% improvement in tic symptoms during the trial, whereas 6 experienced a 25% or greater improvement. The mean improvement in tic symptoms over the course of the trial was 20.6%.
There was also a significant improvement between baseline and endpoint on other measures of tic symptoms – but not on premonitory urges.
The patients experienced “modest” but not significant improvement in comorbid symptoms, including attentional, anxiety, depressive, and obsessive-compulsive symptoms.
Adverse events
All participants experienced some mild side effects for “a couple hours” after taking the medication, particularly during the course of dose escalation and maintenance. However, these were not serious enough to warrant stopping the medication.
These effects typically included fatigue/drowsiness, feeling “high,” dry mouth, dizziness/lightheadedness, and difficulty concentrating.
Side effects of moderate or greater severity necessitating changes in medication dosing were “less common,” the investigators report. No participants experienced significant laboratory abnormalities.
One patient discontinued the trial early because he felt that the study medication was not helpful, and a second discontinued because of drowsiness and fatigue related to the study medication.
Twelve participants elected to continue treatment with THX-110 during an open extension phase and 7 of these completed the additional 24 weeks.
“THX-110 treatment led to an average improvement in tic symptoms of roughly 20%, or a 7-point decrease in the YGTSS total tic score. This improvement translates to a large effect size (d = 0.92) of improvement over time,” the investigators write.
More data needed
Commenting on the findings, Yolanda Holler-Managan, MD, assistant professor of pediatrics (neurology), Northwestern University, Chicago, cautioned that this was not a randomized, double-blind, parallel-group placebo-controlled study.
Instead, it was a clinical study to prove safety, tolerability, and dosing of the combination medication in adult patients with TS and “does not provide as much weight, since we do not have many studies on the efficacy of cannabinoids,” said Dr. Holler-Managan, who was not involved with the research.
She noted that the American Academy of Neurology’s 2019 practice guideline recommendations for treatment of tics in individuals with TS and tic disorders reported “limited evidence” that delta-9-THC is “possibly more likely than placebo to reduce tic severity in adults with TS, therefore we need more data.”
The current investigators agree. “Although these initial data are promising, future randomized double-blind placebo-controlled trials are necessary to demonstrate efficacy of TXH-110 treatment,” they write.
They add that the psychoactive properties of cannabis-derived compounds make it challenging to design a properly blinded trial.
“Incorporation of physiologic biomarkers and objective measures of symptoms (e.g., videotaped tic counts by blinded raters) may be particularly important when examining these medications with psychoactive properties that may be prone to reporting bias,” the authors write.
The study was supported by an investigator-initiated grant to Dr. Bloch from Therapix Biosciences. The state of Connecticut also provided resource support via the Abraham Ribicoff Research Facilities at the Connecticut Mental Health Center. Dr. Bloch serves on the scientific advisory boards of Therapix Biosciences, and he receives research support from Biohaven Pharmaceuticals, Janssen Pharmaceuticals, NARSAD, Neurocrine Biosciences, NIH, and the Patterson Foundation. The other investigators and Dr. Holler-Managan have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.